Children’s researCh institute researCh at the nation’s Children’s hospital

research at The Nation’s Children’s hospital
The nation’s children deserve nothing less.
Children’s Research Institute
Academic Annual Report 2009
Children’s Research Institute
Academic Annual Report 2009
Table of Contents
3 2
43 9
From the Directors
About CRI
Research Funding
The Nation’s Children’s Hospital Fights the Obesity Epidemic
Center for Cancer and Immunology Research
Center for Genetic Medicine Research
Center for Neuroscience Research
Center for Molecular Physiology Research
Center for Clinical and Community Research
Education, Training, and Academic Excellence
The Sheikh Zayed Institute for Pediatric Surgical Innovation
Highlighted NIH Grants and Awards
On the cover: A collage of immortalized human proximal tubule cells showing the distribution and
colocalization of GRK4 (green) and dopamine D3 receptor (red) upon agonist stimulation.
The cells were labeled with a cell membrane-impermeable biotin to delineate the cell boundaries
(cell membrane is in blue or magenta). The images were taken via laser scanning confocal microscopy.
Children’s Research Institute
Our Mission
Children’s Research Institute will conduct and promote
medical research and education programs within Children’s
National Medical Center that will lead to improved prevention,
diagnosis, and treatment of childhood diseases through
basic, clinical, and community research and education.
Our Vision
We will lead the quest to cure childhood’s most
devastating diseases.
We will train future leaders in academic pediatrics.
We will serve as the center for clinical and translational
research among all the universities and academic
health centers in Washington, DC.
We will be among the top NIH grantees nationally for
children’s hospitals and departments of pediatrics.
Introduction | 1
From the Directors
A major goal of this academic year has been to look ahead and map the
course forward for research and education at Children’s National Medical
Center through the development of a 5-year strategic plan. We had a year
full of accomplishments and have laid the groundwork for a promising and
successful future for the Children’s Research Institute.
2009 Highlights
New Research Centers and Institutes
n The new Sheikh Zayed Institute for Pediatric
Surgical Innovation will focus on advancing
research through translational and clinical studies
on pain management, cancer immunology,
imaging technology, and genomic medicine.
Made possible by one of the largest gifts in the
history of Washington, DC, in the amount of
$150 million from the Government of Abu Dhabi,
United Arab Emirates, this effort at Children’s
National is led by Kurt Newman, MD, senior vice
president for the Joseph E. Robert, Jr., Center for
Surgical Care.
n We recruited a 12-faculty-member team from
Georgetown University, led by Pedro Jose, MD,
PhD, that, together with the research team of
Patricio Ray, MD, established a new Center
for Molecular Physiology Research. The new
center’s research efforts focus on the genetics
of hypertension and salt sensitivity, as well as
on HIV nephropathy and related disorders of
the kidney.
n A new basic science department of the School
of Medicine and Health Sciences at George
Washington University (GWU) was established
within Children’s National. The Department of
Integrative Systems Biology, which is chaired by
2 | Introduction
Children’s Eric Hoffman, PhD, and housed at
CRI, is the first basic science department of a
university located within a children’s hospital.
This department will use genomic approaches
to understand the biology of childhood diseases
and to develop new therapies.
n We also added two more multidisciplinary
institutes aimed at fostering clinical and research
collaborations throughout Children’s National: the
Urea Cycle Disorders Institute and the Clinical
and Translational Science Institute.
NIH Funding
n Extramural funding to CRI increased by 13
percent over the past two years. We now have
approximately $30 million a year in NIH funding
and $53 million in total funding. Our independent
research grant portfolio has grown to 31 R01
awards. We continue to excel in career
development awards (21) and large infrastructure
grants (8).
n We submitted a total of 120 American Recovery
and Reinvestment Act (ARRA) grants and have
received notification for approximately $7 million
of new funding from ARRA over the next two
years for 26 grants—an impressive figure relative
to the size of our institution.
Mark L. Batshaw, MD (left)
Chief Academic Officer, Children’s National
Director, CRI
Mendel Tuchman, MD (right)
Scientific Director, CRI
nTwo of our faculty were nominated by the NIH
Center for Scientific Review to chair permanent
NIH study sections. Mendel Tuchman, MD, chairs
the review panel on Therapeutic Approaches for
Genetic Diseases, and Vittorio Gallo, PhD, chairs
the panel on Neurogenesis and Cell Fate.
More than half of our clinical division chiefs are
physician scientists with significant research programs.
This year, we recruited several more research intensive
clinical division chiefs, including:
nCharles Berul, MD (Boston Children’s,
electrophysiology of congenital heart disease),
to be chief of Cardiology.
nMarshall Summar, MD (Vanderbilt, genetics of
urea cycle disorders), to be chief of Genetics
and Metabolism.
nD. Ashley Hill, MD (Washington University,
pathogenetics of rare cancers), to be chief of
Additionally, senior vice president for the clinical
Center for Cancer and Blood Disorders Max Coppes,
MD, MBA, now directs both clinical and research
efforts for Cancer and Immunology to more closely
unite these programs.
During the last 10 years, we have built an
infrastructure for a nationally renowned pediatric
research program in the nation's capital, which
supports strong investigators and the careers of
promising new scientists. The hard work of our
scientists and staff has truly raised the level of our
research programs at the nation’s children’s hospital,
and we are well-equipped to lead the way in pediatric
research that is collaborative, multidisciplinary,
and innovative.
Mark L. Batshaw, MD
Chief Academic Officer
Children’s National Medical Center
Children’s Research Institute
Mendel Tuchman, MD
Scientific Director
Children’s Research Institute
Introduction | 3
Children’s National Structure
Children’s Research Institute Centers
Cancer and
Cancer and
Blood Disorders
and Behavioral
Heart, Lung,
and Kidney
Joseph E. Robert, Jr,
Center for
Surgical Care
Children’s National Clinical Centers
4 | Introduction
Clinical and
Diana L. and
Stephan A. Goldberg
Center for Community
Pediatric Health
Edwin K. Zechman, Jr.
President and CEO,
Children's National Medical Center
Elizabeth Singer
Chair of the Board, CRI
Senior Leadership
Center Directors and Associate Directors
Administrative Directors
Max Coppes, MD, PhD, MBA
Jill Joseph, MD, PhD
Kolaleh Eskandanian, PhD
Director, Center for Cancer
and Immunology Research
Director, Center for Clinical
and Community Research
Director, Clinical and Translational
Research Administration
William Gaillard, MD
Patricio Ray, MD
Kerstin Hildebrandt
Scientific Director
Associate Director, Center for
Neuroscience Research
Associate Director, Center for
Molecular Physiology Research
Director, Operations and Planning
Naomi Luban, MD
Vittorio Gallo, PhD
Stephen Teach, MD, MPH
Director, Center for
Neuroscience Research
Program Director, Academic Services
Associate Director, Center for
Clinical and Community Research
Carmen Mendez, MBA
Eric Hoffman, PhD
John van den Anker, MD, PhD
Edwin K. Zechman, Jr.
President and CEO
Mark L. Batshaw, MD
Director and Chief Academic
Mendel Tuchman, MD
Vice Chair for Faculty Affairs
Mary Ottolini, MD
Vice Chair for Education
Director, Center for Genetic
Medicine Research
Gaetano R. Lotrecchiano, PhD
Director, Research Finance
Associate Director, Center for
Clinical and Community Research
Pedro Jose, MD, PhD
Director, Center for Molecular
Physiology Research
Board of Directors
Elizabeth Singer
Jutta Parsons
Chair of the Board
Fred T. Goldberg, Jr.
Norman A. Barker
Vice Chairman
Edwin K. Zechman, Jr.
Mark L. Batshaw, MD
Val G. Hemming, MD
Alan I. Leshner, PhD
Evan Jones
Floyd J. Malveaux, MD, PhD
Susan Kettering
Richard A. Sauber
Scott Koenig, MD, PhD
Joel Wood
Introduction | 5
2009 Research Funding
Research Funding by Center
nCancer and Immunology
$10,556,786 20.0%
nChief Academic Officer 
$658,012 1.2%
nClinical and Community
$17,250,015 32.6%
nGenetic Medicine
$15,010,801 28.4%
nMolecular Physiology
$2,527,273 4.8%
nNeuroscience  $6,835,618 12.9%
$52,838,505 100%
nFederal (non-NIH)
$13,656,499 25.8%
$31,173,269 59.0%
$6,974,871 13.2%
$1,033,866 2.0%
Total   $52,838,505 100%
Total   Research Funding by Source
6 | Introduction
CRI Federal Grant Funding
nCancer and Immunology
$9,055,144 20.2%
nChief Academic Officer 
$593,012 1.3%
nClinical and Community
$13,870,206 30.9%
nGenetic Medicine
$12,958,487 28.9%
nMolecular Physiology
$2,527,273 5.6%
nNeuroscience  $5,825,646 13.0%
Total   $44,829,768
CRI Non-Federal Grant Funding
nCancer and Immunology
nChief Academic Officer 
$1,212,626 17.4%
$65,000 0.9%
nClinical and Community
$3,179,809 45.6%
nGenetic Medicine
$1,707,464 24.5%
nMolecular Physiology
nNeuroscience  Total   $809,972 $6,974,871
Introduction | 7
The nation’s children’s hospital
fights the obesity epidemic
riven by grim statistics about the
increasing numbers of obese children,
especially in metropolitan areas like
Washington, DC, it seems that everyone is
talking about the epidemic of childhood obesity,
how we got here, and what needs to be done
to reverse this trend.
In the heart of a city with some of the highest
pediatric obesity rates in the country, the Obesity
Institute at Children’s National leads a team of
clinicians who treat obese children and the various
life-threatening complications of this disorder.
The institute also organizes the researchers
who are hard at work identifying causes and
precursors, understanding the impacts of weight
gain and weight loss on the body, and designing
interventions to reverse the fatal trajectory of weight
gain in the nation’s children.
Early Identification Is Key
For some children, genetic makeup may predict a
lifetime of obesity and related disorders, including
type 2 diabetes and hypertension. Though research
teams recognize that lifestyle choices such as diet
and exercise can effectively combat some genetic
predisposition, some people are more prone to
these disorders than others. These individuals can
8 | Introduction
make wrong lifestyle choices and suffer the longterm consequences.
Metabolic syndrome
Metabolic syndrome is a collection of symptoms:
hypertension, above average waist circumference
(central obesity), high triglycerides, lower HDL
cholesterol, and an increased level of glucose,
which can indicate a likelihood for the development
of cardiovascular disease and/or type 2 diabetes.
Typically, if a patient has three or more of these
clinical features, he or she may be diagnosed with
metabolic syndrome. Researchers in the Center for
Genetic Medicine collected clinical and genetic
information from a large number of local college
students around the country, and discovered that
there is a subset of young adults with metabolic
syndrome or its precursors to it who also possess
a specific set of single nucleotide polymorphisms
(SNP), or small variations of genetic code, that may
make them less likely to benefit from an increase
in exercise alone. Current research, led by Eric
Hoffman, PhD, and Chiatogu Onyewu, MD, PhD,
identifies students from Howard University who are
at risk for developing metabolic syndrome, with the
intention of developing intervention programs that
will arm students with tools to make lifestyle changes
that lessen their chances of developing metabolic
syndrome or progressing to type 2 diabetes.
Hypertension, one of the symptoms of metabolic
syndrome, can have dangerous long-term health
effects, including increased risk of cardiovascular
disease and stroke. Scientists now know that in some
groups of people, hypertension is inevitable. Known
as essential hypertension, high blood pressure can
continue unabated from a very young age, and grow
worse as a person ages. Researchers in the Center
for Molecular Physiology believe that for some people
with high blood pressure, the problem started many
years before identification, possibly even with higher
than normal levels as young children. Not corrected,
over time, the toll of hypertension grows worse.
Through a study of how the kidneys regulate sodium
levels in the body, scientists in the center identified a
series of dopamine receptors in the kidney’s cells that
when malfunctioning, can lead to improper regulation
of salt and higher than normal blood pressure levels.
The research team also is working to determine if, at
the genetic level, specific DNA variations called SNPs
can contribute to the likelihood of these malfunctioning
receptors and therefore the onset of hypertension.
It is hoped that identifying biomarker proteins and
genetic propensities will allow doctors to test for and
find subtle indicators early in life, so that families can
be mindful of diet and other controllable factors before
facing a lifetime of medical problems.
Seeking Effective Clinical And
Community Interventions
For certain ethnic groups, especially the Hispanic
and African-American communities in Washington,
DC, the rates of childhood obesity are significantly
higher than average. From the Center for Clinical
and Community Research and the Goldberg Center
for Community Pediatric Health, pediatrician Nazrat
Mirza, MD, succeeded in designing diet and
exercise programs targeted at helping the families
of overweight children learn better habits day-to-day.
Data drawn from her Improved Diet, Exercise, and
Activity for Life (I.D.E.A.L.) clinic allow Dr. Mirza to track
the progress of overweight children with comorbidities
and monitor the program. In the Combating Obesity
and Overweight in Latino Kids (C.O.O.L.) program,
Dr. Mirza takes nutrition and exercise benefits directly
to teens and families in the city’s Latino community.
On weeknights, a bilingual educator teaches parents
how to read nutritional labels, grocery shop, and cook
healthy meals for the whole family, while their teens
learn about the food groups, proper serving sizes, and
practice basic physical activity they can incorporate
into their daily lives at home. Additionally, a bilingual
educator works with Latino families with preschoolaged children in a neighborhood community center to
teach them how to monitor nutrition. These targeted
interventions show anecdotal success over time.
Introduction | 9
From research laboratories to clinic exam rooms and out
into the community, the Obesity Institute at the nation’s
children’s hospital will continue to investigate all aspects
of this disease until the trend of ever-increasing childhood
obesity is stopped in its tracks.
Dr. Mirza also runs a research intervention program
called FitFamily in conjunction with the Boys &
Girls Clubs out of the Town Hall, Education, Arts,
and Recreation Campus (THEARC) in Southeast
Washington, DC, where she implements a similar
educational diet and exercise intervention for the
families of that neighborhood.
Social and behavioral issues related to
childhood obesity
Psychologist Eleanor Mackey, PhD, works to better
understand the mental strains and struggles of
overweight children. Overweight children also
frequently suffer from eating disorders and other
maladaptive behaviors. Ultimately, these behaviors
may be the very things that prevent them from
losing weight or help them gain more weight as time
goes on. Dr. Mackey seeks to better understand
how overweight children develop these behavioral
disorders to help doctors learn how to add
emotional and psychological support components
to fitness and nutrition focused interventions.
10 | Introduction
The Future of Childhood
Obesity Research
The city’s high pediatric obesity rate puts Children’s
doctors and scientists at the heart of a population
that desperately needs help, providing our
physicians and investigators with unlimited
opportunities to make a difference. Evan Nadler, MD,
a newly recruited surgeon, studies the effectiveness
of bariatric surgical procedures on morbidly obese
teens. Monica Hubal, PhD, a recent faculty addition
to the Center for Genetic Medicine, studies the
molecular differences between overweight and
post-weight loss muscle fibers to detect changes
and determine if there is a trend that will help
determine the success of physical interventions
that lead to drastic weight loss.
From research laboratories to clinic exam rooms
and out into the community, the Obesity Institute
at the nation’s children’s hospital will continue to
investigate all aspects of this disease until the trend
of ever-increasing childhood obesity is stopped in
its tracks. n
Center for
Cancer and Immunology Research
Max Coppes, MD, PhD, MBA
Professor of Medicine, Pediatrics, and Oncology, Georgetown University
Anamaris M. Colberg-Poley, PhD
Lawrence J. D’Angelo, MD, MPH
Roberta L. DeBiasi, MD
Jeffrey Dome, MD
Terry Fry, MD
Cynthia Gingalewski, MD
D. Ashley Hill, MD
Lewis Hsu, MD, PhD
David Hyun, MD
Shana Jacobs, MD
Lawrence Jung, MD
Naynesh R. Kamani, MD
Stephan Ladisch, MD
David Leitenberg, MD, PhD
Yihui Liu, PhD
Brett J. Loechelt, MD
Naomi L.C. Luban, MD
Jeffrey Lukish, MD
Holly Meany, MD
Parvathi Mohan, MBBS
Kurt D. Newman, MD
Evelio Perez-Albuerne, MD, PhD
Sasa Radoja, PhD
Tamara A. Rakusan, MD, PhD
Gregory H. Reaman, MD
Brian R. Rood, MD
Jane Sande, MD
Anthony Sandler, MD
Nalini Singh, MD, MPH
Xiaoyan Song, PhD, MSc
Raymond Sze, MD
Zoreh Tatari-Calderone, PhD
Amanda Thompson, PhD
Stanlislav Vukmanovic, MD, PhD
Steve Zeichner, MD, PhD
HCMV infected human neural precursor cells at
three days after infection. Cells were infected with
HCMV and stained to visualize the F-actin cytoskeleton
(red) and a viral UL37 anti-apoptotic protein (green).
The confocal image is a 3D transparent rendering of an
uninfected cell (on the left with intact red fibers) and
infected (rounded cells with disrupted F-actin fibers with
green staining). (Colberg-Poley AM laboratory)
To develop the foundation for
the best and most compassionate
care of children with cancer,
immunologic, hematologic,
rheumatologic, infectious, and
allergy related disorders, through
basic, translational, epidemiologic,
and population based research.
Major Strategic Goals
Develop meaningful interaction between
clinically intensive and research intensive
Foster translational research, especially
in the areas of cancer immunology and
Elucidate cellular mechanisms underlying
oncogenesis, immune dysregulation, and
viral diseases.
Develop novel therapeutic approaches
for intractable pediatric cancers and
infectious diseases.
Strategic Plan Accomplishments
n Develop meaningful interaction between clinically intensive
and research-intensive faculty.
• The appointment of Max Coppes, MD, PhD, MBA, as
center director provided a unique opportunity to accelerate
integration between laboratory research faculty, clinical
investigators, and clinicians. The creation of four sections
within the Center provided researchers and clinicians
from four clinical Centers of Excellence (Surgical Care,
Neurosciences and Behavioral Medicine, HospitalBased Specialties, and Cancer and Blood Disorders)
the opportunity to more readily identify specific research
endeavors that they could associate themselves with.
Weekly lectures are now attended by both laboratory
investigators and clinicians, resulting in the development
of more integrated goals.
• The section Cancer Immunology attracted two basic
scientists (Stanislav Vukmanovic, MD, PhD, and Sasa
Radoja, PhD) to join the laboratory of Anthony Sandler, MD,
Chief of General and Thoracic Surgery, with the goal to
develop a collaborative research proposal focused on the
development of a cancer vaccine in neuroblastoma.
n Foster translational research, especially in the areas of cancer
immunology and neuro-oncology.
• Jeffrey Dome, MD, PhD, Chief of Oncology developed
promising preclinical data for the effectiveness of
GRN 163L, a small molecule telomerase inhibitor, in
osteosarcoma and other pediatric cancers.
• Holly Meany, MD, received the prestigious 3-year American
Society for Clinical Oncology Career Development grant,
based on a recent clinical research project performed
collaboratively within the Pediatric Oncology Branch of
the National Cancer Institute and Children’s National. This
grant will allow her to evaluate repeated low doses of
Azedra (carrier-free 131I-MIBG) in children with recurrent
neuroblastoma. This investigator-driven research project is
also supported by Molecular Insights,
a drug company, and will be performed under an
investigational new drug application.
n Elucidate cellular mechanisms underlying oncogenesis
• The demonstration of germline loss of function of DICER1
mutations in familial pleuropulmonary blastoma by D. Ashley
Hill, MD, Chief of Pathology, and her colleagues, published
in Science, not only provided insight in the genetic cause
of this rare pediatric cancer, but also revealed a previously
unknown function of this important gene that works to
suppress other genes through microRNAs.
12 | CCIR
Programmatic Areas and Accomplishments
Section: Childhood Cancers
Our cancer researchers are involved in laboratory,
translational, clinical, and cancer control research activities.
Current areas of focus include brain tumors, pleuropulmonary
blastoma, Wilms tumor, and new drug development
(telomerase inhibitor).
Brain Tumors
Brain tumors are the most common solid tumor in children,
with about 3,750 new patients diagnosed every year.
Children’s National has one of the largest and most active
programs in the United States for the diagnosis and treatment
of these children. Through a multidisciplinary team approach
that includes neuro-oncology, neurology, neurosurgery,
neuropathology, neuropsychology, and neuroradiology,
Children’s not only provides state-of-the-art clinical care,
but also performs cutting-edge research investigating the
genetic causes, biology, and new treatments of these tumors.
Tumor Biology
HIC1 is a tumor suppressor gene that is frequently
inactivated in neural tumors. The laboratory of Brian Rood,
MD, employs a novel protein constructed to inactivate the
protein product of the HIC1 gene to gain an understanding
of its tumor promoting mechanisms. Recently, in
collaboration with Dominique Leprince, MD, at the Centre
National de la Recherche Scientifique in Lille, France,
the research team has discovered that the expression
of the cytokine receptor CXCR7 is under HIC1’s direct
control, potentially influencing pro-migrational tumor-host
Tumor Biomarkers
Drs. Rood, Tobey MacDonald, MD, Javad Nazarian, PhD,
and Yetrib Hathout, PhD (Center for Genetic Medicine
Research), characterized the CSF proteome in pediatric
brain tumor patients. Current diagnostic and therapeutic
monitoring studies are limited in their ability to accurately
characterize a brain tumor’s biological response to therapy.
Using cutting-edge proteomics technology, they are working
to develop a means to:
n Augment the ability of MRI scanning to differentiate tumor
from post-surgical or post-radiation effects
n Assess treatment response in an era of small molecule
inhibitors and anti-angiogenic agents that may not
primarily cause tumors to shrink
n Detect minimal residual disease states
n Identify the rational biological selection of targets for new
agents and predict response to specific targeted therapies
A coronal section of a P1 mouse brain electroporated at E14.5 with a FLAGtagged dominant negative HIC1 gene. Immunohistochemistry reveals TBR1+
cells (green), FLAG+ cells (blue) and pyramidal neurons (red). These studies
examine the function of HIC1 in the mouse brain during development. (Rood B)
The systematic evaluation of control and brain tumor
cerebrospinal fluid (CSF) samples is building the foundation
for the solution to the above problems. CSF is uniquely
suited to these tasks due to its continuous turnover, ready
availability, and its relatively low protein complexity. In
collaboration with the Pediatric Brian Tumor Consortium, the
investigators have been able to collect relevant samples
from around the United States, providing a unique and
powerful resource.
Tumor Immunology
Stanislav Vukmanovic, MD, PhD, studies the interaction
between elements of the immune system and tumor biology.
MHC class I expression by cancer cells enables specific
antigen recognition by the immune system and protection
of the host. However, in some cancer types MHC class
I expression is associated with an unfavorable outcome;
one such cancer is the brain tumor medulloblastoma. The
team found that peptide- and/or ß2m-free forms of MHC
class I may contribute to a more malignant phenotype of
medulloblastoma by modulating activation of signaling
molecules such as ERK1/2 that stimulates cell mobility.
Pediatric Brain Tumor Consortium (PBTC)
The PBTC was formed by the National Cancer Institute in
1999 to improve the treatment of primary brain tumors in
CCIR | 13
Pleuropulmonary blastoma (PPB) is a deadly lung sarcoma. This photomicrograph of a solid PPB shows marked atypia of the cells and an abnormal mitotic
figure indicating excess chromosomes (left panel). The photomicrograph in the right panel shows an immunohistochemical stain for the protein DICER1 in a
child who was born with a mutation in one of his DICER1 genes. The lack of DICER1 protein staining (brown) in the layer of cells above the tumor suggests
that the normal copy of DICER1 has been lost. Note that the tumor cells retain DICER1. (Hill DA)
children. Roger Packer, MD, an internationally renowned
neuro-oncologist, serves as Children’s primary investigator
for the PBTC.
Clinical Trials: Children’s Oncology Group (COG)
Established in 1999, the COG vision is to “eliminate the
personal, family, and societal burden of cancer in children
and adolescents.” Greg Reaman, MD, is chair of the
NIH-funded COG. Jeffrey Dome, MD, PhD, serves as
Children’s principal investigator and chair of COG’s renal
tumor committee. D. Ashley Hill, MD, is the vice chair of
the pathology committee, and Kathy Kelly, RN, PhD, is the
co-chair of the nursing research committee. Pamela Hinds,
RN, PhD, serves on the COG scientific review committee
and co-chairs a task force to develop and incorporate
patient reported outcomes in COG clinical trials.
Children’s National is one of a select group of 21 institutions
in North America to conduct phase I pediatric oncology
trials in the context of COG. Anne L. Angiolillo, MD, serves
as Children’s principal investigator, while Max Coppes, MD,
PhD, MBA, serves as the co-principal investigator. As part
of this cooperative research endeavor Children’s National is
devoted to developing new Phase I and Phase II therapies
for children and adolescents with cancers resistant to
standard chemotherapy.
Gangliosides in cancer
Role of gangliosides in tumor progression
Tumor progression, and particularly that of some
neuroectodermal and brain tumors (e.g., neuroblastoma,
14 | CCIR
medulloblastoma, glioma), causes most cancer-related
morbidity and mortality. The synthesis and shedding of the
membrane glycosphingolipids, or gangliosides, have been
strongly implicated in contributing to tumor progression.
The laboratory of Stephan Ladisch, MD, delineated some
basic mechanisms by which tumor gangliosides modulate
the behavior of host cells in the tumor microenvironment,
such as amplification of cell signaling and subsequent
angiogenic responses. To test these findings in vivo, they
developed a novel animal model system of specific and
constitutive inhibition of ganglioside synthesis. They are now
comprehensively determining how ganglioside knockout in
these ganglioside-depleted tumor systems affects tumor
progression, providing the first unambiguous insights in
a genetically controlled and stable system. They now will
begin to elucidate the role and basic mechanisms by which
gangliosides modulate tumor progression.
Gangliosides and antitumor immune response
(human neuroblastoma)
Dr. Ladisch’s laboratory also focuses on the characterization
of the effect of tumor gangliosides on the biology of human
neuroblastoma, and specifically the antitumor immune
response. This is based upon the hypothesis that specific
gangliosides shed by tumors act as intercellular signaling
molecules and protect tumor cells from host destruction.
They have found significant shedding and potent
immunosuppressive activity of human neuroblastoma tumor
gangliosides. They have also shown inhibition of murine antitumor immune responses, and identified antigen presenting
cells as primary tumor ganglioside targets.
Ganglioside expression and neuroblastoma differentiation
It has long been speculated that specific ganglioside
abnormalities are linked to the clinical and biological
behavior of many types of tumors, including neuroblastoma
(NB). Recent work by Dr. Ladisch demonstrated that low
or absent expression of complex "b" pathway gangliosides
(GD1b, GT1b and GQ1b, termed CbGs) correlates with
unfavorable clinical behavior and an aggressive biological
phenotype in primary NB tumors while high CbG expression
is highly predictive of a favorable disease outcome. The
team is testing the hypothesis that CbGs ameliorate the
malignant phenotype in human NB by specifically altering
one or more cellular processes that contribute to the
malignant behavior of NB cells in vivo.
Pleuropulmonary blastoma, a model of pediatric solid
tumor pathogenesis
D. Ashley Hill, MD (Chief of Pathology), studies
pleuropulmonary blastoma (PPB), a rare lung sarcoma that
arises during fetal lung development and affects children
under 6 years of age. Dr. Hill and her team demonstrated
germline loss of function DICER1 mutations in familial
PPB. The study of families that show predisposition to PPB
represent a unique opportunity to learn about the cellular
processes in the borderland between lung development and
neoplasia and to study how tissue-specific loss of DICER1
(and the miRNAs it regulates) manifests in human disease.
For more information, see the story on page 22.
Telomerase as a therapeutic target for pediatric cancer
One of the hallmarks of cancer cells is unlimited proliferative
capacity, which is dependent upon the length and integrity
of telomeres. To maintain telomere length, most cancers
activate the enzyme telomerase, a specialized reverse
transcriptase that replenishes nucleotide repeats that are
lost during DNA replication. Because telomerase is relatively
specific to cancer cells and is critical to cancer cell
immortality, it represents a highly attractive therapeutic
target. The laboratory of Jeffrey Dome, MD, PhD, focuses
on the telomere biology of osteosarcoma, the most common
bone tumor of children and teenagers. Osteosarcoma is
distinct from most cancers in that only 50 percent of tumors
express telomerase. The remaining tumors utilize a poorly
characterized recombination-based telomere maintenance
mechanism called “ALT” (alternative lengthening of
telomeres). Ongoing studies in the lab are deciphering
the molecular mechanisms of ALT and the features that
distinguish ALT-dependent osteosarcomas from their
telomerase-dependent counterparts. In addition, the lab
is evaluating the efficacy of GRN163L, a small molecule
telomerase inhibitor, in preclinical models of osteosarcoma
and other pediatric cancers. The preclinical studies have
yielded promising results that will allow researchers to
The image shows neural stem cell neurospheres undergoing differentiation into neurons (red), oligodendrocytes (blue), and astrocytes (green).
Tumorspheres or tumor stem-like cells have similar properties. (Sandler A)
rationally design clinical studies of agents that target
telomeres and telomerase.
Section: Cancer Immunology
Cancer Immunology focuses on studying the interaction
between the immune system and cancer cells. In particular,
our investigators seek to take advantage of the fact that the
immune system is capable of recognizing cancer specific
antigens. Two avenues are being pursued, one seeking
to optimize the patients’ own immune system to recognize
and subsequently destroy cancer cells, the other seeks to
provide a patient with a new immune system (from a donor)
capable of destroying cancer cells.
Adoptive T cell therapy of tumors
Stanislav Vukmanovic, MD, PhD, studies adoptive T cell
therapy of cancer using a combination of alloreactivity (the
reactivity responsible for transplant rejection) and high
avidity T cells. This approach can bypass partial tolerance
of the immune system for tumor antigens and outgrowth of
tumor variants with loss of tumor antigen or HLA expression.
This dramatically reduces the ability of the immune system
to recognize the tumors. Alloreactive MTB T cells could
be an effective therapeutic approach counteracting tumor
evasion of the immune system and a source of high
avidity T cells with multiple specificities.
Bone marrow transplantation (BMT) as treatment of
Terry Fry, MD (Chief of Bone Marrow Transplantation),
studies a vaccine approach to boost the effectiveness
of bone marrow transplantation either during or following
CCIR | 15
of immune cells that then stimulate the immune system to
specifically target the tumor whose antigens match those
that are loaded in the particles, creating tumor specific
immunity. The research team is currently exploring the role
of regulatory T cells in inhibiting the ISAP impact on tumor
growth. If successful, this vaccine could be used for tumors
such as neuroblastoma as a follow-up to standard therapies
that include chemotherapy and surgical resection to
drastically reduce the likelihood of recurrence. Additionally,
Dr. Sandler’s laboratory is exploring the role of progenitor
tumor cells and their resistance to standard therapy. These
cells may offer effective targets for tumor vaccines and
A Children’s National patient with sickle cell disease. (Hsu L)
transplant. Specific tumor antigens are introduced to donor
T-lymphocytes to prepare those T-lymphocytes to effectively
target the tumor’s cells once introduced into the body.
T-lymphocytes are the immune cells that fight infection and
have been shown to effectively kill tumors if able to target
the tumor cells alone. The targeted T-lymphocytes can
then be infused to prevent or halt a relapse of leukemia.
Currently, such adoptive therapy is a standard treatment,
but without specifically targeting tumor cells, the donor
T-lymphocytes have a high likelihood of attacking normal
organs as well, which creates serious side effects for the
patient. Targeting the cells will reduce the side effects of this
treatment while effectively halting relapse at the same time.
Additionally, Dr. Fry and his team study whether these donor
T-lymphocytes could be infused into the body of a patient at
the time of BMT to bind to tumor cells, then kill these cells
and limit or stop tumor growth as part of the initial therapy
and as part of preventive treatment moving forward, rather
than after the fact to prevent relapse.
Cancer vaccines in neuroblastoma
Anthony Sandler, MD (Chief of General and Thoracic
Surgery), is developing a vaccine and delivery system that
uses tumor specific genetic material to induce, or teach, the
body’s own immune system to respond and prevent tumor
growth or re-growth. Treatments are tailored to an individual
tumor’s proteins—allowing for a personalized molecular
medicine approach to care. A novel delivery system involves
the creation of synthetic microparticles known as “immune
stimulatory antigen loaded particles” (ISAPs) that consist
of specific tumor antigens as well as immune stimulatory
agents. The ISAPs are detected and engulfed by specialized
immune cells and are sensed to be immune-stimulating
“foreign bodies.” ISAPs have been shown to be effective at
blocking the growth of tumors in mice by inducing activation
16 | CCIR
Regulation and use of cytolytic T cell function
in therapy of tumors
Sasa Radoja, PhD, studies mechanisms that regulate
granule exocytosis mediated cytotoxicity, a major mechanism
used by cytotoxic T cells to kill tumor cells. Granule
exocytosis-mediated cytotoxicity by CD8+ T cells is one
of the major mechanisms of adaptive immunity to tumors.
This T cell function is often inhibited in tumor-bearing hosts,
which contributes to uncontrolled tumor growth. Attempting
to redirect the specificity of cytotoxic T cells by using
chimeric cell surface receptors will allow the use of cytotoxic
T cell potential for specific treatment of tumors without the
need to induce cancer-specific immune responses.
Section: Hematology and Transfusion Medicine
Investigators in this section are involved in many aspects of
hematology research, including optimization of the treatment
of patients with clotting disorders, developing new therapies
for sickle cell disease, and improving our understanding of
immune perturbations associated with blood transfusions.
Sickle cell disease (SCD)
Basic and translational research
Emily Meier, MD, studies fetal hemoglobin (HbF) expression
patterns in children with SCD. Using specialized flow
cytometric assays, she is investigating how HbF expression
patterns correlate with disease severity in the laboratory of
Jeffery Miller, MD, at the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK). Predictors of
disease severity would help doctors institute disease
modifying therapy prior to the development of life
threatening sequelae of SCD.
Lewis Hsu, MD, was recruited this year to direct this sickle
cell program. He examines vascular complications and
therapy to improve nitric oxide availability in mouse models
of SCD in collaboration with the intramural National Heart,
Lung, and Blood Institute (NHLBI) program. These mouse
models have the potential to help test therapeutic concepts
and to speed the progression of new treatments for sickle
cell disease from bench to bedside.
Clinical trials in sickle cell disease
Children’s National is recognized as one of the three
largest pediatric sickle cell centers in the country, and is a
fertile field for clinical and translational research. Currently,
Children’s National participates in the NIH-sponsored
national Sickle Cell Disease Clinical Research Network,
plus regional consortia including the NIH-funded Howard
University Sickle Cell Center. Naynesh Kamani, MD, and
Jane Sandé, MD, are at the forefront of new approaches to
bone marrow transplantation to cure SCD and thalassemia
with non-myeloablative preparative regimen and with
unrelated donor transplants in multi-center clinical trials.
Zohreh Tatari-Calderone, PhD, and Ross Fasano, MD, work
in the laboratory of Naomi Luban, MD, to elucidate the
molecular understanding of the blood bank complexity of
sickle cell disease.
The effects of the sickle hemoglobin mutation causes
severe abnormalities for the red blood cell, but also causes
complications in nearly every part of the body with a
complexity that naturally requires expertise in multiple
specialties to manage. Helge Hartung, MD, and a
developmental psychology team led by Penny Glass, PhD,
examine early cognitive development in the multidisciplinary
Sickle Cell Infant Clinic. Stroke and stroke prevention are the
focus for Lori Luchtman-Jones, MD, in the multidisciplinary
Sickle Cell Neurology Clinic, with neurologist Jessica
Carpenter, MD, and radiologist Dorothy Bulas, MD. Health
services delivery research on reducing the contribution of
lung disease to sickle cell complications is the focus of
pulmonologist Folasade Ogunlesi, MD. Approaches to
improve adolescent transition to adult care are being
researched by Dr. Hsu, social worker Lisa Thaniel, and
education expert Maxine Freund, PhD. Genetic polymorphisms
affecting sickle cell vaso-occlusive pain are examined by
pain specialists Julia Finkel, MD, and Zenaide Quezado,
MD, with the potential for future customizing selection of
pain medications to the individual’s opioid metabolism.
Cardiologists Niti Dham, MD, and Craig Sable, MD, are
analyzing the nation’s largest collection of echocardiograms
in SCD patients as cardiology core team members of the
Pulmonary Hypertension and the Hypoxic Response in SCD
(PUSH) study.
Clinical trials in pediatric coagulation
Children’s National has several research studies and clinical
trials underway with an eye to the future in hopes of finding
safer and more effective methods to screen for, prevent,
diagnose, and treat a variety of blood disorders including
hemophilia (A, B, and C), von Willebrand disease,
thrombophilia, and neutropenia. Participating in a research
study allows participants to play a more active role in their
own health care, gain access to new research treatments
before they are widely available, and help others by
contributing to medical research.
Children’s investigators participate with the Centers for
Disease Control (CDC) in monitoring the health status of
individuals with hemophilia and other bleeding disorders.
The information gained will be used to help plan future
medical care and develop and evaluate programs to reduce
or prevent complications of hemophilia. Children’s National
takes part in an international study to determine the optimal
dose of factor VIII to induce immune tolerance. After immune
tolerance is achieved, children will be closely followed for
an additional 12 months. Physicians at Children’s National
hope to learn whether the two regimens of immune tolerance
induction are equally effective or whether one regimen is
superior to the other.
Children’s National participates in the severe chronic
neutropenia International Registry (SCNIR) to collect
information about the health of persons with severe chronic
neutropenia over time. The purpose of the study is to learn
more about severe chronic neutropenia and assess the
long-term safety of primary treatments, provide a research
base for establishing better treatments; and minimize side
effects of existing therapies for severe chronic neutropenia.
The splenectomy study is an international registry of children
and adults with idiopathic thrombocytopenic purpura (ITP).
The goal is to study patients with chronic (lasting more
than six months) ITP, who will have the spleen removed as
Transfusion medicine
Research in transfusion medicine, led by Naomi Luban, MD,
includes basic and translational research, epidemiology,
clinical research, and device evaluation. Dr. Luban continues
her successful Transfusion Related Infections in Pediatric
Patients (TRIPPS) study in collaboration with Harvey Alter, MD,
and colleagues at the NIH. This unique epidemiological
study provides the opportunity to directly link transfusion
recipients to their donors and study post-transfusion
infectious diseases and microchimerism. Other investigators
in the laboratory are examining the development of
red blood cell (RBC) alloimmunization using a multipronged approach. The studies aim to further elucidate
the importance of genes and the immune perturbations
associated with RBC alloimmunization. Research by Zohreh
Tatari-Calderone, PhD, MBA, is focused on uncovering
single nucleotide polymorphisms and biomarkers that are
CCIR | 17
predictive of alloimmunization and elucidating the molecular
mechanisms underlying these phenomena. Discovering
predictors of alloimmunization using SNPs will have a
significant impact on the translation of research findings into
clinical trials that could potentially prevent alloimmunization
early on in children and ensure the full benefit of improved
and safer RBC transfusion practices.
The Rh system is the most complex of all blood group
systems, expressing more than 54 antigens. Individuals of
African descent often have Rh variants that are not identifiable
with standard serological tests and account for the high
rates of alloantibodies to both C, c and E, e. Ross Fasano,
MD, in collaboration with Willy Flegle, MD, of the NIH is
investigating the genetics and inheritance of the Rh system
in children with SCD and other hemoglobinopathies.
Yaser Diab, MD, and Edward Wong, MD, in collaboration
with Gary Moroff, PhD, and Steven Wagner, PhD, of the
American Red Cross, investigate the effect of collection
methods, storage, and infusion devices on platelet function
with particular concern for neonatal transfusion practices.
Dr. Wong also studies the epidemiology of infectious
disease serology among volunteer, familial, and directed
donors and the indications for safety and efficacy of
apheresis methodologies. Dr. Luban collaborates with Lillian
Su, MD, and John Berger, MD, on a study of BPA and DEHP,
plasticizers which leach from plastic blood bags and
devices used in catheterization and in cardiopulmonary
bypass (CPB) procedures. This work is done in collaboration
with the FDA and is an outgrowth of a long standing interest
in unexpected consequences of extra-corporeal membrane
oxygenation (ECMO) and CPB on immune function,
coagulopathy, and endocrine disturbances secondary to
the estrogenic effect of plasticizers. Additional studies of the
hemolytic and thrombogenic characteristics of ECMO have
begun with Khodayar Rais-Bahrami, MD, Andrew Meyer,
MD, Robert Freishtat, MD, and Children’s biomedical
engineering division.
Section: Infectious Diseases
Investigators in this section are primarily involved in
infectious disease epidemiology, laboratory and clinical
research in HIV/AIDS, and laboratory research in human
cytomegalovirus (CMV) and viral myocarditis.
Bacteriology and molecular epidemiology research
Nalini Singh, MD, MPH (Chief of Infectious Diseases),
Xiaoyan Song, PhD, MB, MSc, and David Hyun, MD, focus
on the prevention and control of healthcare-associated
infections, molecular diagnostics related to multi-drug
18 | CCIR
resistant organisms, and global health initiatives related to
infection prevention. Specific areas of research include
studies to detect and control the spread of multi-drug
resistant gram negative pathogens, methicillin-resistant
staphylococcus aureus (MRSA), and clostridium difficile
(c. diff.) within the hospital environment, as well as reducing
the number of blood stream and surgical site infections in
hospitalized patients. Since the Washington, DC, patient
population includes a large number of international patients,
the research program also focuses on detection and
prevention of diseases of global importance, including
tuberculosis and malaria. Study of these pathogens is
critical to maintaining the highest degree of safety for
hospitalized patients, as well as maximizing the preservation
of efficacy of available antimicrobial therapies to treat these
infections. To promote the prevention effort, Dr. Song also
conducts outcome research to assess the clinical and
financial impact of healthcare associated infections on
hospitalized patients and the society at large. In addition,
Dr. Song is interested in utilization of computerized medical
records for improved effectiveness of detecting and
managing infectious diseases in healthcare facilities.
Basic research in HIV related disorders
The laboratory of Steven Zeichner, MD, PhD, studies human
immunodeficiency virus-1 (HIV-1; HIV) and Kaposi’s sarcomaassociated herpesvirus (KSHV), the etiologic agent of
Kaposi’s sarcoma and other neoplasms associated with
immunosuppression due to HIV infection and other causes.
In past work the laboratory defined the program KSHV uses
to reproduce. The lab is now expanding that work, aiming
to understand how different stresses on the host cell of
the virus influence the program of virus replication. This
knowledge may lead to innovative new treatments for the
cancers associated with KSHV and other herpes viruses.
One of the lab’s HIV projects involves studying how HIV
remains latent and what stimuli lead to HIV activation. After
HIV infects certain cells, a DNA copy of the virus can remain
latent within the genome of the host cell for many years.
This creates a long-lived reservoir of latently infected cells,
which is the reason why HIV infection cannot now be cured.
Much recent interest has focused on working to find ways
to effectively and safely activate HIV in that latent reservoir
without harming other cells or organs. If a safe method
could be found to activate HIV, that method could be used,
along with currently available drugs that can block the new
infections of cells, to attack and deplete the long-lived
reservoir of cells latently infected with HIV. In another HIV
project the lab is developing novel screening methods to
identify highly effective immunogens, which may be useful
in the development of new HIV vaccine candidates.
Clinical research in pediatric HIV disease
Washington, DC, is ranked first in the nation regarding AIDS
prevalence and among the top regarding HIV infection
prevalence, particularly among youth. Additionally, the
Washington, DC, region experiences very high rates
of perinatal HIV transmission. Several investigators are
involved in funded research looking at infection trends and
responses to treatment.
Lawrence D’Angelo, MD, MPH (Chief of Adolescent
Medicine), is the principal investigator for the Adolescent
Trials Unit site in Washington, DC, part of the Adolescent
Trials Network. This 15-site network looks at a range of
behavioral and biologic factors influencing HIV disease
in adolescents and young adults. Currently 12 different
protocols are open to patients focusing on early treatment
interventions, adjunctive vitamin D therapy, vaginal
microbicides, risk factors for HIV infection, and adherence to
Natella Rakhmanina, MD, collaborates with investigators
at the Washington Hospital Center to look at the current
algorithm used for maternal HIV testing during pregnancy
and the use of antiretrovirals as prophylaxis for effective
perinatal HIV transmission. Specifically, Dr. Rakhmanina
is interested in determining whether any differences exist
in transmission rates between African-American women
of U.S. origin and African immigrant mothers. In addition,
Dr. Rakhmanina leads a multidisciplinary team of clinical
researchers studying the most efficient mechanism of
screening youth in pediatric emergency departments.
Steven Zeichner, MD, PhD, is the principal investigator for
the International Maternal Pediatric Adolescent AIDS Clinical
Trials (IMPAACT) group, a large multi-center international
network of investigators sponsored by the NIH. IMPAACT
sponsors many trials for HIV-infected children, including
studies of HIV disease in children and its complications,
approaches to preventing infants born to HIV-infected
mothers from acquiring the disease, and new drugs for HIV
infection and the diseases that accompany HIV infection.
The Children’s National IMPAACT site has sub-sites at
Washington Hospital Center, where HIV-infected pregnant
women are treated, and at Johns Hopkins University. Dr.
Zeichner is the local principal investigator for several
industry-sponsored studies that give HIV-infected children in
the Washington area access to new investigational agents
for HIV infection that may prove useful in patients for whom
conventional therapies are no longer effective.
Pharmacology of antiretroviral therapies
The treatment of HIV infection requires lifelong administration of
multiple antiretroviral (ARV) agents. Natella Rakhmanina, MD,
Stress responsive cellular proteins. Mitochondria-associated membranes
(MAM) are endoplasmic reticulum (ER) subdomains which regulate critical
cell fate decisions. Sigma-1 receptor (green) accumulates within MAMlocalized lipid rafts (top panels) in human fibroblasts. Mitochondria are
labeled in red. During ER stress, sigma-1 receptor responds by trafficking
from the MAM to the periphery of the ER (bottom panels). This dramatic
change in localization shows the dynamic and responsive nature of cellular
components of the MAM. (Williamson CD and Colberg-Poley AM)
focuses her research on the pharmacology of ARV therapy in
pediatric patients. She has a particular interest in therapeutic
drug monitoring (TDM) and the effects of developmental
changes on the pharmacokinetics and pharmacodynamics of
pediatric HIV therapy. Her work in this field has contributed to
the identification of saliva as a non-invasive alternative for TDM
of nevirapine in children. She found that the recommended and
approved dose of the ARV drug lopinavir provides suboptimal
plasma concentrations in treatment-experienced children and
adolescents and is related to suboptimal virologic suppression.
Dr. Rakhmanina works in close collaboration with Eric Hoffman,
PhD, in the Center for Genetic Medicine Research to establish
the role of human host factors, such as CYP 450 mutations in
the metabolism and distribution of ARV drugs. Her most recent
studies focus on the effect of development during puberty
on the expression of the CYP2B6 enzyme and metabolism of
the ARV drug efavirenz. These studies are aimed at creating
effective, tested paradigms for the study of HIV therapeutics
that will lead to individualized therapy and improved outcome
in pediatric and adolescent patients with HIV infection
Human cytomegalovirus (HCMV) pathogenesis
HCMV is the leading viral cause of congenital disorders
CCIR | 19
in developed countries and is a significant contributor to
morbidity and mortality in immunosuppressed patients,
including recipients of allogeneic transplantation.
Understanding the trafficking and functions of HCMV
UL37 anti-apoptotic proteins, a focus of the work of
Anamaris Colberg-Poley, PhD, is of high impact as they
partially underlie HCMV pathogenesis. Trafficking of UL37
proteins from the endoplasmic reticulum to mitochondria
is unconventional but central to the ordered events in the
viral lytic cycle, host cell survival during infection, and the
assembly of infectious progeny virus. Dr. Colberg-Poley’s
studies seek to understand the mechanistic basis of this
protein trafficking during HCMV infection. Because proper
trafficking of viral proteins is necessary for their function,
discovering the requirements for MAM to mitochondrial
trafficking of essential viral proteins may provide novel
targets for the rational design of anti-viral drugs.
In collaboration with Vittorio Gallo, PhD (Director, Center for
Neuroscience Research), the Colberg-Poley laboratory also
examines HCMV infection in human neural precursor cells.
Viral myocarditis
The laboratory of Roberta DeBiasi, MD, focuses on
identifying novel targets for therapy of viral myocarditis,
a serious viral infection of heart tissue for which effective
treatments are currently lacking. Up to 20 to 50 percent
of children and adults with viral myocarditis develop
significantly impaired heart function, resulting in death or
the need for cardiac transplantation. Many viruses can
cause heart injury, but specific antiviral therapies are not
available. A common virus-induced mechanism of injury
to heart cells is likely, but not yet identified. Dr. DeBiasi’s
laboratory has been particularly interested in the role of
virus-induced apoptotic death (specifically death-receptor
induced apoptosis) of cardiac myocytes in the pathogenesis
of viral myocarditis. The laboratory has demonstrated
that manipulation of apoptotic signaling is an effective
therapeutic intervention in the reovirus animal model of
viral myocarditis. Using microarray analysis of cardiac
myocytes infected with myocarditic (heart damaging) and
nonmyocarditic (non-damaging) viruses, the laboratory
identified several additional cellular signaling pathways that
are significantly altered in the setting of viral myocarditis.
Her laboratory is validating and manipulating these cellular
signaling pathways, including G protein coupled receptor
and heat shock proteins, in cardiac cells and tissues from
animals infected with myocarditic viruses. Additional studies
are planned to evaluate the involvement of candidate
pathways in human cardiac biopsy tissues from patients with
viral myocarditis. Targeted manipulations of these pathways
are expected to lead to novel treatment strategies for this
severe disease of humans.
Significant Peer Reviewed Journal Publications
n Anderson B, Sprague B, Short B, Campos J, Singh N. “Molecular and
descriptive epidemiology of multidrug-resistant enterobacteriaceae in
hospitalized infants.” Infection Control Hospital Epidemiology.
n Capitini C, Herby S, Milliron M, Anver MR, Mackall CL, and Fry TJ. “Bone
marrow deficient in gamma interferon signaling selectively reverses
GVHD-associated immunosuppression and enhances a tumor-specific GVT
effect.” Blood. May 2009;113(20):5002-5009.
n Capitini, C, Derdak, J, Hughes, MS, Love, CP, Baird, K, Mackall, CL, Fry,
TJ. “Unusual sites of extraskeletal metastases of Ewing sarcoma after allogeneic hematopoietic stem cell transplantation.” J Pediatr Hematol Oncol.
2009 Feb;31(2):142-4.
n Chung, YJ, Choi, CW, Slape, C, Fry, T, Aplan, PD. “Transplantation of a
myelodysplastic syndrome by a long-term repopulating hematopoietic
cell.” Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14088-93.
n Cross SJ, Rodman JH, Lindsey JC, Robbins BL, Rose CH, Yuen GJ,
D’Angelo LJ. “Abacavir and metabolite pharmacokinetics in HIV-1 infected
children and adolescents.” J Acquir Immune Defic Syndr. 2009;51:54-59.
20 | CCIR
n Dean JB, Boslaugh S, Albert CM, Hayashi SS, et al. “Risk Factors For
Hearing Loss In Pediatric Oncology Patients.” Journal of Pediatrics, in
n Dean R, Fry T, Mackall C, Steinberg S, Hakim F, Fowle D, Odom J, Foley
J, Gress R, Bishop M. “Association of serum interleukin-7 levels with the
development of acute graft-versus-host disease.” J Clin Oncol. Dec10
n Dromi, SA, Walsh, M, Herby, S, Traughber, B, Xie, J, Sekhar, K, Luk, A,
Liewehr, D, Dreher, M, Fry, TJ, Wood, B. “Radiofrequency Ablation Induces
Antigen Presenting Cell Infiltration and Amplification of Weak TumorInduced Immunity.” Radiology. 2009 Apr; 251(1):58-66.
n Fernandez CV, Anderson J, Breslow NE, Dome JS, Grundy PE, Perlman
EJ, and Green DM. “Anthropomorphic measurements and event-free survival in patients with favorable histology Wilms tumor: A report from the
Children’s Oncology Group.” Pediatr Blood Cancer. 52 (2): 254-8, 2009.
n Freeman SS, Allen SW, Ganti R, Wu J, Ma J, Su X, Neale G, Dome JS,
Daw NC, and Khoury JD. “Copy number gains in EGFR and copy number
losses in PTEN are common events in osteosarcoma tumors.” Cancer.
113: 1453-61, 2008.
n Fry, TJ. “Is a little GVHD a Good Thing?” Blood. 2009 June; 113(25):
n Fry TJ, Shand J, Milliron M, Tasian S, Mackall C. “Antigen Loading of DC
Induces Superior Immunity Compared to other Approaches.” Journal of
Cancer Cancer Immunol Immunother. 2009 August;58(8):1257-1264.
n Goforth R, Salem AK, Miles S, Zhu X, Zhang XQ, Lee J and Sandler A.
“Immune stimulatory antigen loaded particles combined with depletion
of regulatory T-cells induce potent tumor specific immunity in a mouse
model of melanoma.” Cancer Immunol Immunother. 2009;58(4):517-530.
n Hill DA, Ivanovich J, Priest JR, Gurnett CA, et al. “DICER1 Mutations in
Familial Pleuropulmonary Blastoma.” Science. 2009. (5493);325:965.
n Huang CC, Gadd S, Breslow N, Cutcliffe C, Sredni ST, Helenowski IB,
Dome JS, Grundy PE, Green DM, Fritsch MK, and Perlman EJ. “Predicting
relapse in favorable histology Wilms tumor using gene expression analysis: A report from the Renal Tumor Committee of the Children’s Oncology
Group.” Clin Cancer Res. 2009.
n Levin MJ, DeBiasi RL, Bostik V, and Schmid DS. “Herpes zoster with
skin lesions and meningitis caused by two different genotypes of the Oka
Varicella-Zoster Virus vaccine.” Journal of Infectious Diseases. 2008.
n Liu Y, Su Y, Wiznitzer M, Epifano O, Ladisch S. “Ganglioside depletion
and EGF responses of human GM3 synthase-deficient fibroblasts.”
Glycobiology. 2008;18:593-601.
n Lyon ME, D’Angelo LJ. “Adolescents living with HIV/AIDS.” In Behavioral
Approaches to Chronic Disease in Adolescence. O’Donohue WT (ed.),
Springer Science+Business Media, LLC. New York, New York. 2009.
n Lyon ME, McCarter R, D’Angelo LJ. “Detecting HIV associated neurocognitive disorders in adolescents: What is the best screening tool?” J
Adolesc Health. 2009; 44:133-135.
n Lyon ME, Garvie PA, McCarter R, Briggs L, Jianping H, D’Angelo LJ.
“Who will speak for me? Improving end-of-life decision-making for adolescents with HIV and their families.” Pediatrics. 2009;123:e199-e206.
n Minkov M, Steiner M, Pötschger U, Aricò M, Braier J, Donadieu J, Grois
N, Henter JI, Janka G, McClain K, Weitzman S, Windebank K, Ladisch S,
Gadner H; International LCH Study Group. “Reactivations in multisystem
Langerhans cell histiocytosis: data of the international LCH registry.”
J Pediatr. 153:700-5, 2008.
n Miyamoto SD, DeBiasi RL, and Long CS. “Novel therapeutic targets in viral
myocarditis.” Future Virology. 2008;3(4):373-381.
n Miyamoto SD, Robinson BA, Tyler KL, Brown RD, Long CS, DeBiasi RL.
“Cardiac cell-specific apoptotic and cytokine responses to reovirus
infection: Determinants of myocarditic phenotype.” Journal of Cardiac
Failure. 2008;(6):529-539.
n Neale G, Su X, Morton CL, Phelps D, Gorlick R, Lock RB, Reynolds, CP,
Maris JM Friedman HS, Dome J, Khoury J, Triche T, Seeger RC, Gilberson
R, Khan J, Smith MA, and Houghton PJ. “Molecular characterization of the
pediatric preclinical testing panel.” Clin Cancer Res. 2008. 14: 4572-83.
n Rood BR, Van Rechem C, Touka M, et al. “The scavenger chemokine
(C-X-C motif) receptor 7 (CXCR7) is a direct target gene of hypermethylated
in cancer 1 (HIC1).” J Biol Chem. 2009; 284:20927-20935.
n Sportes, C, Hakim, F, Memon, S, Zhang, H, Chua, K, Fleisher, T, Krumlauf,
M, Rabb, R, Chow, C, Fry, T, Engels, J, Buffet, R, Morre, M, Amato, R,
Venzon, D, Korngold, R, Pecora, A, Gress, R, Mackall, C. “Administration
of rhIL-7 In Humans Increases in vivo TCR Repertoire Diversity by
Preferential Expansion of Naive T cell Subsets.” J Exp Med. 2008 Jul
n Song X, Bartlett JG, Speck K, Naegeli A, Carroll K, Perl TM. “Rising
economic impact of clostridium difficile – associated disease in adult
hospitalized patient population.” Infect Control Hosp Epidemiol. 2008
n Williamson CD, and Colberg-Poley AM. “Access of viral proteins to
mitochondria via mitochondria-associated membranes.” Reviews in
Medical Virology. 2009;19:147-164.
n Lyon ME, Garvie PA, Briggs L, He J, McCarter R, D’Angelo LJ.
“Development, feasibility, and acceptability of the family/adolescent-centered (FACE) advance care planning intervention for adolescents with HIV.”
J Palliat Med. 2009;12:363-372.
n Meany HJ, Seibel NL, Sun J, Finklestein JZ, et al. “Phase 2 trial of
recombinant tumor necrosis factor-alpha in combination with
dactinomycin in children with recurrent Wilms tumor.” J Immunother.
n Milstone AM, Maragakis LL, Townsend T, Speck K, Sponseller P, Song X,
Perl TM. “Timing of preoperative antibiotic prophylaxis: a modifiable risk
factor for deep surgical site infections after pediatric spinal fusion.”
Pediatr Infect Dis J. 2008 Aug;27(8):704-708.
n Milstone AM, Song X, Beers C, Berkowitz I, Carroll KC, Perl TM.
“Unrecognized burden of methicillin-resistant Staphylococcus aureus and
vancomycin-resistant Enterococcus carriage in the pediatric intensive care
unit.” Infect Control Hosp Epidemiol. 2008 Dec;29(12):1174-6
CCIR | 21
DICER1 gene mutation linked
to rare childhood cancer
hildren’s National researcher and Chief
of the Division of Pathology, D. Ashley Hill,
MD, demonstrated the first definitive link
between mutations in the gene DICER1 and a rare
form of childhood lung cancer. By studying the
patterns of DNA from 11 families with an unusual
predisposition to pleuropulmonary blastoma (PPB),
Dr. Hill and her colleagues found that children with
the cancer carried a mutation in one of two DICER1
gene copies.
DICER1 makes an important protein that works
to suppress other genes through intermediary
molecules known as microRNAs. Scientists think
that microRNAs can fine-tune the expression of
many other genes, which is particularly important
in normal human development. Recent research
also has focused on DICER 1 as having a potential
role in cancer because the micro-RNA molecules it
produces appear vastly different from those found
in cancer cells.
“When we realized that DICER1 was in the segment
of chromosome that was shared among children
with PPB, we were very excited,” said Hill. “PPB
is a tumor that appears to arise out of a localized
abnormal lung development. The implications of a
defect in a master controller gene for normal organ
development would be significant.”
22 | CCIR
Hill says not everyone who inherits a mutation
develops PPB, and children with PPB are typically
normal in every other way. The team theorizes that
something else must happen to the normal copy of
DICER1 in lung cells for a tumor to develop. Then
the research team looked at PPB tumors to see if
there is any DICER1 protein being made from the
remaining normal copy of the gene. They were
surprised by the results. They found that the benign
cells that grew on the surface of the tumor had lost
the DICER1 protein.
Studying tumor cells for genetic mutations has
led to many advances in the understanding of
cancer. This discovery may represent a first step in
understanding a new mechanism for how cancer
begins. Conceivably, the mutated cells do not
turn into tumors themselves. Instead, these cells
influence surrounding cells to grow quickly, setting
the stage for additional genetic mutations in cells
that then become cancerous.
Only 50 or 60 cases of PPB are diagnosed
worldwide each year. The cancer presents as
cysts in early stages and progresses to solid lung
tumors in time. If detected, 90 percent of patients
appear to be cured when treated with a surgical
intervention and sometimes chemotherapy. n
Center for
Genetic Medicine Research
Eric Hoffman, PhD
Chairman, Department of Integrative Systems Biology, George Washington University
Kristy Brown, PhD
Ljubica Caldovic, PhD
Yi-Wen Chen, DVM, PhD
Stephanie Constant, PhD
Joseph Devaney, PhD
Robert J. Freishtat, MD, MPH
Stanley Fricke, PhD
Yetrib Hathout, PhD
Monica Hubal, PhD
Sabah Iqbal, MD
Susan Knoblach, PhD
Jyoti Jaiswal, PhD
Robert T. Leshner, MD
Richard Levy, MD
Nazrat M. Mirza, MD, ScD
Hiroki Morizono, PhD
Kanneboyina Nagaraju, PhD
Javad Nazarian, PhD
Terence A. Partridge, PhD
Perry Payne, MD, JD
Maria T. Pena, MD
Dinesh Pillai, MD
Hans George Pohl, MD
Diego Preciado, MD
Mary Callaghan Rose, PhD
Dashuang Shi, PhD
Christopher Spurney, MD
Laura L. Tosi, MD
Mendel Tuchman, MD
Zuy Wang, PhD
Adeline Vanderver, MD
A transverse muscle section that has been stained for collagen (red), laminin (green), and DNA (blue).
The large polygonal structures are muscle fibers, having both collagen and laminin at their surface
(and hence appearing yellow). The spots of blue are nuclei, either belonging to the muscle fiber
(inside the yellow stain), or belonging to cells located in the interstitial tissue between the muscle fibers—
and some of which express collagen on their surface. Red circles without a nucleus are blood vessels.
This research investigates the factors responsible for fibrosis in diseases of muscular dystrophy.
(Partridge T, Duguez S, Duddy W)
To transform children’s health through
genome-enabled research, pre-clinical
studies of experimental therapeutics,
and clinical trials.
Major Strategic Goals
Take a leadership role in drug
development for muscular dystrophy,
including exon skipping (systemic
antisense) and non-hormonal steroids
(with Validus Biopharma).
Establish and expand an interdisciplinary
program in Systems Biology of Surgical
Weight Loss, in collaboration with the new
Sheikh Zayed Institute for Pediatric Surgical
Establish and expand an interdisciplinary
program in the Systems Biology of Asthma,
including molecular, environmental, public
health, and drug development components.
Increase the number of NIH-funded
training programs.
Successfully re-compete for key center
grants, including the Wellstone Center,
National Center for Medical Rehabilitation
Research (NCMRR) and Clinical and
Translational Science Award (CTSA).
24 | CGMR
Strategic Plan Accomplishments
n Transition promising experimental therapeutic approaches to
clinical trials.
• Muscular dystrophy: Ed Connor, MD, director of the
Office for Investigational Therapeutics at CRI assumed a
leadership role in relationships between CINRG, Children’s
muscular dystrophy programs, and multiple biotech and
pharmaceutical companies. This facilitated a focus on
appropriate drug development programs in exon skipping
and non-hormonal steroids. The for-profit off-shoot of
the Center for Genetic Medicine, Validus Biopharma
(VBpharm), made strong progress in drug development
of non-hormonal steroids, and was selected as one of the
initial recipients of Muscular Dystrophy Association Venture
Philanthropy funding nationally. The CINRG clinical trials
unit formed an alliance with the trans-Europe Treat-NMD
network, jointly developing standard operating procedures
for both pre-clinical and clinical trials.
• Urea cycle disorders: The urea cycle disorders consortium
received the top score in a highly competitive Rare
Diseases Clinical Research Center RFA (Mark Batshaw, MD,
and Mendel Tuchman, MD), and this $6.5 million grant
was matched with a $5.7 million grant from the Thomas
A. and Mary Alice O’Malley Family Foundation. This aided
in the recruitment of a new clinical chief of Genetics and
Metabolism Marshall Summar, MD. His laboratory brings
molecular diagnostic and genetic anthropology expertise,
as well as successful drug development programs.
• White matter disorders: Adeline Vanderver, MD, received
a K award to continue developing her molecular
pathophysiology research, as well as an international
network of white matter disorder clinical researchers.
• Asthma: Close collaboration with the Center for Clinical
and Community Research led to strong progress in asthma
research, including a recent finding of a close association
of vitamin D deficiency with the high rate of asthma in
African American Washington, DC, youth. This finding has
significant clinical implications for asthma prevention.
n Implement a series of population-based interventions for
inactivity, obesity, and type 2 diabetes in children and young
adults. A Systems Biology of Obesity initiative was funded
by the center and the new Institute for Pediatric Surgical
Innovation, where the center takes a leadership role in the
Systems Biology section (Eric Hoffman, MD). Monica Hubal,
PhD, was retained as a new faculty member in this effort, and
paired up with a newly recruited NIH-funded surgeon, Evan
Nadler, MD, who works on gastric bariatric banding. AIMM
Young, a study of metabolic syndrome in African American
Washington, DC, college students (Dr. Hoffman, Chiatogu
Onyewu, MD, PhD) has been highlighted by the NIH National
Center on Minority Health and Health Disparities Health
Disparities P20 Centers, with impressive recruitment. A
series of interventions on college freshman to reduce the
high rate of abnormal metabolic syndrome markers is
under design.
n Develop a coordinated systems biology research focus.
The center formally established a new basic sciences
department at the George Washington University School
of Medicine and Health Sciences (Dr. Hoffman, Chair).
The Department of Integrative Systems Biology developed
a new doctoral concentration in systems biology, as well
as associated coursework and laboratory rotations. There
are now 35 faculty in the department, corresponding to
extensive recruitment in the Center for Genetic Medicine
Research and the new George Washington University
n Recruited new young investigators.
• Kristi J. Brown, PhD, was promoted to faculty, with more
than eight years experience in mass spectrometry
• Javad Nazarian, PhD, was promoted to faculty and
published the first molecular characterization of brain
stem gliomas, using a novel technique of proteomic
profiling of FFPE tissue.
Programmatic Areas and Accomplishments
Publications and Sponsored Research
Muscular Dystrophies
During the last year, Genetic Medicine faculty published
53 research papers and received research awards totaling
$8.3 million. Nearly half of the publications (25) were
collaborations between two or more faculty and typically
were interdisciplinary and translational in nature. A new
Department of Defense Program Project in Translational
Research in Duchenne muscular dystrophy was awarded,
as well as a $2.5 million toxicology program for drug
development. In one of the first funded efforts from the
Muscular Dystrophy Association Venture Philanthropy Fund,
the for-profit branch of the Center, Validus Biopharma, will
receive $360,000.
Pre-clinical drug testing facility for muscular dystrophies
Transition of potential therapeutic approaches for muscular
dystrophy from the laboratory bench to human clinical trials
involves obtaining “pre-clinical” data in mouse models.
Kanneboyina Nagaraju, DVM, PhD, made significant
progress this past year and performed more than 20
preclinical efficacy trials sponsored by industry, foundations,
and academic investigators in mouse models of Duchenne
muscular dystrophy (DMD), limb girdle muscular dystrophy
2B (LGMD2B), and autoimmune myositis.
NIH Center Grants and Public Access Web
n AsthMaP:
n National Center for Medical Rehabilitation Research:
Wellstone Muscular Dystrophy Research Center:
Department of Defense Program Project on Translational
Research in the Muscular Dystrophies:
Wicker Project for Muscular Dystrophy Research:
Cooperative International Neuromuscular Research Group
Bioinformatics resources:
Muscle Inflammation
Muscle inflammation is a characteristic feature of several
genetic and autoimmune muscle diseases. Dr. Nagaraju, in
collaboration with Eric Hoffman, PhD, recently uncovered
novel mechanisms of muscle fiber damage in dysferlin
deficiency. These findings form the basis for ongoing
preclinical trials in LGMD2B. Dr. Nagaraju is funded by NIH
to investigate immune and non-immune mechanisms of
muscle fiber damage and dysfunction in autoimmune and
genetic muscle disease. Dr. Nagaraju has several ongoing
projects with Drs. Hoffman and Yi-Wen Chen, PhD, to
investigate inflammatory processes in DMD and LGMD2B.
Yetrib Hathout, PhD, also initiated a collaborative project with
Terence Partridge, PhD, and Dr. Hoffman to tackle molecular
mechanism leading to fibrosis and muscle wasting in
muscular dystrophies. Using proteomics studies in cell
cultures and mouse models, the team has successfully
generated preliminary data that might explain in part the
source and mechanism of fibrosis that develops in patients
with muscular dystrophies.
CGMR | 25
Yi-Wen Chen, PhD, dissects the molecular pathophysiology
of facioscapulohumeral muscular dystrophy (FSHD). By
comparing genome-wide gene expression of FSHD to
profiles generated from other neuromuscular disorders, she
found that paired-like homeodomain transcription factor 1
(PITX1) was specifically up-regulated in patients with FSHD.
A conditional muscle-specific PITX1 transgenic mouse
model was generated to study the function of the gene in
skeletal muscles. Over-expression of PITX1 leads to muscle
atrophy and weakness in the transgenic mice with pathology
similar to human FSHD. The model is a valuable tool to
study the pathological mechanisms of muscle atrophy in
FSHD and for developing treatments of the disease.
The Cooperative Neuromuscular International Research
Group (CINRG) added new sites in Tokyo and at the
Carolinas Medical Center, and is now at 24 sites in 12
countries. The Coordination Center, run by faculty Avital
Cnaan, PhD, (joint appointment with Children’s Center for
Clinical and Community Research) worked closely with Ed
Connor, MD (director, Office of Investigational Therapeutics)
and Dr. Hoffman to establish formal relationships with a
number of biotech and pharmaceutical companies. A
longitudinal natural history study of 347 DMD patients is fully
enrolled and is providing key data for clinical endpoints in
clinical trials, dependent on patient age.
Dr. Hoffman published a key article demonstrating the first
clinical improvement of the large (and clinically severe)
dog model of Duchenne muscular dystrophy using exon
skipping. The article was in collaboration with the National
Center for Neurology and Psychiatry in Tokyo, and Dr.
Partridge in the Center for Genetic Medicine Research.
This study showed that non-toxic doses of a cocktail of
morpholino antisense oligonucleotides, administered by
intravenous infusion caused production of therapeutic
amounts of dystrophin in widespread muscles of the dogs
and stabilized the disease against further progression. This
work is now being extended by use of modified morpholinos
designed to promote efficient entry into cells in the
laboratories. Dr. Hoffman’s lab also identified the first genetic
modifier locus for DMD (manuscript submitted). During
the past year, Dr. Partridge’s lab developed a number
of techniques to measure the relative importance of the
component parts of diseases involving muscle loss, such as
a decrease in size of individual muscle fibers, loss of muscle
fibers, repair and regeneration of damaged muscle fibers,
and the numbers and activities of the muscle stem cells
called satellite cells. These developments are being added
to the range of assessments conducted in Dr. Nagaraju’s
core unit for assessing the beneficial effects of putative
therapeutic agents on the progress of muscular dystrophies.
26 | CGMR
An additional new line of research in Dr. Partridge’s lab is
the development, in collaboration with Dr. Hathout, of a
tissue culture system that measures the loss of proteins from
normal and dystrophic muscle fibers as potential biomarkers
for drug development. This work demonstrated that
dystrophic muscle fibers leak many large proteins into the
surrounding culture medium. This is the first robust disease
marker to be developed in tissue culture and is valuable
because it could be used to conduct screens of large
numbers of reagents for their beneficial effects in preventing
such leakage. During the course of this tissue culture
work, his lab showed that muscle cells are badly affected
by exposure to oxygen at normal atmospheric levels, and
that it would be wise to reduce the oxygen content of gas
in incubators to 5 percent. This is likely to apply to other
internal body tissues as well.
Dr. Partridge’s group began studying two other mechanisms
involved in causing muscle disease. Tatiana Cohen, PhD,
investigates the role of defects in nuclear membrane
proteins in causing muscle disease. Jonathan Cohen, PhD,
began a project on muscle diseases caused by defects in
a protein called dysferlin, which is thought to be implicated
in the control of membrane trafficking and in repair of cell
surface membranes of muscle cells.
Asthma and Respiratory Tract Diseases
The center continued to build interdisciplinary research
programs (emergency medicine, community pediatric
health, pulmonary medicine, and otolaryngology) that focus
on asthma, lung complications of sepsis, otitis media (OM),
and chronic rhinosinusitis (CRS). We are now in our third
year of a five-year K12 Genomics of Lung grant from the
National Heart, Lung, and Blood Institute (NHLBI), which is
increasing our ability to train young investigators in genetic
and proteomic approaches to respiratory tract diseases. A
fourth scholar started training in July 2009.
Asthma research continued its rapid growth within the
center this past year with translational and multidisciplinary
approaches. These may ultimately impact our understanding
of host gene and environmental interactions and patient
care, especially with regard to personalized medicine. In
response to the inordinate rate and severity of asthma in the
pediatric population in Washington, DC, Robert Freishtat
MD, MPH, in collaboration with Stephen Teach, MD, MPH,
of the clinical Division of Emergency Medicine and the
Center for Clinical and Community Research initiated and
expanded the Asthma Severity Modifying Polymorphisms
Project (AsthMaP) with new patients and additional funding.
They studied approximately 350 Washington, DC, area
asthmatic children to understand the genetic variations
that lead to racial disparities in chronic asthma severity,
medication responsiveness, and the effect of second-hand
smoke. Particular attention is paid to the contribution of low
vitamin D levels to asthma severity (Dr. Freishtat) and to a
secretory mucin that may be an innate immune responder to
asthmatic triggers (Mary Rose, PhD).
One of the newly recruited faculty for the Department of
Integrative Systems Biology from George Washington
University and a K12 trainee, Perry W. Payne, Jr, MD, JD, MPP,
works on novel approaches for using ancestry informative
genetic markers to create unique risk groups for asthma
severity and researching the policy implications of this new
approach for characterizing individuals in clinical research.
Mucin hypersecretion in respiratory tract diseases
The overproduction of mucins, mucin hypersecretion, in the
upper and lower respiratory tracts contributes to the morbidity
and/or mortality rates of respiratory tract diseases like asthma
and cystic fibrosis (CF). Studies on the regulation of mucin
gene expression by inflammatory mediators and of mucin
gene repression by glucocorticoids (used clinically during
asthmatic exacerbations) and macrolides (used as antibiotics
and anti-inflammatory reagents) and their subsequent effects
on chromatin remodeling of the MUC5AC mucin gene are
ongoing in the laboratory of Dr. Rose. Goblet cell hyperplasia
contributes to mucin overproduction in lung diseases like
asthma. Dr. Rose’s lab investigates pathways that lead to
goblet cell metaplasia in the IL-13 induced murine models of
allergic asthma.
Mucin hypersecretion in the upper respiratory tract has
clinical consequences in children with chronic rhinosinusitis
(CRS). This reflects submucosal gland hyperplasia in the
sinus mucosa of children with CRS, as shown by Maria
Pena, MD. Dr. Pena, an otolaryngologist, performed
microarray expression profiling on sinus mucosal tissues
from control patients, patients with CRS, and patients with
CRS/CF, and showed that previously unreported chemokines
and glandular-associated genes are markedly unregulated
in CRS patients. Drs. Rose, Wu, and Pena developed an in
vitro glandular acinar model system to investigate pathways
that lead to acinar development in respiratory tissues,
which may ultimately impact the ability to revert glandular
Mucin hypersecretion also contributes to the pathology
of otitis media (OM) in children. Mechanisms that lead to
OM are being investigated by Diego Preciado, MD, PhD,
a K12 genomics of lung scholar and otolaryngologist who
investigates the effect of cytokines, bacterial products, and
tobacco smoke on mucin gene regulation in middle ear
Image depicting drusen formation beneath the retinal pigment epithelial cells
(RPE) and the Bruch’s membrane. According to Dr. Hathout proteins secreted
by RPE cells are believed to be involved in the buildup of drusen leading to
progressive degeneration of both RPE cells and photoreceptors. (Hathout Y)
epithelial cells in vitro and in vivo. Dr. Preciado’s studies
focus on the MUC5B mucin gene, which he demonstrated is
the major mucin found in the ear secretions of patients with
chronic otitis mucoid effusion.
Lung-related diseases
Lung-related research at Children’s National continues to
increase. Dr. Freishtat leads Children’s efforts on behalf
of NIH-funded multicenter studies of genetic changes in
overwhelming infections (sepsis) in children. Additionally,
he published an important paper describing a new blood
platelet protein target for sepsis treatment. Dr. Rose served
as vice co-chair of the Gordon Research Conference
on Mucus, Cilia, and Mucociliary Interactions held at Il
Ciocco in Feb. 2009. Linda Leatherbury, MD (Division of
Cardiology), in conjunction with Iman Sami, MD (Division of
Pulmonary Medicine), showed that nasal nitric oxide levels
and ciliary dysfunction in nasal tissues are indicative of
ciliary dysfunction in congenital heart disease patients with
heterotaxy, which may represent a ciliopathy distinct from
primary ciliary dyskinesia.
CGMR | 27
Urea Cycle Disorders
The Center for Genetic Medicine Research and the
Center for Clinical and Community Research continue to
collaborate as the leading national center for the study of
rare disorders, including research on urea cycle disorders
(UCD). The strength of this program was acknowledged this
year by the CRI and Children’s National Board of Trustees
establishing the Urea Cycle Disorders Institute, directed
by Mendel Tuchman, MD, which brings together clinical
practice and translational research in these disorders.
The Institute is funded by six NIH grants on urea cycle
disorders and nitrogen metabolism. The clinical research
urea cycle disorders team (Mark L. Batshaw, MD, Dr.
Tuchman, Andrea Gropman, MD, Uta Lichter, MD, PhD,
Lauren Krivitzky, PhD, and Marshall Summar, MD) was
the top-ranked Rare Diseases Clinical Research Center in
a highly competitive NIH RFA funded in 2009. This grant
seeks to follow 550 individuals with UCD longitudinally
for 5-10 years to understand the medical and cognitive
outcome of these devastating disorders. As part of this
program Drs. Gropman and Krivitzky use neurocognitive
and neuroimaging techniques to assess the cognitive
deficits associated with these disorders. Additionally, Dr.
Lichter assembled a multicenter trial to study the value of
hypothermia as neuroprotection during hyperammonemic
coma. The program is collaborating with four biotechnology
and pharmaceutical companies to test new treatments for
these disorders.
In terms of translational research, Hiroki Morizono, PhD,
Ljubica Caldovic, PhD, Dashuang Shi, PhD, and Dr.
Tuchman discovered new protein:protein interactions among
the mitochondrial urea cycle enzymes, and explored new
extrahepatic roles of the urea cycle genes. Dr. Morizono
and Dr. Batshaw (with long-term collaborator, James Wilson,
MD, PhD, at the University of Pennsylvania) tested the
efficacy of adeno-associated virus based gene therapy for
treatment of ornithine transcarbamylase (OTC) deficiency
in a rodent model. They study newly reengineered vectors
that promise to show greater activity and more rapid onset
of gene expression. Dr. Caldovic’s laboratory showed that
increased protein load induces post-translational proteolytic
processing modification of N-acetylglutamate synthase
(NAGS) led to increased production of N-acetylglutamate
and, presumably, increased urea production. This data
confirms a model of how post-translational modification
of NAGS regulates the activity of the urea cycle. Insights
from this model better explain how patients with the
same mutation can have very different presentations of
hyperammonemia. Dr. Caldovic received an NIH K01 award
to study the molecular mechanisms regulating the amounts
28 | CGMR
of urea cycle enzymes in response to changing dietary
nitrogen loads. Dr. Shi determined the very first crystal
structures of any NAGS and uses the insights derived from
these structures to improve the quality of NAGS crystals
from other organisms. Dr. Tuchman was awarded an
R01 to study carbamylglutamate in treating patients with
Children’s National successfully recruited Dr. Summar from
Vanderbilt University to become chief of the clinical Division
of Genetics and Metabolism. Dr. Summar brings translational
studies of carbamyl phosphate synthetase deficiency, as
well as innovative work on nitric oxide in urea cycle and
related disorders.
Type 2 Diabetes, Inactivity, and Obesity
The lab of Eric Hoffman, PhD, continued a series of NIHfunded studies of genetic predispositions to metabolic
syndrome and endophenotypes of type 2 diabetes in
children and young adults. Dr. Hoffman’s group works
closely with the Obesity Institute at Children’s National
(Denice Cora-Bramble, MD, MPH, director) to develop
community-based interventions that integrate genetics and
molecular mechanistic understanding into experimental
design and research. Chiatogu Onyewu, MD, PhD, received
a prestigious UNF-Merck fellowship to pursue research
with Dr. Hoffman, as well as an NIH supplement for studies
of Howard University students with regards to metabolic
White Matter and Spinal Cord Disorders
Adeline Vanderver, MD, spearheaded research on white
matter disorders (leukodystrophies), funded by a prestigious
young investigator fellowship from the American Academy of
Neurology Foundation and by a K08 award from the National
Institute of Neurological Disorders and Stroke (NINDS). She
continued research on vanishing white matter disease, a
tragic disorder of children where a mild viral illness may
trigger sudden loss of white matter and an early death.
Using glial cell cultures, she identified basic mechanisms
for white matter destruction after cellular stress. She hopes
that this work will have implications for vanishing white
matter disease, as well as for more common disorders such
as neurotrauma. She also expanded her work to additional
leukodystrophies, including Aicardi Goutieres syndrome,
a leukodystrophy caused by inherited disturbances in the
brain’s immune system. A newly established bioregistry
for Aicardi Goutieres syndrome allowed Dr. Vanderver to
explore the molecular mechanisms of this disorder using
cultured white blood cells and measurement of immune
messengers called cytokines in patient samples. In addition,
Non-invasive brain tumor cells
Quantitative Proteomics
Invasive brain tumor cells
Protein expressed equally in
invasive and non-invasive cells
Protein expressed three times more
in invasive versus non-invasive cells
Quantitative analysis of proteins released by brain tumor cells in culture. Left image shows invasive and non-invasive brain tumor cell lines that passed through
a matrigel matrix. (Hathout Y)
Dr. Vanderver identified, with collaborators, a novel
leukodystrophy characterized by disturbances in sialic acid
metabolism, a sugar necessary for normal myelin proteins.
Finally, Dr. Vanderver developed a second opinion and
bioregistry program for the leukodystrophies, featuring a
web site that will permit collaboration between a team of
researchers describing novel leukodystrophies.
Susan Knoblach, PhD, continues analysis of a spinal cord
injury expression profiling data set. This year the analysis
shifted to data collected during the chronic phase of the
injury response. Previous work indicated that MRI and
histological changes are still occurring at the site of impact
months after spinal cord trauma, but to date, no study
has examined global molecular changes. To that end, the
database contains gene expression profiles taken at three
and six months after injury. By sorting these data according
to the functional status of the profiled animals, Dr. Knoblach
and Zuyi Wang, PhD, identified specific genes that are
associated with poor recovery and permanent paralysis, and
other genes that are associated with a return toward normal
function. The plan is to focus on some of the less well-known
genes within these groups, to determine what role they may
play in secondary injury mechanisms and in neurological
Dr. Knoblach and Bruce Lerman, a George Washington
University doctoral student, continued their work on the
role of galectins in amyotrophic lateral sclerosis (ALS).
Last year, they determined that galectin-3 likely acts as an
endogenous anti-inflammatory immunomodulator during
the progression of chronic motor neuron degeneration, and
that mice with motor neuron disease that do not express
galectin-3 develop paralysis and succumb to the disease
earlier than mice that express galectin-3. Recently, they
found that galectin-3 is directly neuroprotective, because it
prevents the death of neurons even when immune cells are
not present.
Age-related Macular Degeneration
The proteomics laboratory directed by Yetrib Hathout, PhD,
continues to implement cutting-edge technologies to
elucidate molecular mechanisms involved in human
diseases and to define therapeutic targets. This year,
one major focus of the laboratory was defining the role of
secreted proteins or “secretome” in pathologies such as age
related macular degeneration (AMD), pediatric brain tumors,
and muscular dystrophies. The laboratory established
a robust and accurate method to identify and quantify
secreted proteins using stable isotope labeling by amino
acid in cell cultures (Hathout 2007, An et al 2008).
AMD is the leading cause of blindness in the elderly
population and is characterized by macular deposits called
“drusen” that occur beneath the retinal epithelium (RPE)
and Bruch’s membrane (Figure 1). While the genetics
responsible for the disease are becoming clear, the
pathogenesis leading to drusen formation and macular
degeneration is not well understood. Dr. Hathout and his
team are defining key pathways in the RPE secretome that
might explain drusen formation and macular degeneration.
CGMR | 29
Skeletal Muscle Physiology and Genetics
Discovery of a functional variant in BMP2 gene that
controls fat levels and gains in skeletal muscle volume
Joseph M. Devaney, PhD, and Dr. Hoffman discovered
a single nucleotide polymorphism (SNP) in the bone
morphogenetic protein 2 (BMP2) gene that affects
subcutaneous fat levels and the response of skeletal muscle
to resistance training in young men. In addition, this work
was part of a collaboration with Laura L. Tosi, MD (Division
of Orthopaedics and Sports Medicine), and Melissa B.
Rogers, PhD (University of Medicine and Dentistry of New
Jersey). A common A to C single nucleotide polymorphism
(SNP) in the BMP2 gene (rs15705, +A1123C) that disrupts
a putative post-transcriptional regulatory motif (an AU-rich
element, ARE) within the human ultra-conserved sequence
was examined in the FAMUSS study. The FAMUSS study is a
multi-institutional cooperative study of young adults (average
age 24 yrs), to identify genetic variations responsible for
effects on muscle, bone, and fat mass. The study uses MRI,
muscle strength testing, and response of these variables
to 12 weeks of progressive supervised resistance training.
The C/C genotype was associated with lower baseline
subcutaneous fat volume and a gain in skeletal muscle
volume following resistance training in a cohort of young
males. The rs15705 variant explained 2 to 4 percent of interindividual variability in these phenotypes. This variant is one
of the first genetic markers that may be exploited to facilitate
early diagnosis, treatment, and/or prevention of diseases
associated with poor fitness. Furthermore, understanding the
mechanisms by which regulatory polymorphisms influence
BMP2 synthesis will reveal novel pharmaceutical targets for
these disabling conditions.
Identification of a genetic variant in the INSIG2 gene that
is associated with fat and response to training
Funda Orkunoglu-Suer, PhD, together with Drs. Hoffman and
Devaney studied a common SNP upstream of the INSIG2
gene, rs7566605 (g.-10,1025G>C) that was reported to be
associated with obesity (body mass index) in the FAMUSS
study. They found that women with a copy of the C allele
had higher levels of baseline subcutaneous fat. They did not
show the same in men but did show that men with a copy
of the G ancestral allele showed a loss of subcutaneous
fat, while those with one or two copies of the C allele
gained a greater percentage of subcutaneous fat with
resistance training. This suggests that the INSIG2 rs7566605
polymorphism underlies variation in subcutaneous adiposity
in young adult women and suppresses the positive effects
of resistance training on men. This supports and extends
the original finding that there is an association between
30 | CGMR
Normal (A) and tumor (B) sections of the first genetically engineered mouse
model of brainstem gliomas. The tumor exhibits histological characteristics of
pediatric brainstem gliomas including microvascular formation and pseudopalisading necrosis. (Nazarian J)
measures of obesity and INSIG2 rs7566605 and further
implicates this polymorphism in fat regulation.
Heart Disease
Richard J. Levy, MD, was recruited to Children’s National as
director of Cardiac Anesthesiology from New York Medical
College. Dr. Levy, funded by a K08 NIH award, investigates
mitochondrial dysfunction, and cytochrome oxidase
inhibition in the septic heart. In addition, his lab expanded
its scope to evaluate the effect of subclinical carbon
monoxide exposure on the developing brain.
Joseph Devaney, PhD, participated in a study to identify
SNPs that contribute to the development of heart attack
at an early age (men < 50 years old or women < 60 years
old). This study is part of a large multi-center Myocardial
Infarction Genetics Consortium that includes Dr. Devaney’s
collaborators at the Cardiovascular Research Institute at
the Washington Hospital Center (Stephen Epstein, MD, and
Mary Susan Burnett, PhD). This study found three newly
identified loci (21q22 near MRPS6-SLC5A3-KCNE2, 6p24
in PHACTR1, and 2q33 in WDR12) and replicated six prior
observations (9p21, 1p13 near CELSR2-PSRC1-SORT1,
10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR,
and 1p32 near PCSK9). With the identification of SNPs that
predispose individuals to heart attack, they plan to further
study the pathophysiology of the disease and recommend
lifestyle changes to avoid heart attacks.
Significant Peer Reviewed Journal Publications
n Baudy AR, Saxena N, Gordish H, Hoffman EP, Nagaraju K. A robust in vitro
screening assay to identify NF-kappaB inhibitors for inflammatory muscle
diseases. Int Immunopharmacol. 2009 Sep;9(10):1209-14. Epub 2009 Jul
21.PMID: 19596085.
n Devaney JM, Tosi LL, Fritz DT, Gordish-Dressman HA, Jiang S,
Orkunoglu-Suer FE, Gordon AH, Harmon BT, Thompson PD, Clarkson
PM, Angelopoulos TJ, Gordon PM, Moyna NM, Pescatello LS, Visich PS,
Zoeller RF, Brandoli C, Hoffman EP, Rogers MB. Differences in fat and
muscle mass associated with a functional human polymorphism in a posttranscriptional BMP2 gene regulatory element. J Cell Biochem. 2009 Aug
15;107(6):1073-82.PMID: 19492344.
n Freishtat RJ, Benton AS, Watson AM, Wang Z, Rose MC, Hoffman EP.
Delineation of a Gene Network Underlying the Pulmonary Response
to Oxidative Stress in Asthma. J Investig Med. 2009 Sep 2. Zoeller RF,
Angelopoulos TJ.
n Freishtat RJ, Nagaraju K, Jusko W, Hoffman EP. Glucocorticoid Efficacy in
Asthma: Is Improved Tissue Remodeling Upstream of Anti-Inflammation.
J Investig Med. 2009 Sep 2.
n Freishtat RJ, Natale J, Benton AS, Cohen J, Sharron M, Wiles AA, Ngor
WM, Mojgani B, Bradbury M, Degnan A, Sachdeva R, Debiase LM,
Ghimbovschi S, Chow M, Bunag C, Kristosturyan E, Hoffman EP. Sepsis
alters the megakaryocyte-platelet transcriptional axis resulting in granzyme
B-mediated lymphotoxicity. Am J Respir Crit Care Med. 2009 Mar
n Haskins N, Panglao M, Qu Q, Majumdar H, Cabrera-Luque J, Morizono
H, Tuchman M, Caldovic L. Inversion of allosteric effect of arginine on
N-acetylglutamate synthase, a molecular marker for evolution of tetrapods.
BMC Biochem. 2008 Sep 18;9:24.
n Kesari A, Fukuda M, Knoblach S, Bashir R, Nader GA, Rao D, Nagaraju
K, Hoffman EP. Dysferlin deficiency shows compensatory induction of
Rab27A/Slp2a that may contribute to inflammatory onset. Am J Pathol.
2008 Nov;173(5):1476-87. Epub 2008 Oct 2.PMID: 18832576.
n Kesari A, Neel R, Wagoner L, Harmon B, Spurney C, Hoffman EP. Somatic
mosaicism for Duchenne dystrophy: evidence for genetic normalization
mitigating muscle symptoms. Am J Med Genet A. 2009 Jul;149A(7):1499503.PMID: 19530190.
n Mew NA, Payan I, Daikhin Y, Nissim I, Nissim I, Tuchman M, Yudkoff
M. Effects of a single dose of N-carbamylglutamate on the rate of
ureagenesis. Mol Genet Metab. 2009 Dec;98(4):325-30. Epub 2009 Jul 14.
n Min L, Jin Z, Caldovic L, Morizono H, Allewell NM, Tuchman M, Shi D.
Mechanism of allosteric inhibition of N-acetyl-L-glutamate synthase by
L-arginine. J Biol Chem. 2009 Feb 20;284(8):4873-80. Epub 2008 Dec 18.
n Orkunoglu-Suer FE, Gordish-Dressman H, Clarkson PM, Thompson PD,
Angelopoulos TJ, Gordon PM, Moyna NM, Pescatello LS, Visich PS,
Zoeller RF, Harmon B, Seip RL, Hoffman EP, Devaney JM. INSIG2 gene
polymorphism is associated with increased subcutaneous fat in women
and poor response to resistance training in men. BMC Med Genet. 2008
Dec 23;9:117.PMID: 19105843.
n Pistilli EE, Devaney JM, Gordish-Dressman H, Bradbury MK, Seip RL,
Thompson PD, Angelopoulos TJ, Clarkson PM, Moyna NM, Pescatello
LS, Visich PS, Zoeller RF, Gordon PM, Hoffman EP. Interleukin-15 and
interleukin-15R alpha SNPs and associations with muscle, bone, and
predictors of the metabolic syndrome.Cytokine. 2008 Jul;43(1):45-53.
Epub 2008 Jun 2.PMID: 18514540.
n Reeves EK, Gordish-Dressman H, Hoffman EP, Hathout Y. Proteomic
profiling of glucocorticoid-exposed myogenic cells: Time series
assessment of protein translocation and transcription of inactive mRNAs.
Proteome Sci. 2009 Jul 30;7:26.PMID: 19642986.
n Spurney CF, Gordish-Dressman H, Guerron AD, Sali A, Pandey GS,
Rawat R, Van Der Meulen JH, Cha HJ, Pistilli EE, Partridge TA, Hoffman
EP, Nagaraju K. Preclinical drug trials in the mdx mouse: assessment
of reliable and sensitive outcome measures. Muscle Nerve. 2009
May;39(5):591-602.PMID: 19260102.
n Spurney CF, Knoblach S, Pistilli EE, Nagaraju K, Martin GR, Hoffman EP.
Dystrophin-deficient cardiomyopathy in mouse: expression of Nox4 and
Lox are associated with fibrosis and altered functional parameters in the
heart. Neuromuscul Disord. 2008 May;18(5):371-81. Epub 2008 Apr
25.PMID: 18440230.
n Thompson BC, Wenta MR, Price TB, Thompson PD, Moyna NM, Seip RL,
Clarkson PM, Gordon PM, Pescatello LS, Devaney JM, Gordish-Dressman
H, Hoffman EP, Visich PS. Vascular Remodeling in Response to 12 wk of
Upper Arm Unilateral Resistance Training. Med Sci Sports Exerc. 2009 Oct 6.
n Tuchman M, Caldovic L, Daikhin Y, Horyn O, Nissim I, Nissim I, Korson
M, Burton B, Yudkoff M. N-carbamylglutamate markedly enhances
ureagenesis in N-acetylglutamate deficiency and propionic acidemia as
measured by isotopic incorporation and blood biomarkers. Pediatr Res.
2008 Aug;64(2):213-7.
n Tuchman M, Lee B, Lichter-Konecki U, Summar ML, Yudkoff M,
Cederbaum SD, Kerr DS, Diaz GA, Seashore MR, Lee HS, McCarter RJ,
Krischer JP, Batshaw ML. Cross-sectional multicenter study of patients
with urea cycle disorders in the United States. Urea Cycle Disorders
Consortium of the Rare Diseases Clinical Research Network. Mol Genet
Metab. 2008 Aug;94(4):397-402. Epub 2008 Jun 17.
n Walsh S, Kelsey BK, Angelopoulos TJ, Clarkson PM, Gordon PM, Moyna
NM, Visich PS, Zoeller RF, Seip RL, Bilbie S, Thompson PD, Hoffman EP,
Price TB, Devaney JM, Pescatello LS. CNTF 1357 G -> A polymorphism
and the muscle strength response to resistance training. J Appl Physiol.
2009 Oct;107(4):1235-40. Epub 2009 Jul 23.PMID: 19628720.
n Yao Z, Hoffman EP, Ghimbovschi S, Dubois DC, Almon RR, Jusko WJ.
Pharmacodynamic/Pharmacogenomic modeling of insulin resistance genes
in rat muscle after methylprednisolone treatment: exploring regulatory
signaling cascades. Gene Regul Syst Bio. 2008 Apr 23;2:141-61.PMID:
n Yokota T, Takeda S, Lu QL, Partridge TA, Nakamura A, Hoffman EP.
A renaissance for antisense oligonucleotide drugs in neurology: exon
skipping breaks new ground. Arch Neurol. 2009 Jan;66(1):32-8. Review.
PMID: 19139297.
CGMR | 31
Battling sepsis through
epsis is an illness that results when the
body’s immune system works to fight a
bacterial infection that overwhelms normal
blood processes. It is the tenth leading cause
of death in the United States with more than
40 percent of sepsis cases resulting in fatality.
Unfortunately, this percentage has not improved in
decades despite other medical advances. In most
of these cases, organ failure is the primary cause
of death. Robert Freishtat, MD, MPH, a researcher
at the Center for Genetic Medicine Research at
Children’s National, led a study that identified a
previously unknown contributor to organ failure in
patients suffering from sepsis.
The findings, published in the American Journal of
Respiratory and Critical Care Medicine, is the first
time doctors have looked at and linked platelets to
poor outcomes from this often fatal infection.
Through gene and protein analyses in septic mice
and humans, Dr. Freishtat and his team found that
in severe cases the platelets had genes that were
triggered to produce granzyme B. Past research
shows that granzyme B is a protein that contributes
to cell death as a part of the body’s immune
response to cancer and viruses.
32 | CGMR
“Detection of granzyme B in platelets could be
a huge step forward in battling sepsis,” said Dr.
Freishtat. “First, as a prognosis indicator, the
protein’s presence could show more aggressive
treatments are needed right off the bat. Eventually
perhaps this knowledge will help us find a way
to prevent organ failure by targeting interventions
directly at the platelets and granzyme B
During sepsis platelets collect within major organs
including the spleen, which is an important
infection-fighting organ. As these platelets collect,
they come into contact with the organ’s cells, and
the granzyme B, if present, will cause the organ’s
cells to die. Previous research shows that this may
be a major contributor to organ failure.
This is the first time that doctors have looked
at and linked platelets to poor and potentially
fatal outcomes from sepsis. “Now we know that
platelets, which we previously believed to be
‘innocent bystanders,’ can actually contribute to the
development of fatal complications from sepsis,”
said Dr. Freishtat. “We can use this knowledge to
better gauge someone’s risk of dying and to design
new interventions.” n
Center for
neuroscience Research
Vittorio Gallo, PhD (left)
Wolf-Pack Chair in Neuroscience, Professor of Pediatrics and Pharmacology
William Davis Gaillard, MD, PhD (right)
Associate Director
Professor of Pediatrics and Neurology
Maria Acosta, MD
Candice A. Alfano, PhD
Laura Anthony, PhD
Madison Berl, PhD
Li-Jin Chew, PhD
Joshua Corbin, PhD
Gerard Gioia, PhD
Penny Glass, PhD
Andrea Gropman, MD
Tarik F. Haydar, PhD
Richard A. Jonas, MD
Parmajit T. Joshi, MD
Lauren Kenworthy, PhD
Lauren Krivitzky, PhD
Uta Lichter-Konecki, MD
Roger J. Packer, MD
Phillip L. Pearl, MD
Jay A. Salpekar, MD
Billie Lou Short, MD
Chandan J. Vaidya, PhD
Louis-Gilbert Vezina, MD
Hui Xie, MD, PhD
Irene Zohn, PhD
The image shows a myelinating cell—
the oligodendrocyte—labeled in green.
The processes of this cell make contacts
with and myelinate several axons
(labeled in red). (Gallo V)
To understand the development of
the central nervous system and the
cellular and molecular mechanisms
of brain dysfunction to prevent or
treat neurological and behavioral
disorders of childhood.
Strategic Plan Accomplishments
n Establish a translational and clinical research program on
perinatal hypoxia and brain injury. This program was
established with the support of a new NIH P01 program
project grant together with the Child Study Center at Yale
n Establish a translational research program in epilepsy.
The center recruited an investigator in basic epilepsy
research, Molly Huntsman, PhD, who works on inhibition/
excitation in epilepsy and on the physiology of inhibitory
neural circuits in Fragile X mouse mutants.
Major Strategic Goals
To establish a translational and clinical
research program on perinatal hypoxia
and brain injury.
To establish a translational research
program in epilepsy.
To continue to expand our neuroimaging
program to include autism and traumatic
brain injury.
To establish research projects in animal
models of perinatal hypoxia and hyperoxia,
Down syndrome, and Fragile X syndrome/
34 | CNR
n Develop new basic/translational research components of the
program in brain protection studies. The center is working to
conduct neuroprotection studies in the Neonatal Intensive
Care Unit (NICU).
n Expand our neuroimaging program to include autism and
traumatic brain injury. The center significantly expanded
functional imaging initiatives in traumatic brain injury, autism,
urea cycle disorders, and epilepsy by adding studies
supported by the Singer Foundation, Medstar, the Gudulsky
Foundation, and internal awards.
n Establish research projects in animal models of perinatal
hypoxia and hyperoxia, Down syndrome, and Fragile X
syndrome/autism. All these projects have been established
and are supported by NIH awards. These projects are
expanding to include behavioral studies in animal models.
n Recruited new young investigators.
• Molly Huntsman, PhD, from Georgetown University, studies
brain function and dysfunction in neurodevelopmental
• Judy Liu, MD, PhD, from Harvard Medical School,
studies cytoskeletal regulation of transport in neurons
and trafficking through the secretory pathway in neuronal
Programmatic Areas and Accomplishments
The research program of the Center for Neuroscience
Research can be divided into eight major programmatic
Developmental Neurobiology
Neural stem cells
Neural stem cells are present in both the embryonic and
postnatal brain, can self-renew, and are able to generate
all the major cell types within the central nervous system.
Tarik Haydar, PhD, continues his studies on neural stem
cell development in the cerebral cortex, and established
new approaches to continuously express neural genes
to alter the functional and physiological properties of
specific populations of progenitors and neurons in the
developing brain. His studies have uncovered fundamental
cellular and functional differences between distinct neural
stem cell populations of the ventricular zone. Dr. Haydar
and his team also are performing direct labeling and
molecular perturbation of hippocampal neural stem cells in
combination with electrophysiological studies on excitatory
neurons during prenatal and postnatal development. These
studies make use of a novel technique developed by the
Haydar lab to specifically target hippocampal pyramidal
neurons. This work will characterize the role of brain-derived
neurotrophic factor (BDNF) on development and function
of the hippocampus and will have particular relevance to
learning disabilities and epilepsy. Joshua Corbin, PhD,
is interested in understanding the relationship between
amygdala progenitor cell specification and physiology,
and continues a very productive collaboration with Molly
Huntsman, PhD, recently recruited to the center from
Georgetown University. Their studies identified a previously
unknown progenitor pool dedicated to the limbic system.
These cells give rise to a unique subclass of inhibitory
neurons in the amygdala. Vittorio Gallo, PhD, studies
intrinsic and extrinsic signals that regulate development
of multipotential progenitors in the perinatal and adult
brain. His laboratory is extending these studies to animal
models of brain injury and disease, including demyelinating
disorders of the white matter and white matter injury
after perinatal hypoxia. Adan Aguirre, PhD, supported by
an NIH-National Institute of Neurological Disorders and
Stroke (NINDS) K99 “Pathway to Independence Award,”
in collaboration with Dr. Gallo, continued his studies on
the generation of oligodendrocytes from different neural
progenitor populations in the developing and adult brain,
and their potential to repair demyelinating lesions.
Neural stem cells of the mouse embryonic neocortex expressing red fluorescent protein after being transfected with DNA using in utero surgery. Their
DNA is also stained in green if they are undergoing cell division. (Haydar T)
Myelin and white matter development
Myelin formation during postnatal brain development
represents one of the most crucial steps in the
establishment of mature white matter and of fully functional
connections between neurons. Dr. Gallo and Li-Jin
Chew, PhD, continue to study new cellular and molecular
approaches that promote oligodendrocyte maturation,
myelination, and white matter development. Dr. Chew
continues to study signal transduction pathways that
regulate oligodendrocyte development in cultured cells
and in transgenic mice. The focus of these studies is on
mechanisms that promote oligodendrocyte progenitor
differentiation and developmental myelination. Drs. Gallo
and Haydar continue their collaboration utilizing advanced
microscopic technology to study oligodendrocyte
progenitor cell migration during normal development and
during remyelination after injury. In collaboration with the
Center for Genetic Medicine Research, Drs. Gallo and
Chew completed a larger molecular screening of novel
oligodendrocyte regulatory genes by microarray analysis
and identified downstream targets of specific transcription
factors that regulate oligodendrocyte development.
CNR | 35
and progenitor cells during prenatal development of the
cerebral cortex. These studies use DNA expression and
recombination (molecular fate mapping) to label and
track neural precursors in their intact environment in the
developing brain. 2) Embryonic studies on the Ts65Dn
mouse model of Down syndrome have demonstrated
that prenatal development of the cerebral cortex and
hippocampus is delayed, resulting in fewer synaptic
contacts in these forebrain areas after birth. Recently, the
Haydar lab found that certain types of inhibitory interneurons
also are over-produced in the Ts65Dn fetal brain and have
found two genes which are triplicated in Ts65Dn and Down
syndrome that cause this defect.
Iron is required for neural tube development. Mutation of an iron transporter
essential for delivery of iron to the developing embryo results in neural tube
defects including exencephaly, spina bifida, microphthalmia, and forebrain
truncations. Forebrain truncations can be mimicked by culture of wildtype
embryos in iron chelators during a critical developmental time window.
Top left: E13.5 wildtype mouse embryo; Top right: !3.5 Fpn1 mutant embryo;
Bottom left: in situ hybridization of E8.5 wildtype embryo showing Six3
expression in the forebrain; Bottom right: Six3 expression is reduced when
cultured with iron chelator. (Zohn I)
Cerebral cortex development
It is widely accepted that proper cognitive development in
humans is dependent upon appropriate interactions with
one’s environment through sensorial exploration, didactic
training, and social experience. However, evidence has
shown that cognitive ability also is specified by a genetic
component. This is most readily seen in the increasing
number of reports linking genetic abnormalities to various
forms of mental retardation. Cognitive performance
depends, in large part, on proper prenatal development of
the cerebral cortex. More specifically, cortical growth must
proceed at a specific tempo and certain milestones must be
achieved to enable proper connections between the cortex
and other brain structures. Studies in the laboratory of Dr.
Haydar investigate the molecular controls of neural stem
cell development in the mammalian forebrain. Research on
cortical development in the Haydar lab is broadly classified
in two areas: 1) Molecular labeling of neural stem cells in
utero is combined with laser-scanning imaging to define
the proliferative and lineage identity of different stem cells
36 | CNR
Neural tube development
Neural tube defects are one of the most common
developmental malformations in humans with poorly
understood underlying causes. From studies in model
organisms including the mouse, we are beginning to gain
insight into the pathways that are critical for proper neural
tube closure. Irene Zohn, PhD, established a vigorous
research program in this area. She obtained funding
from the NIH, the March of Dimes, and the Spina Bifida
Foundation to study pathways regulating growth, patterning,
and morphogenesis of not only the neural tissue, but also
the surrounding epithelium and mesenchyme. These tissues
are essential for neural tube closure. While these studies
have implicated many genes, it is clear that we only know
the identity of a fraction of the candidate genes for human
neural tube defects. Furthermore, detailed mechanisms
of how mutation of these genes results in neural tube
defects has been investigated for only a few of these
candidates. These experiments promise to provide a greater
understanding of the molecular pathways, which when
disrupted, contribute to human birth defects. In addition,
these studies demonstrate that iron, in addition to folic acid,
is an important nutrient to prevent neural tube defects.
Validation of these results with clinical trials and promotion
of periconception multivitamin usage has the potential to
further reduce the incidence of neural tube defects.
Amygdala development and dysfunction
The mammalian basal telencephalic limbic system is
comprised of a number of structures that are involved
in the regulation of complex emotional and motivational
behaviors. The most prominent of these is the amygdala,
which regulates specific aspects of emotional memory,
attention, and appropriate responses to environmental
stimuli. Dr. Corbin studies the cellular and genetic processes
that govern normal development of the amygdala, as well
as the underlying defects in these processes that occur
during developmental disorders, such as autism spectrum
disorders. Specifically, Dr. Corbin and his lab focus on
understanding the genetic and cellular pathways involved
in the generation of inhibitory neurons of the amygdala from
progenitor cells in the embryonic brain, and the mechanisms
regulating formation of inhibitory synaptic connections of
neurons generated from these progenitors. In relation to
autism spectrum disorders, one or more of these normal
developmental processes are altered, which results in
specific aspects of the behavioral defects characteristic of
this disorder. These studies ultimately aim to understand
the link between developmental events and the assembly
and function of the mature amygdala at a genetic, cellular,
structural, and functional level. From these studies, the
hope is to not only elucidate the normal mechanisms of
brain development, but also gain a greater understanding
of the etiology of developmental disorders, such as autism
spectrum disorders, in which development of the amygdala
is significantly affected.
Developmental Disabilities
Intellectual and Developmental Disabilities Research
Center (IDDRC)
This National Institute of Child Health and Human
Development (NICHD) funded center, directed by Vittorio
Gallo, PhD, continues to support five scientific core
resources used by more than 90 NIH funded investigators
studying brain development and function, and various
aspects of neurodevelopmental disorders at George
Washington University, Georgetown University, and
Children’s National. The activities of IDDRC investigators are
distributed among seven areas of research, corresponding
to different IDD-associated conditions: autism, brain
tumors, epilepsy, neuromuscular disease, brain injury,
urea cycle disorders, and white matter disorders. In each
of these areas, genetic, translational neuroscience, and
behavioral science programs are integrated to provide
a multidisciplinary approach to each research theme.
The seven areas of research are strongly supported by
the following scientific cores: the Molecular Genetics
and Proteomics Core, the Cellular Imaging Core, the
Neuroimaging Core, the Neurobehavioral Evaluation Core,
and the Biostatistics and Informatics Core. Each of these
cores has grown based on steady institutional investment
on infrastructure, personnel, state-of-the-art equipment,
and software. The Cellular Imaging, Neuroimaging, and
Neurobehavioral Evaluation Cores are all part of the Center
for Neuroscience Research and are directed by Tarik
Haydar, PhD, Willilam Gaillard, MD, and Gerard Gioia, PhD,
Embryonic progenitor cells marked in blue are observed pooling in the region
of the brain that will later become the amygdala. These cells will differentiate
into a combination of inhibitory and excitatory neurons. (Corbin J)
Brain Injury and Brain Protection
Traumatic brain injury (TBI) is the leading cause of acquired
brain damage in children, producing persistent functional
disability. The response to and recovery from TBI differs in
adults and children. Brain damage from TBI is determined
not only by direct mechanical injury to neural structures,
but also by delayed axonal degeneration and neuronal
apoptosis. The overall goal of this research project is to
determine if fundamental differences in the molecular
pathways that produce neuronal death are related to brain
maturity. Gerard Gioia, PhD, and his team adapted for
children four cognitive rating scales originally established to
assess adults following mild TBI, and tested them in 2,200
children. Dr. Gioia will direct a new multi-center study CDC
TBI grant awarded this year: Feasibility of Acute Concussion
Evaluation System (FACES) in the Emergency Department.
Addtionally, the team completed a five-year CDC Mild
TBI grant that recruited more than 2,200 participants
and developed four new clinical/ research measures.
Lauren Krivisky, PhD, and her collaborators at National
Rehabilitation Hospital are investigating the structural and
functional consequences of mild TBI on brain structure
CNR | 37
VBM Difference maps of two patients, one with typical (top) and the other with atypical language dominance (bottom). Left image, left brain. (Gaillard W)
and function with functional MRI and Diffusion Tensor
Imaging. Phillip Pearl, MD, completed a feasibility and
phamacokinetic study of leviteracitam, a new anti-epileptic
drug (AED) in preventing epilepsy following mild TBI.
Richard Jonas, MD, continues his program in researching
neuroprotection during congenital heart surgery, including
white matter injury prevention. Drs. Gallo and Chew are
studying signals that induce reactive gliosis after injury.
Taeun Chang, MD, Tammy Tsuchida, MD, PhD, and Stephen
Baumgart, MD, continue investigations of hypothermia to
ameliorate hypoxic ischemic encephalopathy in neonates.
They use an array of imaging and electrophysiological
techniques to monitor and guide therapy. Andrea Gropman,
MD, uses magnetic resonance spectroscopic imaging
(MRS) to examine brain based metabolic perturbations
hypothesized to cause subcortical cognitive deficits
in heterozygotes with the urea cycle disorder ornithine
transcarbamylase deficiency (OTC).
Perinatal Hypoxia and Hyperoxia
Preterm birth is a major pediatric public health concern.
Today, as many as 1 to 2 percent of all live births are
preterm; the survival rate of these infants is 85 to 90 percent,
however as many as 30-50 percent of children that survive
preterm birth have a high incidence of cerebral palsy,
38 | CNR
intellectual disability, and other cognitive handicaps. While
some prematurely-born children progressively improve, a
significant percentage still suffer major cognitive deficits,
as many have repeated a grade by age 8, and more than
50 percent receive special help at school. Circulatory
disturbances and oxygen deprivation are the two major
causes of neurodevelopmental impairments in these
children. Hypoxia, due to lung immaturity and respiratory
disturbances, is an important mechanism underlying these
devastating neurological complications at this critical time
in development. The research program on perinatal hypoxia
and brain injury is a collaborative effort between Dr. Gallo’s
research team and Flora Vaccarino, MD (Child Study Center,
Yale University), together with a group of investigators at
Yale. Joseph Scafidi, MD (supported by the NINDS funded
Neurological Sciences Academic Development Award
Program at Children’s National directed by Roger Packer,
MD), and Beata Jablonska, PhD, are using a clinically
relevant mouse model of chronic sublethal hypoxic injury to
study the developing brain. This model reproduces all the
brain injury landmarks found in children, including cognitive
behavioral abnormalities. Animal studies are combined with
clinical research on premature babies and with post-mortem
human brain tissue. Thomas Schmitz, MD, a visiting scholar
to the Center for Neuroscience Research from the Charité
Pediatric Hospital (Berlin, Germany) established a research
Axial slices of whole brain activation for ADDT task. Yellow represents the activation for all 64 children age 4-12 years old (FWE, p<.05). Blue represents activation unique to the youngest age group (t-test p<.001, uncorrected). Green represents activation that is significantly greater in the 4-6 year old group and overlaps with the group map. The limited significant differences for both the older age groups are not visible on this display. Both of the older groups do not activate
any area of yellow differently. Axial slices are in neurological convention (left is left hemisphere). (Gaillard W)
project on the cellular effects of hyperoxia on white matter
Epilepsy affects 1 to 2 percent of all children and 8
percent will experience one seizure before adulthood. The
Comprehensive Pediatric Epilepsy Program (CPEP) is a
multidisciplinary group designed to provide clinical care
and conduct clinical research into the origins, impact, and
treatment of epilepsy in children. This multidisciplinary team
has active research in: 1) neuroimaging of seizure disorders;
2) mood and anxiety disorders in epilepsy populations;
3) identification and evaluation of recent onset epilepsy;
4) medication trials; and 5) development of coping and
socialization skills in children with epilepsy. Jay Salpekar,
MD, is exploring mood, anxiety, and attention deficit
disorders in children with epilepsy. The study should lead to
the development of new models for the interrelationship of
epilepsy and mood/anxiety disorders, and to new treatment
intervention strategies. Sandra Cushner-Weinstein, MSW,
continues her studies that examine the effect of camp
on functional adaptability in children with epilepsy and
expanded these models to neurofibromatosis, Tourette
syndrome, and Asperger disorder. Phillip Pearl, MD,
continues his research on the GABAergic mechanisms of
epileptogenicity in the inborn error of metabolism, succinic
semialdehyde dehydrogenase deficiency. This project is a
collaborative effort with William H. Theodore, MD, at NINDS,
and Michael Gibson, PhD, at Oregon Health Sciences
University, funded through a recent Bench to Bedside grant.
Experimental therapeutics continues to play an important
role in the epilepsy program. Joan Conry, MD, in addition
to participation in several new industry-sponsored trials,
plays a leading role in the recently concluded nationwide
study that evaluates the efficacy and pharmaco-genomics
of ethosuximide, lamotrigine, and valproate, in childhood
absence epilepsy. William Gaillard, MD, in collaboration
with Gerard Gioia, PhD, Chandan Vaidya, PhD, and
Madison Berl, PhD, investigates the functional organization
of language networks in children. Their studies suggest
that “reorganization” of language networks is linked to the
underlying substrate rather than to epilepsy presenting
CNR | 39
before age six. Dr. Berl performs fMRI studies of working
memory and language in children with epilepsy, funded
through a K-12 Award. Dr. Gaillard leads an international
and national consortium of pediatric epilepsy centers to
use fMRI and other imaging modalities to evaluate children
with refractory epilepsy and to investigate factors that
underlie plasticity of cognitive functions. Dr. Gaillard also
works with Barbara Kroner, PhD, (RTI International) on an
epidemiological and quality of life study in Washington, DC.
The epilepsy program holds the nation’s largest database
of children with new onset epilepsy. Findings from this
database are being used to inform clinical practice in the
care of infants with newly diagnosed epilepsy.
Brain tumors are the most common solid cancers of
childhood. Roger Packer, MD, senior vice president of
Children’s clinical Center for Neuroscience and Behavioral
Medicine, continues to orchestrate national multidisciplinary
neuro-oncological clinical research. Children’s National
continues to be a leading institution with continuous
funding through the Pediatric Brain Tumor Consortium,
which received a new five-year funding agreement from the
National Cancer Institute (NCI) and Children’s Oncology
Group. The neuro-oncology program is pursuing innovative
translational research in childhood low-grade gliomas,
brain stem gliomas, medulloblastomas, ependymomas,
and malignant glial tumors. Results of a recent trial of
bevacizumab and irinotecan for treatment of recurrent
low grade gliomas will likely change how these tumors
are treated. Dr. Packer continues his research activities in
neurofibromatosis type 1 (NF-1), a neurogenetic disease
that has a host of manifestations including malignant
and pre-malignant entities and is group chair of the
Neurofibromatosis Clinical Consortium, a cooperative
group of institutions funded in 2007 by the Department
of Defense to perform translation studies for children and
adults with neurofibromatosis. The Consortium opened the
first prospective randomized therapeutic trial for children
with neurofibromatosis and learning disabilities, utilizing a
drug (lovastatin) that inhibits the RAS/MAP kinase pathway.
The drug reversed learning disabilities in adult mice with
neurofibromatosis type 1. Maria Acosta, MD, is the vice
chair for this national study. This study is being extended
to functional imaging studies of medication response. Dr.
Acosta continues collaborative work with Kathryn North,
PhD, (Sydney, Australia) as site Primary Investigator for
phenotyping of early cognitive profiles in NF-1 children and
studies on their executive function.
40 | CNR
Attention Deficit Hyperactive Disorder (ADHD)
and Mood Disorders
Gerard Gioia, PhD, developed and validated measures to
assess executive function in young children—an extension
of his Behavioral Rapid Inventory of Executive Functions
(BRIEF). Chandan Vaidya, PhD, continues her work using
functional neuroimaging to study working memory and
attention in children with ADHD, and response to treatment
in relation to genetic differences in the dopamine transporter.
Adelaide Robb, MD, will extend her work in the treatment of
mood disorders as a member of the NICHD collaborative
effort to evaluate the use of lithium in the treatment of
childhood bipolar disorder. Dr. Robb also conducts several
therapeutic trials in children with ADHD, bipolar disorder,
and schizophrenia.
Autism Spectrum Disorders
The Center for Autism Spectrum Disorders (CASD), led by
Lauren Kenworthy, PhD, continues cognitive and functional
imaging studies, the latter directed by William Gaillard, MD,
supported by generous gifts from the Fred and Elizabeth
Singer Foundation and the Gudulsky Foundation. A new gift
from the Fred and Elizabeth Singer Foundation supports
collaborative research efforts with Vinod Menon, PhD,
at Stanford University, Drs. Vaidya, Gaillard, and Angela
Bollich continue their collaborative work with Maximillian
Reisenhuber, PhD (Georgetown University), investigating
the neurobiology of face processing in adults with autism.
These programs use functional imaging to elucidate the
neurobiology of autism spectrum disorders (ASD). Dr.
Kenworthy continues pursuing studies with Alex Martin,
PhD, in the intramural NIMH program, to examine emotional
processing in older patients with Asperger disorder, and
expanded studies to include genetic mechanisms of
disease with Eric Hoffman, PhD, and Ben Yerys, PhD, a
former T32 IDDRC fellow who joined the faculty this year.
Dr. Yerys is using fMRI and diffusion tensor imaging (DTI)
to investigate cognitive flexibility in children with ASD. Dr.
Robb continues to investigate the effectiveness of new
antipsychotics in ASD and, with Dr. Hoffman, is investigating
the genetic predispositions of adverse effects of older
generation antipsychotics in at risk children. Dr. Kenworthy
and Laura Anthony, PhD, received an Autism Supplement to
the Leadership Education in Neurodevelopmental Disorders
(LEND) program and continue to develop practical
intervention programs based on executive function models
with Ivymount School in Rockville, MD.
Significant Peer Reviewed Journal Publications
n Armstrong GT, Liu Q, Yasui Y, Huang S, Ness KK, Leisenring W, Hudson
MM, Donaldson SS, King AA, Stovall M, Krull KR, Robison LL, Packer RJ.
“Long-term outcome among adult survivors of childhood central nervous
system malignancies: A report from the Childhood Cancer Survivor Study.”
JNCI. 2009;101:946-958.
n Bennett IJ, Madden DJ, Vaidya CJ, Howard DV, Howard JH Jr. ”Age-related
differences in multiple measures of white matter integrity: A diffusion
tensor imaging study of healthy aging.” Hum Brain Mapp. 2009, Aug 6.
[Epub ahead of print].
n Chronis-Tuscano A, Seymour KE, Stein MA, Jones HA, Jiles CD, Rooney
ME, Conlon CJ, Efron LA, Wagner SA, Pian J, Robb AS. “Efficacy of
osmotic-release oral system (OROS) methylphenidate for mothers
with attention-deficit/hyperactivity disorder (ADHD): preliminary report
of effects on ADHD symptoms and parenting.” J Clin Psychiatry.
n Conry JA, Ng YT, Paolicchi JM, Kernitsky L, Mitchell WG, Ritter FJ, Collins
SD, Tracy K, Kormany WN, Abdulnabi R, Riley B, Stolle J. “Clobazam in
the treatment of Lennox-Gastaut syndrome.” Epilepsia. 2009;50:1158-66.
n Corbin JG, Gaiano N, Juliano SL, Poluch S, Stancik E, Haydar TF.
“Regulation of neural progenitor cell development in the nervous system.”
J Neurochem. 2008 Sep;106(6):2272-87. Review.
n deBont J, Packer R, Michiels E, et al. “Biologic background of pediatric
medulloblastoma and ependymoma: A review from a translational research
standpoint.” Neurooncology. 2008;10:1040-1060.
n Wells EM, Walsh KS, Khademian ZP, Keating R, and Packer RJ. “The
Cerebellar Mutism Synmdrome and its relation to cerebellar cognitive
function and the cerebellar cognitive affective disorder.” Dev Disabil Res
Rev. 2008;14: 221-228.
n Gadea A, Schinelli S, Gallo V. “Endothelin-1 regulates astrocyte
proliferation and reactive gliosis via a JNK/c-Jun signaling pathway.”
J Neurosci. 2008;28:2394-2408.
n Gioia GA, Collins M, Isquith PK. “Improving identification and diagnosis
of mild traumatic brain injury with evidence: psychometric support for the
acute concussion evaluation.” J Head Trauma Rehabil. 2008;23:230-42.
n Gropman, AL, Sailasuta, N, Harris, KC, Abulseoud, O, Ross, BD. “Ornithine
Transcarbamylase Deficiency with Persistent Abnormality in Cerebral
Glutamate Metabolism in Adults.” Radiology. Jun 30. [Epub ahead of print]
n Lim YM, Cho YW, Shamim S, Solomon J, Birn R, Luh WM, Gaillard
WD, Ritzl EK, Theodore WH. “Usefulness of pulsed arterial spin labeling
MR imaging in mesial temporal lobe epilepsy.” Epilepsy Research.
n Loulier K, Lathia JD, Martiens V, Relucio J, Mughal MR, Tang S-C,
Coksaygan T, Hall PE, Chigurupati S, Patton B, Colognato H, Rao MS,
Mattson MP, Haydar TF, and ffrench-Constant C. “beta1 integrin maintains
integrity of the embryonic neocortal stem cell niche.” PLoS Biology. 2009
Aug;7(8);e1000176. Epub 2009 Aug 18.
n Loulier K, Lathia JD, Martiens V, Relucio J, Mughal MR, Tang S-C,
Coksaygan T, Hall PE, Chigurupati S, Patton B, Colognato H, Rao MS,
Mattson MP, Haydar TF, and ffrench-Constant C. “Laminin-binding
integrins are essential for anchorage of neocortical neural stem cells to the
ventricular surface.” PLoS Biology. 2009. In press.
n Mbwana J, Berl M, Ritzl EK, Rosenberger L, Mayo J, Weinstein S, Conry,
JA, Pearl, PL, Shamim, S, Moore, EN, Sato, S, Vezina, LG, Theodore, WH,
Gaillard, WD Brain. 2009, 132: 347-56.
n Pearl PL, Gibson KM, Cortez MA, Wu Y, Snead OC, Knerr I, Forester K,
Pettiford JM, Jakobs C, Theodore WH. “Succinic semialdehyde
dehydrogenase deficiency: Lessons from Mice and Men.” J Inherit Metab
Dis. 2009;32: 343-352.
n Pearl PL, Vezina LG, McCarter R, Molloy-Wells E, Trzcinski S, Saneto
RP, McClintock WM, Conry JA, Weinstein SL, Elling NJ, Goodkin HP,
Sotero de Menzes M, Miller IO, Ferri R, Gilles E, Gaillard WD. “Cerebral
MRI Abnormalities Associated with Vigabatrin Therapy.” Epilepsia.
n Rosenberger LR, Zeck J, Berl MM, Moore EN, Ritzl EK, Shamin S,
Weinstein SL, Conry JA, Pearl PL, Sato S, Vezina LG, Theodore WH,
Gaillard WD. “fMRI Evidence for Inter and Intra-hemispheric Language
Re-organization in Complex Partial Epilepsy.” Neurology. 2009;72:18301836.
n Yerys BE, Jankowski KF, Shook DA, Rosenberger LR, Barnes KA, Berl MM,
VanMeter JW, Ritzl EK, Vaidya CJ, Gaillard WD. “The fMRI success rate of
children and adolescents: typical development, epilepsy, attention deficit/
hyperactivity disorder, and autism spectrum disorders.” Human Brain
Mapping. 2009 Apr 21. [Epub ahead of print]
n Hirata T, Li P, Lanuza GM, Cocas LA, Huntsman MM, Corbin JG.
“Identification of distinct telencephalic progenitor pools for neuronal
diversity in the amygdala.” Nat Neurosci. 2009;12:141-9.
n Kenworthy, L, Yerys, BE, Anthony, L, Wallace, GL. “Understanding
executive control in autism spectrum disorders in the lab and in the real
world.” Neuropsychology Review. 2008;18: 320-338.
n Lee, PS, Yerys, BE, Della Rosa, A, Foss-Feig, J, Barnes, KA, James,
J.D, VanMeter, J, Gaillard, WD, Vaidya, CJ, Kenworthy, LE. “Functional
connectivity of the inferior frontal cortex changes with age in children with
autism spectrum disorders: Evidence from an fMRI study of response
inhibition.” Cerebral Cortex. 2009;19:1787-1794.
CNR | 41
Understanding Down syndrome
in the pediatric brain
own syndrome is one of the most common
and recognizable developmental disorders
in the world—it touches both sexes and all
ethnicities worldwide. However, only a few research
centers in the world study the underlying causes
and the many complications of this disorder. At
Children’s National, Down syndrome research
is led by Tarik Haydar, PhD, in the Center for
Neuroscience Research. Through studies of the
brain at its earliest state, his laboratory breaks
down the complex cellular mechanisms of brain
development as it occurs in utero.
42 | CNR
the team discovered that two genes (Olig1 and
Olig2), both of which are present in an extra copy in
Down syndrome, cause this nerve cell imbalance.
The team believes restoring a proper balance at
an early stage, perhaps through the use of novel
small molecules or drugs acting on Olig1 and Olig2,
may promote a more normal development curve.
Because the world of research in Down syndrome is
so small, Children’s National frequently collaborates
with other institutions, and shares knowledge as well
as animal models of the disorder, with colleagues
around the world to encourage more groundbreaking
research in the field.
Dr. Haydar and his team map “typical” prenatal
brain development in the hopes of identifying and
tracking development patterns when something
goes wrong, especially in complex and earlydeveloping disorders like Down syndrome. They
located the stage of prenatal growth where the
brain disorder in Down syndrome begins, and
have now isolated a contributor to the onset of
recognizable symptoms.
“We’ve learned so much already,” said Dr. Haydar,
who runs the Cellular Imaging Core of the Intellectual
and Developmental Disabilities Research Center
at Children’s National. “We can pinpoint the when,
where, and why of Down syndrome, and now can
begin to design potential interventions that might
reverse the damaging effects before development
has gone too far off track.”
Using specially designed animal models, Dr. Haydar’s
lab showed that changes in the Down syndrome
brain’s stem cells cause an improper balance
between excitatory and inhibitory nerve cell numbers,
and that this may be a primary cause for the
cognitive disability in Down syndrome. Recently,
The introduction of strategies to correctly balance
nerve cell production is a promising and potentially
translational step toward an intervention strategy
that would mitigate some, if not all, of the lifelong
cognitive disabilities that go hand-in-hand with the
disorder. n
Center for
Molecular Physiology Research
Pedro A. Jose, MD, PhD (left)
Professor of Pediatrics
Patricio Ray, MD (right)
Associate Director
Robert Parrott Professor of Pediatrics
Ines Armando, PhD
Laureano Asico, PhD
Jharna Das, PhD
Crisanto Escano, DVM
Angel Soler-Garcia, PhD
Marina Jerebtsova, PhD
John E. Jones, PhD
Hewang Li, MD, PhD
Patricio Ray, MD
Pingtao Tang, MD, PhD
Van Anthony Villar, MD, PhD
Xiaoyan Wang, MD, PhD
Zheng Wang, PhD
Peiying Yu, MD
Co-localization of ubiquitin and proteasome marker p44S10.
HEK 293 cells, co-overexpressing AT1R and D5R, were teased with a
D1-like receptor agonist, fenoldopam (1μM for 5 min). Blue, ubiquitin;
red, p44S10; magenta, co-localization of ubiquitin and p44S10. (Li H)
To further the understanding of the
The new Center of Molecular Physiology Research
molecular/physiological pathways
was established in February 2009 with the recruitment
involved in the pathogenesis, treatment,
and prevention of cardiovascular/renal
diseases in children and young adults.
of Pedro A. Jose, MD, PhD, and his 11 faculty member
team from Georgetown University. This center now also
includes the existing renal physiology group at CRI
led by Patricio Ray, MD.
Strategic Plan Accomplishments
Major Strategic Goals
Determine genetic variants associated
with essential hypertension. A major
focus will be on those groups that suffer
the most from hypertension because of
genetic predisposition, exacerbated
by excessive sodium consumption and
stress (Diagnostics).
Develop therapeutic agents that selectively
target proteins whose aberrant activities
lead to hypertension and treat the
underlying causes of hypertension, not
just its signs, symptoms, or consequences
Determine the outcome of electrolyte
disorders and the pathogenesis of
pediatric renal diseases (such as HIVassociated nephropathy) that can
adversely affect the growth and clinical
outcome of affected children, elucidation
of the mechanisms that affect the clinical outcome, and development of new
treatments for these disorders (Outcomes
44 | CMPR
n The center obtained approximately $3 million (annualized)
funding, including an NIH MERIT Award (Pedro A. Jose,
MD, PhD) and a competitive renewal of a Program Project
Grant held in conjunction with the University of Virginia that
received a perfect score of 10. An R01 grant with Mordecai
Blaustein, MD (University of Maryland, Baltimore), and Dr.
Jose as collaborating investigator, was renewed.
n The center expanded molecular and cell biological,
morphological (confocal microscopy and biophysical
imaging, Förster resonance energy transfer and
fluorescence lifetime imaging), and physiological methods,
as well as genetically manipulated mice using gene deletion
and gene silencing techniques, with viral-transfer vectors.
n Dr. Jose continues to perform collaborative studies in
human essential hypertension in several ethnic groups,
including African Americans, European Caucasians,
Chinese, Filipinos, Ghanaians, Hispanics, and Thai. Dr.
Jose forged collaborative research with several institutions,
including the National Institute of Molecular Biology and
Biotechnology, the Marine Science Institute of the University
of the Philippines, the National Kidney and Transplant
Center, Philippines and the Philippine Genome Center, to
study the genetics of essential hypertension in Filipinos.
Pharmacogenomic studies are underway with Japanese
collaborators at the Fukushima Welfare Federation of
Agricultural Cooperatives and the Fukushima Medical
University School of Medicine.
Programmatic Areas and Accomplishments
Adult-onset Hypertension Induced by Fluid and
Electrolyte Disorders of Childhood
Patricio Ray, MD, Robert Parrott Professor of Pediatrics,
tests the hypothesis that some forms of adult-onset essential
hypertension may be caused by electrolyte disorders during
childhood. He studies the chronic effects of potassium,
chloride, and sodium deprivation in developing rodent
kidneys. Dr. Ray hypothesizes that these electrolyte
disorders induce silent and progressive renal vascular
and epithelial injury, causing functional and structural
tubule-interstitial disorders, salt wasting, or salt-sensitive
hypertension. Dr. Ray collaborates with Anton Wellstein MD,
PhD, Professor of Medicine, Georgetown University, to test
the hypothesis that an angiogenic Fibroblast Growth Factor
Binding Protein (named BP-1) induces vascular contractility
and hypertension in mice. Kitman Wai, MD, a clinical fellow
in pediatric intensive care, works with Dr. Ray in exploring
how sepsis-induced fluid-electrolyte disorders, hypotension,
and vascular leakage induce acute kidney injury in criticallyill children. Finally, Dr. Ray collaborates with Pedro A.
Jose, MD, PhD, to explore the mechanisms involved in the
pathogenesis of hypertension induced by chronic potassium
deprivation in young animal models that mimic the renal
disorders seen in children subjected to chronic hypokalemia.
Oxidative Stress and Lipid Rafts
Peiying Yu, MD, tests the hypothesis that dopamine
receptors differentially regulate enzyme activity (adenylyl
cyclase and NADPH oxidases) in lipid rafts in the kidney.
Lipid rafts, which are membrane microdomains containing
specific subsets of lipids and proteins, serve as signaling
platforms and play important roles in signal transduction in
a variety of mammalian cells. The two mammalian dopamine
D1-like receptors (D1R and D5R) regulate NADPH oxidase
enzymes in lipid rafts of renal proximal tubule cells. Min Sun,
MD, a post-doctoral fellow of the Georgetown UniversityChina Scholarship Council, works with Dr. Yu on this project.
Quansheng Lu, MD, PhD, and Yu Yang, MD, PhD, study the
role of antioxidants in the aberrant production of reactive
oxygen species (ROS) in hypertension.
Oxidative Stress and Mitochondria
Hewang Li, MD, PhD, studies the hypothesis that the
increased oxidative stress caused by the absence of the D5R
is due, in part, to increased production of reactive oxygen
species (ROS) in the mitochondria. Increased mitochondrial
production of ROS is important in the pathogenesis of
Dr. Jose and his research team showed that AT1R (donor) is ubiquitinated
with fenoldopam (Fen) treatment. FLIM images, histograms, and decay
graphs of cells in the absence (top) or presence (middle and bottom) of an
acceptor (Ub) fluorophore are shown. The left shift (arrow) of AT1R
lifetime in Fen-treated samples demonstrated the occurrence of FRET. With
Fen treatment in the presence of acceptor, the donor lifetime had two peaks:
the first was quenched at 1.68 ± 0.2 ns (τ1) because of the occurrence of
FRET, with a corresponding energy transfer efficiency of 27.6% ± 3.7%; the
second was 2.24 ± 0.3 ns (τ2), which represented the unquenched AT1R. (Li H)
essential hypertension. About 0.2 to 2 percent of consumed
oxygen is converted to superoxide anion in vitro by oxidative
phosphorylation along the mitochondrial electron transport
chain, mainly at Complex I and Complex III. Mitochondrial
dysfunctions can result in disorders in the kidney, which are
associated with perturbation of water and salt excretion,
and the pathogenesis of hypertension. Preliminary studies
suggest that D5R activation decreases mitochondria-ROS
production in the kidney. This project aims to understand
the D5R regulation of mitochondrial ROS in the kidney,
identify the signal pathways involved in this process, and
examine mitochondria-ROS as a molecular, biochemical, and
physiological biomarker of essential hypertension.
Inflammation in Hypertension, Obesity, and
Metabolic Syndrome
Ines Armando, PhD, is testing the hypothesis that dopamine,
through the D2 dopamine receptor (D2R), regulates immune
function and oxidative stress in the kidney. Additionally, Dr.
Armando tests whether the dysfunction of the D2R results in
renal inflammation, oxidative stress, and hypertension could
be a contributing factor in the development of metabolic
syndrome. A number of pathological conditions other than
CMPR | 45
classical immune diseases have as a causal factor, or are
associated with, alterations in the inflammatory response.
Tissue inflammation, infiltration of inflammatory cells, and
oxidative stress in the kidney play an important role in the
induction and maintenance of high blood pressure levels.
Furthermore, obesity and metabolic syndrome are now
considered low-grade systemic inflammatory diseases.
Dopamine has regulatory functions on the immune
response. Annabelle M. Pascua, DVM, MS, and Yu Yang,
MD, PhD, work with Dr. Armando in this project.
Dopamine Receptor Recycling and Hypertension
John Edward Jones, PhD, and Van Anthony M. Villar, MD,
PhD, test the hypothesis that sorting nexins are important
in the recycling of internalized dopamine receptors to the
plasma membrane, and that the aberration of this regulatory
function leads to hypertension.
Sodium Transporters and Hypertension
Xiaoyan Wang, MD, PhD, tests the hypothesis that sodium
transporters, especially the sodium chloride cotransporter
in the distal convoluted tubule, are important in the sodium
retention associated with deletion of specific dopamine
receptor subtypes.
G Protein-Coupled Receptor Kinases (GRK4)
and Hypertension
Zheng Wang, MD, MS, tests the hypothesis that GRK4
variants, by regulating G protein-coupled receptors,
are important in the pathogenesis of human essential
hypertension. This hypothesis is tested using molecular,
biological, and biochemical methods in human GRK4
transgenic and GRK4 knockout mice.
Dr. Jose, Laureano D. Asico, DVM, and Crisanto Escano, DVM,
study the mechanisms involved in the pathogenesis of saltsensitivity and hypertension using dopamine receptor subtype
knockout mice, renal cross-transplantation, and intrarenal
administration of gene-regulating agents. In a multicenter
collaboration, they test the hypothesis that salt-sensitivity
involves abnormal regulation of renal sodium transport, as
well as an aberrant gastrointestinal-renal reflex pathway.
Adaptation of Euryhaline Crabs to High and
Low Salt environment
Ines Armando, PhD, and Dr. Jose, with collaborators at
the University of the Philippines, are testing the hypothesis
46 | CMPR
that dopamine receptors are important in the adaptation to
changing saline environment. These studies may provide
clues to the mechanisms by which the mammalian kidney
adapts to low and high salt intake.
HIV Nephropathy
More than 90 percent of African American HIV-infected
children from Washington, DC, are followed at Children’s
National. These children are at exceptionally high risk for
developing renal and cardiovascular disorders secondary
to immune alterations, infections, cytokine release,
dyslipidemias, insulin resistance, hypertension, and a
genetic predisposition to develop renal disease in the
context of HIV infection. Patricio Ray, MD, Pingtao Tang,
MD, PhD, Ángel Soler-García, PhD, and Marina Jerebtsova,
PhD, study the pathogenesis of these renal-cardiovascular
diseases and develop new treatments to prevent these
complications of HIV. HIV-transgenic mice and rats that
express viral genes in endothelial or renal epithelial cells
have been developed to determine how HIV induces
endothelial and renal epithelial injury. Several adenoviralmediated gene transfer techniques have been developed
to express foreign genes in developing and young rodent
kidneys in vivo, and these models are being used to explore
how HIV induces renal injury.
Epithelial Mesenchymal Transformation
Dr. Jose, Hans Pohl, MD, and collaborators at the University
of Georgia are testing the hypothesis that a response gene
to complement 32 is involved in epithelial-mesenchymal
transition in several disease states, including renal fibrosis.
Biomarkers of Disease
Renal disease
Xiaoyan Wang, MD, PhD, tests the hypothesis that urinary
protein exosomes of dopamine and angiotensin receptor
subtypes and renal sodium transporters can be used
as biomarkers of essential hypertension and metabolic
syndrome. This hypothesis will be tested in cases and
controls in humans and animal models of human essential
hypertension and obesity.
Robin A. Felder, PhD, professor of pathology at the
University of Virginia, and Dr. Jose test the hypothesis that
renal proximal tubule cells cultured from the urine can be
used as biomarkers for the pathogenesis of hypertension
and response to treatment. This hypothesis will be tested in
cases and controls in humans and animal models of human
essential hypertension.
Significant Peer Reviewed Journal Publications
n Liu Y, Yang J, Ren H, He D, Pascua A, Armando MI, Yang C, Zhou L,
Felder RA, Jose PA, Zeng C. “Inhibitory effect of ETB receptor on Na+-K+
ATPase activity by extracellular Ca2+ entry and Ca2+ release from the
endoplasmic reticulum in renal proximal tubule cells.” Hypertens Res.
Aug 7 2009. [Epub ahead of print].
n Wang X, Armando I, Upadhyay K, Pascua A, Jose PA. “The regulation
of proximal tubular salt transport in hypertension: an update.” Curr Opin
Nephrol Hypertens. 2009;18(5):412-20.
n Villar VA, Jones JE, Armando I, Palmes-Saloma C, Yu P, Pascua AM,
Keever L, Arnaldo FB, Wang Z, Luo Y, Felder RA, Jose PA. “G proteincoupled receptor kinase 4 (GRK4) regulates the phosphorylation and
function of the dopamine D3 receptor.” J Biol Chem. 2009;284(32):21425-34.
n Luo Z, Chen Y, Chen S, Welch WJ, Andresen BT, Jose PA, Wilcox CS.
“Comparison of inhibitors of superoxide generation in vascular smooth
muscle cells.” Br J Pharmacol. 2009;157(6):935-43.
n Yu C, Yang Z, Ren H, Zhang Y, Han Y, He D, Lu Q, Wang X, Wang X,
Yang C, Asico LD, Hopfer U, Eisner GM, Jose PA, Zeng C. “D3 dopamine
receptor regulation of ETB receptors in renal proximal tubule cells from
WKY and SHRs.” Am J Hypertens. 2009;22(8):877-83.
n Li H, Han W, Villar VA, Keever LB, Lu Q, Hopfer U, Quinn MT, Felder RA,
Jose PA, Yu P. “D1-like receptors regulate NADPH oxidase activity and
subunit expression in lipid raft microdomains of renal proximal tubule
cells.” Hypertension. 2009;53(6):1054-61.
n Yang J, Cui Z, He D, Ren H, Han Y, Yu C, Fu C, Wang Z, Yang C, Wang X,
Zhou L, Asico LD, Villar VA, Hopfer U, Mi M, Zeng C, Jose PA. “Insulin
increases D5 dopamine receptor expression and function in renal proximal
tubule cells from Wistar-Kyoto rats.” Am J Hypertens. 2009;22(7):770-6.
n Zeng C, Villar VA, Yu P, Zhou L, Jose PA. “Reactive oxygen species and
dopamine receptor function in essential hypertension.” Clin Exp Hypertens.
n Zeng C, Han Y, Huang H, Yu C, Ren H, Shi W, He D, Huang L, Yang C,
Wang X, Zhou L, Jose PA. “D1-like receptors inhibit insulin-induced
vascular smooth muscle cell proliferation via down-regulation of insulin
receptor expression.” J Hypertens. 2009;27(5):1033-41.
n Yang Z, Huang X, Jiang H, Zhang Y, Liu H, Qin C, Eisner GM, Jose PA,
Rudolph L, Ju Z. “Short telomeres and prognosis of hypertension in a
Chinese population.” Hypertension. 2009;53(4):639-45 (subject of editorial
n Huang WY, Li ZG, Rus H, Wang X, Jose PA, Chen SY. “RGC-32 mediates
transforming growth factor-beta-induced epithelial-mesenchymal transition
in human renal proximal tubular cells.” J Biol Chem. 2009; 284(14):9426-32.
nArmando I, Jose PA. “Sensing salt intake.” Hypertension.
n Hu J, Tiwari S, Riazi S, Hu X, Wang X, Ecelbarger CM. “Regulation of
angiotensin II type I receptor (AT1R) protein levels in the obese Zucker rat
kidney and urine.” Clin Exp Hypertens. 2009;31:49-63.
n Charles S, Ammosova T, Cardenas J, Foster A, Rotimi J, Jerebtsova
M, Ayodeji AA, Niu X, Ray PE, Gordeuk VR, Kashanchi F, Nekhai
S. “Regulation of HIV-1 transcription at 3% versus 21% oxygen
concentration.” J Cell Physiol. 2009 Nov;221(2):469-79.
n Xie H, Ray PE, Short BL. “Role of sensory C fibers in hypoxia/
reoxygenation-impaired myogenic constriction of cerebral arteries.”
Neurol Res. Jun 30 2009. [Epub ahead of print]
n Jerebtsova M, Ye X, Ray PE. “A simple technique to establish a longterm adenovirus mediated gene transfer to the heart of newborn mice.”
Cardiovasc Hematol Disord Drug Targets. 2009;9(2):136-40.
n Ray PE. “Shiga-like toxins and HIV-1 ‘go through’ glycosphingolipids and
lipid rafts in renal cells.” Kidney Int. 2009;75(11):1135-7.
n Soler-García AA, Johnson D, Hathout Y, Ray PE. “A urinary biomarker
profile for children with HIV-associated renal diseases.” Kidney Int.
n Ray PE. “Taking a hard look at the pathogenesis of childhood HIVassociated nephropathy.” Pediatr Nephrol. Mar 14 2009.
n Soler-García AA, Johnson D, Hathout Y, Ray PE. “Iron-related proteins:
candidate urine biomarkers in childhood HIV-associated renal diseases.”
Clin J Am Soc Nephrol. 2009;4(4):763-71.
n Yatabe J, Sanada H, Yatabe MS, Hashimoto S, Yoneda M, Felder RA, Jose
PA, Watanabe T. “Angiotensin II type 1 receptor blocker attenuates the
activation of ERK and NADPH oxidase by mechanical strain in mesangial
cells in the absence of angiotensin II.” Am J Physiol Renal Physiol.
CMPR | 47
Introducing the Center for
Molecular Physiology
ifestyle can trump genetics,” says
Pedro A. Jose, MD, PhD, director of the
new Center for Molecular Physiology
Research. Though it might be surprising to hear
a basic scientist make the argument that external
choices could overrule centuries of genetic
evolution and established biochemical processes,
his pronouncement focuses on one specific
area where this is true: overcoming essential
hypertension, or high blood pressure that occurs
for no known reason.
Dr. Jose and his team believe that unlocking the
root causes of essential hypertension will help
doctors identify this disorder before serious
complications occur, and when diet and exercise
could have a greater impact on managing high
blood pressure. They believe they can do this
through intensive study of one of the body’s primary
regulators, the kidney.
In the spring of 2009, Dr. Jose brought a team of
nephrology, genetic, veterinary, and basic science
experts together at Children’s National Medical
Center to continue studies of the kidney’s most
basic processes, and the cellular signaling and
functions that make this complex organ effectively
function. The kidney isn’t just a sodium regulator,
however. The team at the Center for Molecular
48 | CMPR
Physiology also studies the many other ways this
delicate organ packs a powerful punch in the
day-to-day operation of the body. Led by veteran
Children’s National researcher and Robert Parrott
Professor of Pediatrics Patricio Ray, MD, the center
investigates basic and translational science of other
key renal functions and processes, including the
causes and effects of the devastating nephropathy
often seen in patients with compromised immune
systems, specifically those with HIV-AIDS.
There is still no definitive explanation as to why
some children are prone to high blood pressure
and others are not, but researchers in the center
are beginning to make headway in understanding
how the kidney factors in. As a result, they also are
close to identifying potential biomarkers that would
indicate hypertension and other renal diseases
faster, before the long term effects of these
disorders begin to take hold, and while diet and
exercise interventions might have a chance to
improve the lives of those who face a lifetime
struggle with high blood pressure. n
Center for Clinical and Community Research
Jill G. Joseph, MD, PhD, MPH | Director
Agnes Hudson Professor of Pediatrics
Stephen Teach, MD | Associate Director (center)
Professor of Pediatrics and Emergency Medicine
John Van Den Anker, MD, PhD | Associate Director (right)
Evan and Cindy Jones Professor of Pediatric Clinical Pharmacology
Professor of Pediatrics, Pharmacology and Physiology
Claude Abdullah, MD, MSc
Shireen M. Atabaki, MD, MPH
Mark L. Batshaw, MD
Stephen Baumgart, MD
Dana Best, MD, MPH
Kathleen Brown, MD
Randall Burd, MD, PhD
James M. Chamberlain, MD
Irene Chatoor, MD
Avital Cnaan, PhD
Edward Connor, MD
Denice Cora-Bramble, MD, MBA
Nina Deutsch, MD
Julia Cole Finkel, MD
Linda Yu-Sing Fu, MD, MSc
Raafat S. Hannallah, MD
Pamela Hinds, PhD, RN
Ivor Braden Horm, MD, MPH
Brian Jacobs, MD
Barbara Jantausch, MD
Yewande Johnson, MD
Richard Kaplan, MD
Paul Kaplowitz, MD
Kanwal Kher, MD
Terry Kind, MD, MPH
Catherine Klein, PhD, RD
Karen Simpson Kuehl, MD, MPH
Ricardo LaGrange, PhD
Amy B. Lewin, PsyD
Uta Lichter-Konecki, MD
Naomi L.C. Luban, MD
Maureen Lyon, PhD
Robert J. McCarter, Jr, ScD
Nazrat M. Mirza, MD, ScD
Rachel Y. Moon, MD
An Nguyen-Massero, MD
Karen O’Connell, MD
Khodayar Rais-Bharami, MD
Natella Y. Rakhmanina, MD
Adelaide S. Robb, MD
Cynthia R. Ronzio, PhD
Leticia Ryan, MD
Xiaoyan Song, PhD
Randi Streisand, PhD, CDE
Anupama Tate, DMD
Susan Thomas Verghese, MD
Lisa Tuchman, MD, MPH
Jichuan Wang, PhD
Edward Wong, MD
Angela Wratney, MD, MHSc
Joseph L. Wright, MD, MPH
To study the optimal means to
improve the health and health
care of children and their families.
Major Strategic Goals
Identify the factors contributing to racial
and ethnic disparities in health and health
care, and to develop interventions for
reducing such disparities.
Understand the ways in which social
forces and human behavior influence
the health and well-being of children
and their families.
Lead a highly collaborative effort to
submit a successful application for
a Clinical and Translational Science
Award (CTSA) to fund the Clinical
and Translational Science Institute
at Children’s National.
Support rigorous multi-site clinical
and translational research by providing
required services and networked
Support the career development of
junior faculty.
50 | CCCR
Strategic Plan Accomplishments
n Established major new capabilities supporting high value
clinical and translational investigations:
• Office of Investigational Therapeutics
• Multi-Center Studies Section
• Department of Research Nursing
• Clinical Trials Committee
n Significantly increased the efficiency of existing capabilities
supporting high value clinical and translational investigations:
• Eliminated redundancies in Clinical Research Center
and Institutional Review Board (IRB) scientific review of
research protocols
• Created a centralized clinical trial information service
for patient families
• Created a business model to support appropriate
charge-back mechanisms
• Developed IT support for tracking and benchmarking
resource utilization
n Recruited new, young investigators:
• Ricardo LaGrange, PhD, from the University of Maryland
Baltimore who studies coping and adherence in
adolescents infected with HIV
• Lisa Tuchman, MD, MPH, from Children’s Hospital of
Philadelphia who studies the impact of adolescence on
chronic disease
n Maintained a stable portfolio of peer-reviewed and federally
funded clinical and translational research grants
Programmatic Areas and Accomplishments
The Center for Clinical and Community Research includes
a highly collaborative group of investigators from most of
Children’s clinical divisions. By design, the spectrum of
research conducted by the center is wide-ranging, including
investigator-initiated efforts focused on multiple aspects of
pediatric disease and prevention. We have chosen to focus on
three unifying themes that characterize much of the center’s
efforts: child health disparities, cores and consortia for clinical
research, and training junior investigators to become the lead
investigators of the future.
Disparities in Health and Health Care
Children’s National has a long-standing commitment to
ameliorating the disparities in health and health care that
affect the largely disadvantaged, low income, and minority
children in the Washington, DC, region. Investigators in the
center work together on projects that range from a focus on
pregnancy outcomes to specific health conditions such as
asthma, to environmental and social forces, that together
result in significant health disparities. Collectively, these
projects provide important visibility for Children’s National in
the local community through our collaborative engagement,
even as they apply rigorous scientific inquiry to better
understand and address health disparities. Additionally,
many of these investigations provide a training ground for
junior faculty with career development awards and utilize the
resources of our Clinical Research Center (CRC), thereby
demonstrating the significant synergies that exist across the
programmatic areas in the center. Several of the research
programs in the center relevant to health disparities are
described below.
Psychosocial and behavioral risk factors in minority
The research of Jill Joseph, MD, PhD, Director of the Center
for Clinical and Community Research, focuses on issues
relevant to the health and well-being of disadvantaged
families. This includes long-standing collaborations across
the Washington, DC, region, including Head Start programs
in Montgomery County, obstetric providers throughout
Washington, DC, and multiple other academic institutions.
Dr. Joseph was the founding principal investigator of
Children’s NIH-funded Center for Research on Child Health
Disparities, which in the last year convened the first national
conference to identify research priorities in this area. Also in
the past year, Dr. Joseph was the author of a collaborative
report of a randomized behavioral trial testing an intervention
to improve psychosocial and behavioral risk factors for poor
reproductive outcomes among 1,044 African-American
Percent of women reducing one or more risks during pregnancy among
n=913 patients in Health Outcome of Pregnancy Education Project, p=0.019.
Primary care based interventions are effective in reducing health risks in
pregnant African-American women. (DC-HOPE, 2001-2004) (Joseph JG et al.
Am J Pub Health 2009)
women in Washington, DC. The clinic-based intervention,
which Dr. Joseph helped design, resulted in 60 percent
more women eliminating one or more of these risk factors
during pregnancy: cigarette smoking, secondhand smoke
exposure, depression, or intimate partner violence. This
work demonstrates that even in the circumstances of busy
inner-city clinics, much more can be done to promote the
health of vulnerable infants before they are born. Her other
work focuses on improving primary care for infants, children,
and youth enrolled in Medicaid managed care, and on
understanding the effects of violence exposure on young
mothers and their children.
Increasing prevalence of obesity in the United States,
particularly among African-American and Hispanic children,
is the primary health concern of Nazrat Mirza, MD. Studies
of overweight Hispanic and African American children and
adolescents have shown that they are at high risk for insulin
resistance and impaired glucose tolerance (IGT), with IGT
present in 28 percent of overweight Latino children with
a family history of type 2 diabetes. Dr. Mirza’s “C.O.O.L.
Kids Program” (Combating Obesity and Overweight in
Latino Kids) focuses on overweight youth 7-15 years of
age who are at risk of developing type 2 diabetes. This
pilot study (funded through a K23 career development
award, Jack Yanovski, MD, mentor at NIH) examines the
effect of low glycemic load (GL) diets, which have been
proposed to reduce hyperinsulinemia and body weight in
children. However, it is unknown if reducing GL in HispanicAmerican children will improve insulin sensitivity or reduce
the prevalence of overweight. Subjects participate in a
culturally competent, family-based intervention program
that includes behavior modification and enhanced physical
CCCR | 51
Change in Body Mass Index (BMI)
Change in BMI among n=90 obese Latino youth aged 7-15y enrolled in
weight reduction intervention (Mirza NM et al. Pediatric Academic Society
Annual Meeting, 2009)
activity in addition to being on either a low GL or low-fat
diet. Catherine Klein, PhD (Nutrition), from the CRC assists
with the dietary and nutritional assessments, and Robert
McCarter, ScD (Biostatistics), and his team assist in setting
up the longitudinal databases and in performing data
analyses. Preliminary results from the trial indicate significant
decreases in body mass index (BMI), percent body fat,
and systolic blood pressure in participating children. Other
positive trends include an increase in physical activity,
a decrease in TV viewing and computer usage, and an
increase in nutrition knowledge among participating children
and their parents.
The research of Ricardo LaGrange, PhD (Psychology),
a newly recruited faculty member from the University of
Maryland, involves behavioral issues relevant to treating
urban and largely minority adolescents diagnosed with HIV/
AIDS. He focuses on the coping behavior and psychological
adjustment in urban teens infected with HIV, and its
implications for treatment adherence. Under the mentorship
of Lawrence D’Angelo, MD (Chief, Adolescent Medicine), and
Dr. Joseph, and with funding from a K01 career development
award from National Institute of Mental Health (NIMH), Dr.
LaGrange has implemented Coping Styles as Predictors of
Adherence in Young People Living with HIV. This study is built
on data from “Adolescent Impact,” a CDC-funded research
project partially directed by Dr. LaGrange, which studied
stress and coping in 166 adolescents infected with HIV in
three major U.S. cities. The most commonly reported HIV
stressors were related to taking medication and adherence. It
is possible that these strategies provide more immediate relief
or distraction from adherence problems. Dr. LaGrange’s work
should help develop effective interventions to enhance illness
management and overall quality-of-life.
52 | CCCR
Maternal Depression
With funding from a K01 mentored training award from the
NIH, Cynthia Ronzio, PhD, conducts a study on maternal
depression in a sample of African American mothers living
in the Washington, DC, metropolitan region. Maternal
depression is a serious public health problem affecting
10 to 15 percent of mothers and it has been found to be
more common among minority mothers and mothers of
low socioeconomic status. However, the reasons for this
disparity are unclear. In Dr. Ronzio’s research, almost onethird of participants (27 percent) screened positive for
depression, twice the national average. Furthermore, she
found that being employed was associated with greater
symptom severity. Her work theorizes that low-wage
jobs with limited flexibility can heighten the symptoms of
depression, especially when caring for an infant. She also
examined the prevalence of violence. In the respondents’
neighborhoods, 68 percent of the women interviewed
reported that they have heard gunshots, 9 percent have
seen someone shot, and 29 percent have seen someone
beaten. In addition to increasing risk for depression, this
violence also affects the ability to effectively parent and
protect one’s children.
Teen pregnancy
Teen pregnancy disproportionately affects disadvantaged
and minority youth in the local Washington, DC, community;
according to 2000 census data, 88 percent of all births to
women ages 15-19 in DC were to African Americans, and 12
percent were to Hispanics. Teen pregnancy also is a significant
public health problem that is linked to behavioral and mental
health problems for both teen moms and their children. Amy
Lewin, PsyD, conducts research that informs and guides
the development of effective interventions to strengthen
adolescent-headed families. She works closely with the
Generations Program in the Goldberg Center for Community
Health, which provides primary care, mental health, and social
services to adolescent parents and their children. Dr. Lewin’s
current research includes: a longitudinal evaluation of a homebased intervention to improve parenting skills and decrease
repeat pregnancies in adolescent mothers; a qualitative study
about the roles and needs of adolescent fathers; a study
analyzing data from the Early Childhood Longitudinal Study
Baseline Cohort to determine the role of father involvement
and the co-parenting relationship between adolescent parents
in predicting behavioral outcomes for their preschool age
children. She further collaborates in a study led by Dr. Joseph,
which examines the effects of violence exposure on the mental
health and parenting behavior of African American adolescent
mothers. Preliminary results from the qualitative study indicate
that both adolescent mothers and fathers want fathers to be
involved with their children, even when they are no longer
romantically involved with the mothers. This finding suggests
that there is more to be done to support the positive, helpful
involvement of young, urban, African American fathers in the
lives of their children.
Focusing on the epidemic of urban asthma among
the disadvantaged and largely minority children in the
District of Columbia, Stephen J. Teach, MD, MPH, leads a
multidisciplinary and highly collaborative program of clinical
and translational research. His effort, known as IMPACT
DC for “Improving Pediatric Asthma Care in the District of
Columbia,” has funding from National Institute of Allergy
and Infectious Diseases (NIAID), the Department of Health
from the District of Columbia, and several major local and
national foundations. The overall purpose of his work is
to address the disparities in care and outcomes evident
among inner-city children with asthma in Washington, DC,
while serving as a model program for the nation. IMPACT
DC is a full spectrum translational research program.
As a principal investigator with the Inner City Asthma
Consortium and with the infrastructural support of the CRC,
for example, Dr. Teach has studied novel immunomonitoring
and immunotherapy in asthma. His group collaborated in a
recent landmark publication examining the role of exhaled
nitric oxide (eNO) in asthma management (Szefler, Lancet,
2008). This work demonstrated that routine monitoring of
eNO offered no additional benefit to asthma management
over traditional guideline-based therapy.
Dr. Teach also collaborates with Robert Freishtat, MD, MPH,
from the Center for Genetic Medicine in genotyping and
phenotyping studies of inner-city children and adolescents
with asthma with a special focus on the role of environmental
tobacco smoke as a model toxicant mediating gene/
environment interactions. At the other end of the translational
spectrum, Dr. Teach collaborates with Ivor B. Horn, MD,
MPH, from the Center for Clinical and Community Research
in studies that improve the way urban and minority parents
communicate with their practitioners about asthma care.
Sudden Infant Death Syndrome (SIDS)
A persistent, significant, and highly troubling racial disparity
continues to exist in rates of infant mortality attributable to
SIDS and other types of sleep-related sudden unexpected
death in infancy (SUDI), such as suffocation. In fact, racial
disparities in SIDS and other sleep-related deaths have
increased over the past decade, with African American
infants twice as likely to die as other infants. Washington, DC,
reported 39 SUDI deaths from 2005–2007, 38 (97 percent)
of which occurred in African American infants, and 82
percent of which occurred in high-risk sleep environments.
Rachel Moon, MD, developed and evaluated educational
interventions, which have been found to be effective in
Correlation between protein-corrected phenotopic inhibitory quotient (PIQ)
and the HIV RNA viral load < 400 copies/ml. Patients with PIQ > 25 ar emore
likely to have undetectable viral load. (Rakhmanina N et. al. 10th International
Workshop on Clinical Pharmacology of HIV Therapy, 2009)
improving knowledge and changing parental behavior with
regard to SIDS risks, specifically decreasing prone placement
and bed sharing. Her current NIH K 24 study uses a mixedmodel approach to study factors influencing African American
practices regarding infants’ sleep environment.
One of the practices she has focused on is bed sharing in
African American families. Preliminary findings show that
there are many factors affecting parental intention to bed
share or not to bed share, including 1) cultural norms: for
some, the perception is that they are a “bad” parent if they
do not sleep with their infant, 2) the advice of healthcare
professionals, and 3) degree of self-efficacy regarding
prevention of SIDS or accidental death. Parental fatigue,
financial inability to purchase a crib, and the convenience of
bed sharing often impacted parental practice. In addition,
many parents believed that they could best prevent SIDS or
accidental death in their infant by constant vigilance and bed
sharing was a method to maintain vigilance.
Patient-provider communication
Various aspects of patient-provider communication are
associated with differences in patient satisfaction with
care, adherence to treatment plans, and quality of health
care. Not surprisingly, there are disparities in the quality of
patient-provider communication with vulnerable populations
such as racial and ethnic minorities and the economically
disadvantaged. Though less abundant than in the adult
CCCR | 53
literature, pediatric studies of parent-provider communication
have found a relationship between communication and
parent satisfaction with care, adherence to treatment
recommendations, and discussion of psychosocial issues. The
research of Dr. Horn employs a framework of self-efficacy and
empowerment to improve parents’ interactions with the health
care system. By applying this research model, developed in
her K23 research, to broader aspects of medical care such as
chronic diseases, she aims to provide a potential mechanism
for reducing healthcare disparities for vulnerable populations.
To that end, she is principal investigator of a new pilot
randomized controlled trial that received NIH support through
ARRA supplement funding to the CRC to examine the effects
of a health care communication education program for parents
on their children’s asthma outcomes.
Review Board (IRB) to establish a new integrated scientific
review process. Additionally, through this collaboration, the
Data and Safety Monitoring Plan (DSMP), a CRC-developed
tool, is now part of the IRB application. These improvements
are estimated to reduce the CRC review cycle time by more
than 80 percent.
Core facilities
Clinical Research Center (CRC)
With ongoing support from the NIH’s NCRR, the CRC at
Children’s continues its central role in support of research by
providing dedicated research nurses and research assistants,
clinical and specimen processing space, and access to its
Biostatistical, Neuropsychological, Genetic, and Bionutritional
Cores. Under the nursing and administrative leadership of
Marlene Lee, RN, and Kolaleh Eskandanian, PhD, the CRC
made remarkable progress in 2009. Doubled in size through
philanthropic and institutional support, it now operates in
5,880 sq. ft. of inpatient and outpatient clinical research
space. Thanks in part to the newly expanded unit, the CRC’s
outpatient census increased by 26 percent over the last year
as it provided services to 112 open protocols. It also was able
to extend its services to industry-initiated studies.
Biostatistics and Informatics Unit (BIU)
The BIU provides a full range of support to biomedical
researchers throughout Children’s National. Support includes
assistance in developing study designs and proposals, as
well as data analysis plans and sample size calculations;
managing research information as well as web-based data
collection and study monitoring; implementing data analyses
to address research questions and supporting the publication
of results, while providing education in research methods and
management, as well as individual mentoring especially of
new investigators. Under the leadership of Robert McCarter,
ScD, the BIU experienced phenomenal growth in providing
assistance with study development, from 28 in FY05 to
106 in FY09, all the while maintaining a record of having
approximately 50 percent of supported studies funded. The
BIU has developed and continually extended the capabilities
of the Children’s Research Information System (CHRIS),
which provides informatics support to studies for recruitment,
support of web-based data entry, protocol management
and scheduling, as well as quality assurance monitoring.
Support for data analysis has grown as well, from 17 studies
receiving extensive data analysis support in FY07 to 64 in
FY09. Education in research methods and study management
was introduced by the BIU in FY05 and continues to
include classes on “Critical Appraisal of Medical Literature,
Research Design, and Fielding a Research Study.” This menu
expanded to include a class on “Meeting Study Informatics
Needs” and a Grants Workshops. In addition, extensive
mentoring was provided to 10 research career development
awardees in FY 07, growing to 18 in FY09. As an example
of the BIU’s role in protocol development and support, the
Unit collaborated with Mark L. Batshaw, MD, and Mendel
Tuchman, MD, on the development of a Rare Diseases
Clinical Research Center (RDCRC) focused on urea cycle
disorders (UCD), which twice received the top score from an
NIH review panel, both on the initial award and on the 5-year
renewal. The RDCRC includes a core natural history study as
well as a number of secondary studies evaluating biomarkers,
outcomes, and treatment. The BIU provides informatics
support for the screening and verification of UCD cases, as
well as the capture of pedigree information, and biostatistical
support for the studies.
In an effort to continuously streamline its processes and
provide value added services to its investigators, the CRC
worked in close collaboration with Children’s Institutional
In another example, the BIU provided both biostatistical
and informatics support for a pilot study of the safety and
tolerability of using the antiepileptic drug Keppra to prevent
Cores and Consortia for Clinical Research
NIH grants providing support for CRI cores and center grants
supporting multicenter consortia have contributed heavily to
the impressive growth of research at Children’s National in the
past decade. Such grants provide approximately 20 percent
of all CRI funding (rather than less than 5 percent at most
institutions), support the career development of our many
junior faculty members, and facilitate the work of diverse
investigators. Continued growth in CRI’s funding and in the
stature of Children’s National requires the sustained success
and availability of collaborative infrastructure. In addition,
CRI and center resources are invested in making available
additional key support in areas such as research nursing,
biostatistics, and multi-center clinical trials. Key features of
this collaborative infrastructure are described below.
54 | CCCR
post-traumatic epilepsy led at Children’s National by Phillip
Pearl, MD. Statistical support included design of interim and
final analyses and informatics support included using CHRIS
to provide a centralized database to support screening and
enrollment as well as implementation of a detailed and timesensitive protocol involving web-based forms.
Multi-Center Studies Section (MCSS)
Created in 2008 by recruited faculty member Avital
Cnaan, PhD, the MCSS supports multi-center clinical
and community research studies, including operations,
regulatory support, and biostatistical consultation. It
focuses on studies (both clinical trials and observational
cohorts) that include at least two sites and requires
coordination of protocols and approaches for uniformity
and consistency among sites to accomplish scientific rigor
of results. Because of its unique multi-center mission, it
serves investigators both internal and external to CRI.
In collaboration with the Center for Genetic Medicine
Research, the section now serves as the coordinating
center for the Cooperative International Neuromuscular
Research Group (CINRG), a consortium of 23 institutions in
10 countries devoted to research and improvement of care
and quality of life of children and adults with neuromuscular
diseases. The MCSS has been awarded $2 million by the
Department of Defense to be the coordinating center for
this network. The center has funding for statistical analyses
resulting from a 32-site clinical trial in childhood absence
epilepsy (principal investigator: Tracy A. Glauser, MD,
Cincinnati Children’s Hospital) as well as for establishing
a longitudinal database for neurofibromatosis (principal
investigator: Roger Packer, MD, clinical Center for
Neuroscience and Behavioral Medicine). The MCSS has
pending applications for a 20-site coordinating center
submission for a clinical trial of three marketed medications
for localization related epilepsy (principal investigator of
coordinating center Dr. Cnaan), a 10-site clinical trial of
cooling during hyperammonemic coma study in urea
cycle disorders pending review (principal investigator:
Uta Lichter-Konecki, MD), and an international registry with
seven pilot sites (including Italy) and planned up to 50
sites in thrombotic angiopathy (principal investigator: H.
Trachtman, MD, Feinstein Institute of Research, Long Island
Jewish Hospital). Although the MCSS is new, it already
has had the opportunity to analyze results from a baseline
evaluation in a longitudinal natural history study of boys with
Duchenne muscular dystrophy (DMD). The results suggest
that using a more sensitive pulmonary function measure for
future studies may allow better assessment of the efficacy of
experimental therapies in this devastating disease.
Office of Investigational Therapeutics (OIT)
This office was established in 2008 with the mission to
facilitate translation of biomedical discoveries into innovative
products that improve the health and well being of children.
Newly recruited faculty member Edward Connor, MD, the
director of OIT, brought with him to Children’s National
more than 25 years of experience in product development
for children in academics and biotechnology. The office
focuses on product development strategy and management,
clinical trials methodology and operations, domestic and
international regulatory affairs, industry affairs, partnerships,
critical path analyses, opportunity assessment, and
intellectual property management.
Since its inception, OIT has worked with several
investigators at Children’s National and their outside
collaborators, stakeholders, and sponsors to advance
product development. For example, OIT is working with
Mark L. Batshaw, MD, Mendel Tuchman, MD, the RDCRC
Urea Cycle Disorders Consortium, and several U.S. and
international biotechnology companies in launching projects
to evaluate candidate treatments for these serious orphan
disorders. OIT also works with Eric Hoffman, PhD, Robert
Leshner, MD, and the CINRG network in the development of
antisense oligonucleotides for exon skipping as a treatment
of DMD. In related activities, Dr. Connor serves as a board
member of VB Pharm, a startup biopharmaceutical company
spun out of Children’s National engaged in the discovery,
development, and commercialization of proprietary,
small molecule therapeutic products for the treatment of
neuromuscular diseases, particularly muscular dystrophy.
OIT also facilitates several high potential emerging projects
at Children’s National, such as device development for Julia
Finkel, MD, involving management of pain in children. In
total, during its first year OIT has provided service to more
than 30 clinical and translational investigators/projects.
Dr. Connor and OIT work closely with the scientific and
administrative leadership of the Center for Clinical and
Community Research and the CRC to encourage and
support the development of novel methodologies for
application to pediatric clinical and translational research.
Dr. Connor and OIT are taking a lead role in policy and
advocacy in the field of pediatric product development.
This includes drafting guidance for faculty interaction with
industries and authoring an invited featured perspective
on pediatric translational research in the inaugural issue of
Science Translational Medicine.
Pediatric Emergency Care Applied Research Network
Led at Children’s National by one of the group’s four national
principal investigators, James M. Chamberlain, MD, Chief of
Emergency Medicine, PECARN supports a host of clinical
CCCR | 55
Residential addresses
of n=3,764 youth aged
0-17 yr with fractures in
Washington, DC, 2003-2006.
Geospatial data can help
locate services and identify
environmental risks.
(Ryan LM et al. Pediatric
Academic Societies’ Meeting,
and translational efforts dedicated to improving care and
outcomes for acutely ill and injured children (see page 58).
The Collaborative Pediatric Critical Care Research Network
This network was funded by the NIH in 2005 to investigate
the safety and efficacy of treatments and management
strategies of critically ill children in intensive care units. The
network consists of six clinical sites and a data coordinating
center. Led at Children’s National by John Berger, MD,
and David Wessel, MD, CPCCRN has completed three
observational studies on diverse subjects including
pathologic bereavement and quality of survival defined
by level of patient function. An additional five studies
are ongoing, including a randomized controlled trial of
metoclopramide, glutamine, zinc, and selenium to prevent
nosocomial infection in critically-ill children (CRISIS). In
collaboration with PECARN and the National Heart, Lung,
and Blood Institute (NHLBI), CPCCRN is beginning a
randomized trial of therapeutic hypothermia after pediatric
cardiac arrest (THAPCA). In another effort, CPCCRN is
looking at current severity of illness scoring systems in
pediatric critical care, which have dichotomized outcomes
into survival versus death.
Urea Cycle Disorders Consortium (UCDC)
The UCDC (directed by Mark Batshaw, MD, and Mendel
Tuchman, MD), funded by the NIH as a Rare Diseases
Clinical Research Center in 2003, has 13 U.S. and two
international sites and involves more than 50 investigators
and staff. The core study conducted by the consortium is
a longitudinal-natural history investigation of patients with
56 | CCCR
UCD, in which approximately 350 patients have already
been enrolled. The first scientific report from the UCDC
appeared last year and determined the relative frequency
of the various UCD disorders and defined clinical and
biochemical parameters including biomarkers of disease
for each. In addition, the effect of N-carbamylglutamate
(NCG) on the urea cycle and on hyperammonemia is being
studied by the consortium with support of R01 grants
from the National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK) and the National Institute for
Child Health and Human Development (NICHD) awarded
to Dr. Tuchman. This study has now documented that NCG
is curative of one UCD (NAGS deficiency) and ameliorates
the hyperammonemia in propionic acidemia. Importantly
these investigations also revealed that NCG augments the
activity of the urea cycle in healthy individuals, a discovery
which will have therapeutic implications for treatment
of other (acquired) hyperammonemic conditions. Other
studies conducted by the consortium include the use of
neuroimaging (MRI/MRS) to determine biomarkers for the
effect of hyperammonemia on the brain (Andrea Gropman,
MD, principal investigator) and the role of hypothermia in
neuroprotection from hyperammonemia (Uta Lichter-Konecki,
MD, principal investigator). The consortium works closely
with the National Urea Cycle Disorders Foundation, the
patient advocacy organization for urea cycle disorders, and
collaborates with industry to develop innovative therapies for
these disorders.
Pediatric Pharmacology Research Unit (PPRU)
This unit is one of 13 units around the nation funded by
the NICHD to foster clinical and translational research to
improve safe and effective use of medicines in pediatrics.
Led by John van den Anker, MD, PhD, this unit has, since its
inception in 2004, conducted 30 investigator-initiated clinical
investigations, trained three physician-scientists (Julia Finkel,
MD, Adelaide Robb, MD, and Natella Rakhmanina, MD) in
pediatric clinical pharmacology, and received a Mentored
Specialized Clinical Investigator Development Award to
support Yewande Johnson, MD, in her clinical research. The
PPRU also has supported several investigators in acquiring
NIH-funding. In addition to grants and contracts to Drs.
Robb, Rakhmanina, and van den Anker, Dr. Chamberlain
was awarded a major contract to investigate the use of
lorazepam in children with status epilepticus. All these
studies are enrolling participants and will result in findings
that will improve the safe and effective use of medicines in
newborn infants and children with HIV, seizures, psychiatric
disorders, and pain-related issues.
Inner City Asthma Consortium (ICAC)
With support from the National Institute of Allergy and
Infectious Diseases (NIAID), the ICAC consists of ten
national sites and provides infrastructure for investigatorinitiated studies of multiple clinical and translational aspects
of immuno-monitoring and immuno-therapy among urban,
disadvantaged, and largely minority children with moderate
to severe asthma and atopy. Led at Children’s National by
Stephen J. Teach, MD, MPH, the ICAC provides biostatistical
and operational support to its Steering Committee, a group
of the 15 principal investigators (including Dr. Teach)
who plan and implement its studies. Recently completed
efforts include an analysis of obesity as a determinant of
the inflammatory response in asthma, the role of exhaled
nitric oxide in asthma management, and the role of an
IgE-blocking antibody in the management of children
and adolescents with asthma and documented perennial
allergies. Other investigators at Children’s National include
Robert Freishtat, MD, MPH, from the Center for Genetic
Medicine Research, and Hemant Sharma, MD, from the
Division of Allergy and Immunology.
childhood fractures, such as high BMI and poor dietary
intake of calcium, are prevalent in African American children.
Additionally, darker skin pigmentation is a risk factor for
vitamin D deficiency. Lastly, genomic studies suggest that
genetic risk for fracture may reflect an interaction between
vitamin D receptor (VDR) polymorphisms and the presence of
calcium and vitamin D deficiencies for which this population
may be at higher risk. Identifying an association between
forearm fracture in African American children and bone
health deficits would enable targeted intervention that could
markedly reduce fracture risk and improve bone health,
both in later childhood and in adulthood. Preliminary results
suggest that forearm fractures in African American children
are associated with vitamin D insufficiency. Future analyses
will incorporate measurements of dietary intake of calcium
and vitamin D, physical activity and sun exposure, BMI, and
genetic analysis.
The new CRI Strategic Plan for 2011-2016 puts a heavy
emphasis on Children’s role in the training and development
of its junior investigators. The concept of “growing our own”
rather than depending exclusively on recruitments to lead the
next generation of CRI’s scientific investigations is not only
sensible, but cost-effective. The center is therefore heavily
committed to the training and mentorship of junior faculty
members with a special emphasis on preparing them to
secure their own independent research funding. In particular,
the center is proud to be the academic home of six scholars
funded with their own Mentored Training Grants from the
NIH (“K Awards”): Ivor B. Horn, MD, MPH, Nazrat Mirza, MD,
DrPH, Leticia Manning Ryan, MD, Ricardo LaGrange, PhD,
Natella Rakhmanina, MD, and Cynthia Ronzio, PhD. K awards
are given by the NIH for periods up to five years, providing
salary support for nascent investigators to receive the
supervised didactic training they require to succeed as they
develop their individual research programs. The work of Drs.
Horn, Mirza, LaGrange, and Ronzio is described above under
the section on Disparities. Brief descriptions of the works of
Drs. Ryan and Rakhmanina follow, as does a description of
the work of Randi Streisand, PhD, a former K scholar whose
recent R01 award demonstrates the ideal progression from
trainee to independently funded investigator.
Dr. Rakhmanina studies the pharmacology and
pharmacogenetics of antiretroviral drugs in children
and adolescents infected with HIV. She asks critically
important questions about developmental changes and the
pharmacokinetics (PK) and pharmacodynamics (PD) of
pediatric HIV therapy. Her long-term career goals are aimed
at creating effective, tested paradigms for the individualized
pediatric HIV therapy. Her clinical research is conducted
within the CRC with close collaboration and support from the
CRC’s Genetics and Bionanalytical Cores. Dr. Rakhmanina
has conducted several multidisciplinary research projects
in collaboration with the Children’s clinical Divisions of Sleep
Medicine (Daniel Lewin, PhD), Nephrology (Patricio Ray, MD),
and Emergency Medicine (James Chamberlain, MD). Dr.
Rakhmanina’s studies contributed to the identification of saliva
as non-invasive alternative for the therapeutic drug monitoring
of nevirapine. Her collaborative work with David Burger, MD,
in the Netherlands resulted in a revision of current pediatric
dosing guidelines for lamivudine after showing that currently
recommended doses fail to achieve the target concentration
in a large percentage of children. Her most recent work
on predicting response to Lopinavir/ritonavir therapy has
helped explain how specific phenotypes are associated
with treatment associated viral suppression. Currently, Dr.
Rakhmanina is principal investigator of an NIH funded study
of the effect of development during puberty on the expression
of the CYP2B6 enzyme and metabolism of efavirenz.
Dr. Ryan is supported by a K23 career development award
from the NIH. She investigates the role of bone health in
forearm fractures in African-American children. Forearm
fracture rates are increasing in children for unknown reasons
and African-American children may be a vulnerable subset
of the pediatric population at higher risk of fracture due to
both environmental and genetic factors. Risk factors for
The recent career accomplishments of Dr. Streisand illustrate
the ideal model for progression from a Mentored Research
Training Award to independent R01 funding. Dr. Streisand
is an Associate Professor of Psychiatry and Pediatrics,
and serves as Director of Psychosocial Research and
Service for the clinical Diabetes Program. She also leads a
psychosocial and behavioral working group within the center.
Junior Faculty: Investing in CRI’s Future
CCCR | 57
Dr. Streisand’s research focuses on adjustment to illness in
children and families, adherence to medical regimens, and
the impact of behavior on health outcomes. In collaboration
with colleagues including medical director of the Diabetes
Program Fran Cogen, MD, Dr. Streisand is conducting two
randomized controlled trials funded by the NIH, and with
integral support from both the CRC and the BIU. These trials
evaluate the efficacy of behavioral interventions designed to
promote daily management of type 1 diabetes. Through these
projects, Dr. Streisand aims to improve the health outcomes of
children, as well as favorably impact the quality of life (QOL)
of both parents and children affected by childhood illness.
Selected Individual Investigators
Pamela S. Hinds, PhD, RN, FAAN, is an exciting new recruit
to Children’s National. Her research includes patientreported outcomes during illness, interventions to improve
fatigue and sleep quality in ill children and adolescents, and
treatment-decision making and communication at a child’s
Kathleen Brown, MD, MPH, is the principal investigator for
the HRSA/MCHB/EMSC partnership grant for Washington,
DC, which aims to improve the quality of emergency care for
children. She serves as Children’s site principal investigator
for the Pediatric Emergency Care Applied Research Network
(PECARN). Her research interests include translating
evidence into practice, prehospital care, trauma care,
family centered care, pediatric preparedness of emergency
departments, and improving ED patient flow. Clinical Chief of Trauma and Burn at Children’s National
Randall S. Burd, MD, PhD serves as the chairman of the
Trauma Committee for the American Pediatric Surgical
Association. His area of research interest is developing
new approaches for improving pediatric trauma triage and
improving team work during trauma resuscitation through the
development of new technologies and decision support tools.
The primary research focus of Irene Chatoor, MD, from the
clinical Division of Psychiatry has been on feeding disorders
in infants, toddlers, and young children. Together with Benny
Kerzner, MD, from the clinical Division of Gastroenterology,
Hepatology and Nutrition, she has conducted NIH-supported
research on the diagnosis of feeding disorders in infants and
children under the age of six years, examining the reliability
and validity of a unique diagnostic classification system for
feeding disorders.
The primary academic focus of Nina Deutsch, MD, from
the clinical Division of Anesthesiology and Pain Medicine
is on novel methodologies for neurologic protection during
58 | CCCR
pediatric cardiac surgery. She is the lead investigator on a
study examining the effect of reducing spinal cord oxygen
consumption with pentobarbital during repair of coarctation
of the aorta using near infrared spectroscopy (NIRS) as a
means to track spinal cord oxygen supply and demand.
With Julie Finkel, MD, Dr. Deutsch continues to examine the
hemodynamic impact of the medication dexmedetomidine in
children with congenital heart disease.
Linda Y. Fu, MD, MS, a general pediatrician in the Goldberg
Center for Community Pediatric Health, serves as the clinical
services team leader for the DC Preschool Immunization
Improvement Initiative, which is a collaboration between the
District of Columbia Department of Health, Washington, DC,
Medicaid, and healthcare providers in Washington, DC, to
improve the city’s vaccination rates. Her current research
interests include behavioral models and interventions to
increase immunization acceptance and compliance rates.
Working clinically in the Division of Anesthesiology and
Pain Medicine, Yewande J. Johnson, MD, specializes
in the treatment of pain. Her research focuses on the
pharmacogenetics of opioid metabolism and sickle cell
disease-related pain. At present she is involved in genotyping
patients with sickle cell disease to evaluate single nucleotide
polymorphisms (SNPs) which affect opioid responsiveness.
Recent research endeavors include collaboration in a multicenter trial of intravenous acetaminophen and a series of
investigations led by Dr. Finkel that are evaluating alternatives
to opioid analgesics in the perioperative setting.
Karen J. O’Connell, MD, is a faculty member in the clinical
Division of Emergency Medicine. Her area of research interest
is family presence during pediatric trauma evaluations in
the emergency department. Dr. O’Connell holds a Targeted
Issues Grant from HRSA’s Emergency Medical Services for
Children to evaluate the effect of family presence and to
create a nationally distributed practice recommendation.
Adelaide S. Robb, MD, is the clinical chief of Inpatient
Psychiatry at Children’s National. She has federal grants on
bipolar disorder from NIMH and a contract from NICHD on
bipolar disorder. In addition she conducted multiple industry
trials in the psychopharmacology of treatment for a variety
of disorders. Her primary area of interest is developmental
psychopharmacology and tailoring medications to minimize
adverse events.
Significant Peer Reviewed Journal Publications
n Atabaki SM, Stiell IG, Bazarian JJ, Sadow KE, Vu TT, Camarca MA,
Berns S, Chamberlain JM. “A clinical decision rule for cranial computed
tomography in minor pediatric head trauma.” Arch Pediatr Adolesc Med.
n Burd RS, Madigan D. “Evaluation of the impact of injury coding
schemes on mortality prediction in pediatric trauma.” Acad Emerg Med.
n Chatoor I. “Sensory Food Aversions in Infants and Toddlers.” Journal
of Zero to Three. National Center for Infants, Toddlers, and Families
n Chamberlain JM, Lillis K, Vance C, Brown KM, Fawumi O, Nichols S, Davis
CO, Singh T, Baren JM for the Pediatric Emergency Care Applied Research
Network. “Perceived challenges to obtaining informed consent for a timesensitive emergency department study of pediatric status epilepticus:
Results of two focus groups.” Acad Emerg Med. 2009;16:763-70.
n El-Mohandes AE, Kiely M, Joseph JG, Subramanian S, Johnson AA, Blake
SM, Gantz MG, El-Khorazaty MN. “An intervention to improve postpartum
outcomes in African-American mothers: a randomized controlled trial.”
Obstetr Gynecol. 2008;112:611-620.
n Klein CJ, Nielsen FH, Moser-Veillon PB. ”Trace element loss in urine and
effluent following traumatic injury.” J Parenter Enteral Nutr. 2008;32:129-139.
n Lyon ME, Garvie PA, Briggs L, He J, D’Angelo L, McCarter R.
“Development, Feasibility and Acceptability of the Family-Centered (FACE)
Advance Care Planning Intervention for Adolescents with HIV.” J Palliative
Medicine. 2009;12:363-72.
n Mitchell SJ, Lewin A, Horn IB, Rasmussen A, Valentine D, Joseph JG.
“Violence exposure and the association between young African American
mothers’ harsh discipline and child problem behavior.” Academic
Pediatrics. 2009;9:157-163.
n Monaghan M, Hilliard M, Cogen FR, Streisand R. (2009). “Nighttime caregiving behaviors among parents of young children with type 1 diabetes:
Associations with illness characteristics and parent functioning.” Families,
Systems, and Health. 27 (1), 28-38.
n Pritchard M, Burghen E, Srivastava DK, Okuma J, Anderson L, Powell B,
Furman WL, Hinds PS. “Cancer-related symptoms most concerning to
parents during the last week and last day of their child’s life.” Pediatrics.
2008;121(5): e1301-9, 2008.
n Fu L, Cowan N, McLaren R, Engstrom R, Teach SJ. “Is spatial accessibility
to primary care providers associated with vaccination compliance among
children with Medicaid insurance?” Pediatrics. 2009;124:1579-1586.
n Rakhmanina N, Sill A, Baghdassarian A, Bruce K, Williams K, Castel AD,
Rakusan T, Singh N, Spiegel HML. “Epidemiology of New Cases of HIV-1
Infection in Children Referred to the Metropolitan Pediatric Hospital in
Washington, DC.” Pediatr Infect Dis J. 2008;27:837-9.
n Hilliard M, Goeke-Morey M, Cogen FR, Henderson C, Streisand R.
”Predictors of diabetes-related quality of life after transitioning to the insulin pump.” Journal of Pediatric Psychology. 2009;34:137-146.
n Rakhmanina N, Capparelli E, van den Anker JN. “Personalized
Therapeutics: HIV Treatment in Adolescents.” Clin Pharmacol Ther.
n Hinds PS, Gattuso JS, Billups CA, West NK, Wu, J., Rivera C, Quintana J,
Villarroel M, Daw NC. “Aggressive treatment of nonmetastatic osteosarcoma improves health-related quality of life in children and adolescents.”
Eur J Cancer. 2009 (Jul;4SC11):2007-14.
n Shaw KN, Ruddy RM, Olsen CS, Lillis KA, Mahajan PV, Deam JM,
Chamberlain JM for the Pediatric Emergency Care Applied Research
Network. “Pediatric patient safety and emergency departments: Unit characteristics and staff perceptions.” Pediatrics. 2009;124:485-493.
n Hinds PS, Billups CA, Cao X, Gattuso JS, Burghen EA, West N, Rubnitz
J, Daw NC. “Health-Related Quality of Life in Adolescents at the time of
Diagnosis with Osteosarcoma or Acute Myeloid Leukemia.” European
Journal of Oncology Nursing.
n Slonim AD, Joseph JG, Turenne WM, Sharangpani A, Luban NL. “Blood
transfusions in children: a multi-institutional analysis of practices and
complications.” Transfusion. 2008;48:73-80.
n Jaju R, Tate AR. “Multidisciplinary Treatment Team Approach to Cleft Lip/
Palate–A Pediatric Dentistry Perspective.” Pediatr Dent. 2009;31:117-121.
n Joseph JG, El-Mohandes AA, Kiely M, El-Khorazaty MN, Gantz MG,
Johnson AA, Katz KS, Blake SM, Rossi MW, Subramanian S. “Reducing
psychosocial and behavioral pregnancy risk factors: Results of a randomized clinical trial among high-risk pregnant African American women.”
American Journal of Public Health. 2009;99:1053-1061.
n Joyner BL, Gill-Bailey C, Moon RY. “Infant sleep environments as
depicted in magazines targeted to women of childbearing age.” Pediatrics.
n Kind T, Wallace J, Moon RY. “The Digital Divide: A Comparison of Online
Consumer Health Information for African American and General Audiences.”
Journal of the National Medical Association. 2008;100:1333-40.
n Streisand R, Mackey ER, Elliot BM, Mednick L, Slaughter IM, Turek J,
Austin A. “Parental anxiety and depression associated with caring for a
child newly diagnosed with type 1 diabetes: Opportunities for education
and counseling.” Patient Education and Counseling. 2008;73, 333-338.
n Szefler SJ, Mitchell H, Sorkness CA, Gergen PJ, O'Connor GT, Morgan
WJ, Kattan M, Pongracic JA, Teach SJ, Bloomberg GR, Eggleston PA,
Gruchalla RS, Kercsmar CM, Liu AH, Wildfire JJ, Curry MD, Busse WW.
“Management of asthma based on exhaled nitric oxide in addition to
guideline-based treatment for inner-city adolescents and young adults: a
randomised controlled trial.” Lancet. 2008;372:1065-72.
n Wang J. 2008. “Some issues on application of standardization and decomposition analysis.” The Open Demography Journal. 2008;1:15-17.
n Wissow, LS, Gadomski A, Roter D, Larson S, Brown J, Zachary C, Bartlett
E, Horn I, Luo X, Wang MC. “Improving child and parent mental health in
primary care: a cluster-randomized trial of communication skills training.”
Pediatrics. 2008;121:266-75.
CCCR | 59
Research in pediatric
emergency medicine
ediatric Emergency Care Applied Research
Network (PECARN) is the first federally
funded research network dedicated solely
to the needs of children treated for emergency
conditions. The network of 22 hospitals is able to
overcome many of the barriers to such research,
including rare events, the need for geographic
diversity, and the need for a platform for translational
research. Studies have included sample sizes up to
40 times those of previous efforts in the same areas.
Clinical Division Chief of Emergency Medicine,
James M. Chamberlain, MD, is one of four principal
investigators directing PECARN. His research
focuses on quality assessment and severity scoring.
In a multi-site collaboration, he recently developed
and validated a pediatric emergency medicine
severity classification system based on ICD-9 codes
and performance measures for quality assessment
across institutions.
PECARN investigators have used its infrastructure
to successfully compete for extramural funding
to support large-scale research protocols. For
example, one study to identify a clinical decision
rule for the use of CT scan in children with head
injury enrolled more than 44,000 patients, more than
40 times the size of the largest study performed
previously. Dr. Chamberlain is the principal
60 | CCCR
investigator for a PECARN study in collaboration
with the Pediatric Pharmacology Research Unit
Network, including John Van den Anker, MD, PhD,
at Children's National. Utilizing the resources of
Children’s National, this two-phase study involves
determining the pharmacokinetics and efficacy
of lorazepam in children with status epilepticus.
Sponsored by NICHD under the auspices of the Best
Pharmaceuticals for Children Act, this study will be
used to seek FDA approval of lorazepam for children
with seizures.
One of PECARN's important protocols to date has
been the study of corticosteroids for the treatment
of bronchiolitis. PECARN enrolled 600 patients and
demonstrated conclusively that corticosteroids do not
improve the outcome of patients with bronchiolitis.
Additionally, because of the large sample size, the
study demonstrated that corticosteroids had no
effect in the subgroup of patients with atopy, a strong
risk factor for the development of asthma. These
results were published in the New England Journal
of Medicine (Corneli, NEJM, 2007).
PECARN gives clinical emergency medicine
teams the opportunity to develop research-based,
statistically evaluated guidelines as tools to provide
better care for the thousands of children who visit
emergency departments each year. n
Education, Training,
and Academic Excellence
Mary Ottolini, MD, MPH (left)
Vice Chair for Medical Education
Naomi L.C. Luban, MD (right)
Vice Chair for Faculty Affairs
Clinical Fellows by Specialty
Children’s National Faculty
Non-Tenure Track
n Instructor
n Asst. Prof.
n Assoc. Prof.
n Professor
Adolescent Medicine
Critical Care Medicine
Developmental Pediatrics
Emergency Medicine
Tenure Track
n Asst. Prof.
n Assoc. Prof.
Tenured n Asst. Prof.
n Assoc.00 Prof.
n Professor
Hospitalist Medicine
Infectious Disease
Pulmonary Medicine
Diagnostic Imaging/Radiology
Surgery (CV)
Total Faculty
n Male
n Female
Academic Promotions
Tenured Faculty
Professor, non-tenure track
Associate Professor, non-tenure track
Robert McCarter, ScD
Hany Aly, MD
Dana Best, MD
Peter Daniolos, MD
Professor of Pediatrics, and of Epidemiology
and Biostatistics Department
Professor of Pediatrics
Associate Professor of Pediatrics
Stephen Zeichner, MD, PhD
Rachel Moon, MD
Dale Coddington, MD
Associate Professor of Psychiatry
and of Pediatrics
Professor of Pediatrics
Associate Professor of Pediatrics
Maria Pena, MD
Philip Pearl, MD
Terry Kind, MD
Professor of Neurology and of Pediatrics
Associate Professor of Pediatrics
Associate Professor of Surgery
(Otolaryngology) and of Pediatrics
Professor of Pediatrics
Kanneboyina Nagaraju, DVM, PhD
Associate Professor of Integrative Systems Biology
Craig Sable, MD
Professor of Pediatrics
62 | Education
nMary C. Ottolini, MD, MPH
Vice Chair for Medical Education
Designated Institutional Official
Chair, Graduate Medical Education Committee
nEllie Hamburger, MD
Director, Children’s Academy of Master Educators
The Medical Education programs at Children’s National saw
many achievements during the past academic year and look
forward to a continued institutional emphasis on excellence
in patient care through excellence in trainee education. The
new Vice Chair for Education and Designated Institutional
Official, Mary Ottolini, MD, MPH, employs a variety of
educational strategies to strengthen Children’s residency
and fellowship programs’ ability to train experts in pediatric
health care. Areas of focus include development of a
robust simulation program for trainees to hone procedural,
communication, and teamwork skills, an enhanced formative
and summative feedback system to measure graduated
competency over years of training, and an emphasis
on teaching clinical reasoning skills and employing
metacognition to avoid diagnostic errors.
Dr. Ottolini holds national leadership roles in medical
education, as the Education Chair for the Academic
Pediatric Association, a member of the National Board of
Medical Examiners Pediatric Committee and the USMLE
Step 2 Pediatrics Test Material Development Committee,
leader of the Pediatric Hospitalist Medicine Education
Group, and recent graduate of the Hedwig van Ameringen
Executive Leadership in Academic Medicine Program for
Woman. She, along with Ellie Hamburger, MD, plan to launch
the Children’s Academy of Pediatric Educators (CAPE) to
recognize, promote, and reward teaching excellence across
the continuum of medical education. Dr. Hamburger will
lead the academy of more than 40 talented faculty members
who have gained a certificate or master’s degree in
education through the ongoing, successful Master Teacher
collaborative graduate program between the George
Washington University’s Schools of Education and Medicine.
Education is integral to our institutional Clinical, Advocacy,
Research, and Education mission. Education reverberates
throughout Children's mission. Our location in the nation’s
capital creates the ideal opportunity for advocacy training
for our pediatric residents. Residents learn how to best
advocate for the children of our nation, as well as the world.
This year, at the Pediatric Academic Society Annual Meeting
in Baltimore, Md., faculty members and residents presented
papers describing many advocacy educational initiatives.
Our global health elective has expanded under the
leadership of Melanie Anspacher, MD, to include a webbased curriculum, a week-long didactic course with
nationally renowned speakers and a month-long, in-country,
faculty-mentored experience. Grant funding was available
through the Children’s National Board of Visitors to defer
travel expenses. Last year nine residents participated and
trained in eight countries.
In addition to providing our residents with a global
perspective on children’s health needs by learning and
providing care in other nations, Children’s National, in
collaboration with the George Washington University School
of Medicine, under the leadership of Ellie Hamburger, MD,
and Dean Jim Scott, has successfully undertaken a huge
commitment to start the first pediatric post-graduate training
program for local physicians in Eritrea. Numerous Children’s
faculty traveled to the East African country as visiting faculty
and consultants for the program.
Medical Student Education
nTerry Kind, MD, MPH
Director of Pediatric Medical Student Education, and
nCraig DeWolfe, MD, MA
Associate Director of 4th Year Medical Student Education
nElizabeth Seelbach, MD
Associate Director of Howard Medical Student Education
The pediatric medical student curriculum promotes selfdirected learning, reflection, and professionalism through
portfolio building, attentive listening, active reading, and
reflective writing. There was a “literature in pediatrics”
session, where students travel back to the 1930s when a
physician makes a home visit to diagnose a child in William
Carlos Williams’ narrative “The Use of Force.” Students are
prompted to analyze the interactions among the story’s
characters and discuss their own interpretations, some of
which challenge the accepted wisdom about the “right” way
for a physician to feel.
We instituted an innovative Pediatrics Specialty Capstone
course for graduating GWU medical students matching in
pediatrics. Simulated learning environments allowed them to
rehearse the thought processes and procedural skills they
will need to confidently perform well in real scenarios.
Education | 63
Children's Research Day Poster Winners
Faculty Winner
CF Spurney, AD Guerron, M Lantorno, A Sali, J Van den Anker, GS Pandey, S
Ragavarapu, K Nagaraju
Losartan Decreases Cardiac Fibrosis and Prevents Cardiomyopathy in Dystrophin
Deficient Mice
Postdoctoral Fellow Winner
L Chakrabarti, T Best, WE Kaufmann, RSE Carney, S Fertuzinhos, N Sestan and TF
Genetic Rescue of the Neurological Phenotype in a Mouse Model of Down Syndrome
Student/Trainee Winner
EK Stancik, T Haydar
Fate-Mapping Progenitor Cells of the Telencephalic Ventricular Zone Via in Utero
Staff Winner
J Narola, A Glick, Y Chen
Conditional Expression of TGF-AY1 in Mouse Skeletal Muscles Causes Endomysial
Clinical Research
Faculty Winner
AN Massaro, N Kadom, T Chang, P Glass, K Nelson, S Baumgart
Quantitative Analysis of MR Images is Predictive of Adverse Neurological Outcome
in Encephalopathic Neonates Treated with Whole Body Hypothermia
Postdoctoral Fellow Winner
J Pike, A Krishnan, J Kaltma, MT Donofrio
Fetal and Neonatal Atrial Arrhythmias: As Association with Maternal Diabetes
Neonatal Macrosomia
Student/Trainee Winner
KB Blackstone, JM Mayo, CV Vaidya, WG Gaillard, MB Berl
Characterization of Memory Impairment in Pediatric Localization Related Epilepsy
Pediatric Residency Training Program
nDewesh Agrawal, MD, Director
nEdward Sepe, MD, MS, Associate Director
nCara Lichtenstein, MD, MPH, Associate Director
nSandra Cuzzi, MD, Associate Director
nHope Rhodes, MD, Chief Resident
nKaren Perry, MD, Chief Resident
The Pediatric Residency Training Program continues to thrive
under new leadership. In 2009, the program matched 29
first-class applicants for the intern class, one of the most
successful matches in years. More than 40 percent of all
the seniors at U.S. medical schools interested in pediatric
residency training apply to Children’s National. Of those, 28
percent of the new interns had advanced graduate degrees
(14 percent PhD, 7 percent MPH, and 7 percent MS).
64 | Education
Staff Winner
TT Duong, FM Hu, JE Mayhem, M Birkmeier, J Corderi, R Leshner
Comparing height measurements in boys with Duchenne muscular dystrophy
Community-Based Research
Faculty Winner
RY Moon, BL Joyner, RP Oden
African-American Parents’ Understanding of SIDS: Implications for Back to Sleep
Student/Trainee Winner
ET Padder, N Mirza
Food label workshop: A tool in the management of pediatric obesity
Staff Winner
MG Palmer, N Mirza
Food label workshop: A tool in the management of pediatric obesity
Education, Training, and Program Development
Faculty Winner
GR Lotrecchiano
Mechanisms of Transdisciplinary (TD) Learning: Characteristics of Crossing
Postdoctoral Fellow Winner
EM Kreiger, PE Manicone, MC Ottolini
Effect of Frequent Anonymous Feedback from Trainees on Overall Teaching
Effectiveness of Hospitalists During Inpatient Pediatric Rotations
Student/Trainee Winner
H Felman, O Omojokun, E Rosenthal, C Lichtenstein
Evaluation of Advocacy Educational Experiences for Pediatric Residents at Children’s
National Medical Center
Staff Winner
A Naipaul, S Khandelwal, B Pastor, MB Sten, S Young, BR Jacobs
Improving the Quality of Pediatric Pain: Utilizing the EMR for the Assessment and
Management of Pediatric Pain
The Robert H. Parrott REACH program stands for the
cornerstone elements of the program: Research, Education,
and Advocacy in Child Health. This unique program allows
residents the opportunity to receive one half-day per week
protected time in the second and third years of training to
pursue projects and activities in these areas. Last year, 22
pediatric residents published their work in peer-reviewed
journals and presented at major national meetings. In
addition, pediatric residents managed to procure more than
$40,000 in grants to support their pursuits.
Major program enhancements last year included: roll-out of
an Accreditation Council for Graduate Medical Education
(ACGME) core competency based electronic portfolio,
implementation of a new resource for self-directed learning
on Blackboard, and a new curriculum in resuscitation
incorporating usage of the new Simulation Center. Plans for
the new academic year include expansion of the simulation
curriculum, a new curriculum on end-of-life communication,
a new curriculum on training residents as teachers and
leaders, a new curriculum on board preparation, a new
advocacy curriculum, and incorporating health information
technology for medical education.
Graduate Medical Education (GME)
nMary Ottolini, MD, MPH, Director
nJacklyn Fuller, GME Manager
The office of Graduate Medical Education provides
administrative support to more than 205 residents and
fellows who are enrolled in 17 ACGME-accredited and 14
non ACGME-accredited training programs at Children’s
National. This past year, the GME office conducted a
comprehensive review of its organizational structure to
realign the program to meet and exceed the expectations of
the ACGME.
In FY09, eight subspecialty training programs were
reviewed by the ACGME. Seven programs received
continued accreditation, and six of those programs received
commendation statements for their demonstrated substantial
compliance with ACGME requirements for GME.
Academic Services Assistance Program (ASAP)
nGaetano R. Lotrecchiano, PhD, Director
nJoseph Knight, Project Manager
nLorraine Berko, Project Associate
The Academic Services Assistance Program (ASAP)
manages different initiatives dedicated to ensuring
academic success and research education.
Training module
The training module of the program maintained its annual
curriculum, offering weekly instruction in informatics, study
design, e-library, finance, institutional review, leadership,
medical education, and professional writing throughout
the academic year. This resulted in 44 hours of instruction
delivered to more than 322 participants.
9th annual Children's Research Day
Each year Children’s National hosts a poster session
highlighting the research, education, and programmatic
activities of the institution. In FY09 a record number of
posters were submitted and shown and awards were
granted to categories of basic/translational, clinical, and
community research, as well as education, training, and
program development.
Leadership Education in Neurodevelopmental
Disabilities (LEND) Program
nGaetano R. Lotrecchiano, PhD, Director/Principal
nJoseph Knight, Project Manager
nLorraine Berko, Project Associate
The Leadership Education in Neurodevelopmental and
Related Disabilities (LEND) Program at Children’s operates
within the university systems of George Washington
University, Georgetown University, Howard University,
University of Maryland College Park, and the Catholic
University of America with relationships with District of
Columbia-area healthcare programs, local government
offices, and institutes dedicated to servicing children
with developmental disabilities. The program is funded
by the Maternal and Child Health Bureau, a division of
the Health Resources and Services Administration in the
U.S. Department of Health and Human Services. Its goal
is to cultivate interdisciplinary approaches and attitudes
to dealing with children with disabilities by training
professionals in a variety of disciplinary areas emphasizing
future leadership.
In FY09, The LEND program’s funding was secured through
2011 and DC LEND successfully secured additional funding
through expansion programs in the areas of Autism and
Audiology. These two additional programs, in conjunction
with the core LEND program, make the DC LEND program
one of the few sites nationwide possessing this level of
funding support.
Academic Affairs
nNaomi L. C. Luban, MD, Vice Chair for Academic Affairs
nSusan Pfennig, Manager, Medical and Academic Affairs
nPatricia Minor, Staff Assistant
Academic Affairs has several strategic goals to encourage
academic productivity, provide mentorship to all junior
faculty, and enhance the presence of women and minorities
in leadership positions. The programs, workshops, and
activities of Academic Affairs involve both CRI and
clinical faculty and promote academic success, faculty
advancement, and national recognition.
New faculty orientation
This day-long program for incoming faculty provides an
overview of institutional capabilities and the appointment
Education | 65
process. This past year, a primer was provided to all
incoming faculty detailing contact information and defining
resources for clinical and translational research resources.
Academic goals and objectives
The annual performance review process now includes a
review of both academic and educational efforts in addition
to clinical activity. Annually, Drs. Batshaw, Luban, and
Ottolini review every faculty member’s achievements; during
these sessions, they provide improvement metrics that can
be adapted by division chiefs for use with each faculty
member. This year two sessions on “How to Prepare and
Use Goals and Objectives” were held for division chiefs.
Faculty mentorship
The Faculty Mentorship program was established in
2000 to promote the careers of tenure track and research
intensive junior faculty. This program is a one-on-one
program that has successfully launched the careers of
more than 25 faculty with K, career development, and
minority supplements. As the faculty grew, we recognized
that the intense resources required for this program could
not be sustained. Therefore, we implemented the Master
Mentorship Program in 2008 with 14 faculty representing
clinical and research centers of excellence. The goals of the
Master Mentor program are to improve the skills of midlevel
faculty in mentorship, increase the number of fellows
engaged in CRI activities, strengthen interdisciplinary
research among K and career development awardees,
establish Bench-to-Bedside Professional and Grand Rounds,
develop programs on multidisciplinary team science,
and maximize the mentorship team. The group has been
successful in accomplishing more than half of its goals with
a successful spring retreat attended by 35 junior faculty
and 12 master mentors along with senior CRI leadership.
In addition, six Bench-to-Bedside Professorial Rounds
have highlighted team science through our CRI research
and clinical programs. Lastly, we revamped the fellows’
scholarly research objectives with a mandated minimal
clinical research curriculum and two Show and Tell Sessions
given by CRI faculty. Plans for the coming year include presubmission grant review by Master Mentors and sourcing
mentors for fellows.
The ASAP web site was improved to include details on all
career development awards with deadlines and contact
information as well as the ASAP curriculum.
An additional outcome from the retreat is the establishment
of a clinical and translational Team Science Colloquia, a
series of eight presentations focusing on building skills in
Team Science.
66 | Education
Grants Writing Workshops
As part of our shared Georgetown-Children’s-Howard
K30 program, a 50-hour grants workshop program was
developed. Most of the lectures and workshops held were at
Children’s National and therefore were opened to all faculty.
In this coming year, all lectures and workshops will be video
archived and made available to all faculty and fellows in
addition to our current five K30 Scholars. These sessions
will avoid duplication of ASAP lectures/presentations and
improve the quality of grants submitted by our junior faculty.
Introduction to the Principles and Practice of
Clinical Research
This six-month course, which emanates out of the NIH
was offered this year through web casting. In the past two
academic years, a total of 88 research associates, fellows,
and faculty took advantage of the program and 26 obtained
certificates in Clinical and Translational Research.
Women in Medicine Program
WATCH continues both formal and informal mentorship
programming, including a New Faculty Coffee, winter
lecture, and spring Grand Rounds. The winter lecturer
was Manuella W. Hancock, Esq., from Hancock Legal,
who spoke on “Anatomy of the Executive Contract: An
Introduction to Understanding and Negotiating Employment
Contracts.” We were honored to host Barbara M. Alving, MD,
MACP, Director, National Center for Research Resources
(NCRR) who presented “Best Practices for Sustained Career
Success” for the spring Grand Rounds.
This past year, Mary Ottolini, MD, completed the Executive
Leadership Among Women (ELAM) program. Leticia Ryan,
MD, K23 awardee and Emergency Department faculty,
attended the Association of American Medical Colleges
(AAMC) junior faculty program. This fall, Naomi Luban,
MD, will present the WATCH program at the annual AAMC
meeting. Advancing and retaining female leaders at
Children’s National was the topic of a special meeting of
female faculty held this spring; a white paper is in press
which details action plans to improve professional female
Faculty Achievements
Education-Related Publications 2008–2009
nChretien KC, Greysen SR, Chretien JP, Kind T. Online Posting of
Unprofessional Content by Medical Students. JAMA. 2009 (in press).
n Kind T. An Incurable Disease. Academic Medicine. (Teaching and Learning
Moments). Acad Med. 2008 Dec;83(12):1165.
n Kind T, Everett VR, Ottolini M. Learning to Connect: Students’ Reflections
on Doctor-Patient Interactions. Patient Education and Counseling. 2009
n Lotrecchiano GR. (2009) Complexity Leadership in Transdisciplinary (TD)
Learning Environments: A Knowledge Feedback Loop, The International
Journal of Transdisciplinary Research (in press).
n Ottolini MC, Ozuah P, Mirza N, Greenberg L: Evaluation of the “Five Minute
Preceptor” Ambulatory Precepting Model. Teaching and Learning in
Medicine, (in press).
nTurner T, Kind T, Bernstein H. “Hot Topic: Practice Makes Perfect.”
Available May 2009 at
nWaldman Z, Rassbach C: Checklist in Pediatrics. Pocket Medicine. In Press
May 2009.
nBurley D, Savion S, Peterson M, Lotrecchiano GR, Keshnavarz-Nia, N,
Knowledge Integration through Synthetic Worlds. VINE: The Journal of
Information and Knowledge Management Systems, (in press).
National Presentations
nRaphael L, Mintz M, Jablonover R, Macri C, Frank J, Lee J, Kind T. A 3rd
Year Multi-Clerkship Integrated Medical Humanities Curriculum. AAMC
National Meeting. San Antonio, Texas. Nov 2008.
nPediatric Academic Societies Annual Meeting
May 2–May 5, 2009, Baltimore, MD.
Presentations and Poster Sessions
nChanging Your Institutional Teaching Culture: Applying Adult Learning
Principles to the Clinical Setting; Co-Leader: Mary Ottolini, MD, MPH.
nAdvanced Leadership Development: Leading and Managing Change,
Clinician Performance Measures and Time Management; Leader: Denice
Cora-Bramble, Co-Leaders: Claibourne Dungy, Thomas G. DeWitt.
nEducational Scholarship: Writing, Publishing, and Reaping the Rewards;
Co-Leader: Mary Ottolini MD, MPH.
nTeaching Doctors How To “Think”: Keys To Reducing Diagnostic Errors;
Co-Leader: Mary Ottolini MD, MPH.
nIncorporating Best Practices in Conducting Family-Centered Rounds
(FCRs): Teaching the Trainee a Standardized Approach to Family-Centered
Rounds; Co-Leader: Mary Ottolini MD, MPH.
nPerspective-Taking: An Evidence-Based Intervention To Reduce Medical
Student Bias and Increase Patient Satisfaction; Larrie Greenberg, Benjamin
Blatt, Susan LeLacheur, Adam Galinsky, Samuel J. Simmens, Sheik
nCan PGY-1s Teach Better Than PBY-2s? You Bet, with a Brief Intervention!
Larrie Greenberg, Benjamin Blatt, Jennifer M. Keller, Ming Yi K. Mah,
Charles J. Macri, Nancy D. Gaba, Samuel J. Simmens.
nEducational Scholars Program, 2009; Speaker: Mary Ottolini, MD, MPH.
nCoaching for Success: Help Your Faculty and Trainees “Be All They Can Be;
Leader: Christine O. Corriveau MD, MPH.
nPediatricians as Advocates: Preparing Residents To Be Effective
Champions of Children’s Health; Co-Leader: Jerome A. Paulson MD,
Joseph L. Wright MD, Mid-Atlantic Center for Children’s Health and the
nApplying Family-Centered Care in the Inpatient Setting; Speaker: Mary
Ottolini MD, MPH.
nLifelong Learning and Professional Development in the 21st Century; Teri
Turner MD, EdD, Terry Kind MD, MPH, Hank Bernstein, MD.
Other National Workshops
nKind T, Chretien KC, Raphael L. Reflection Is Not An Elective: Integrating
Reflective Practice Into The Clerkship. COMSEP National Meeting April 29,
Other Faculty Awards and Achievements
nPavan Zaveri, MD
2008-2009 Excellence in Teaching Award for Attending, Division of
Emergency Medicine
nPhillip Pearl, MD
ACGME Board of Directors confirmed appointment to the Review
Committee for Neurology at its June 2009 meeting
nSukgi Choi, MD
President of the American Society of Pediatric Otolaryngology
nDorothy Bulas, MD
2009 Alpha Omega Alpha—honorary member bestowed by Drexel Medical
nMichael Guerrera, MD
Nominated to be one of two physicians on the regional executive
committee for the Region III Hemophilia treatment centers
nBarbara Jantausch, MD
Chairman, National Institutes of Health (NIH) Safety Monitoring Committee
for a Biodefense Research Study, 2009
nIra Cohen MD, MA
David Powell, MD
Elda Arce Award for Excellence in Education
nPaul Manicone, MD
2009 “Golden Apple Award” for excellence in teaching, voted by the
pediatric housestaff
nHospitalist Division
The 2009 “Golden Apple Award” for excellence in teaching for a required
rotation, voted by the pediatric housestaff
nInfectious Disease Division
The 2009 “Golden Apple Award” excellence in teaching for a non-required
rotation, voted by the pediatric house staff
Education | 67
The Sheikh Zayed Institute for
Pediatric Surgical Innovation
n September 16, 2009, Children’s
National announced the creation of
the Sheikh Zayed Institute for Pediatric
Surgical Innovation, made possible by a historic
philanthropic gift from the Government of Abu
Dhabi. The $150 million gift will allow the hospital to
bring together surgeons and researchers to make
surgery more precise, less invasive, and pain-free
for children around the world.
The Institute will focus on four initiatives that together
will open a new era for pediatric surgery:
Medicine: The Institute’s goal is to eliminate
pain before, during, and after surgery by
accurately measuring pain and identifying more
effective medications and treatments.
n Bioengineering: Surgeons and researchers will
harness the full power of biomedical imaging
and the computational sciences to achieve
unprecedented levels of precision.
n Immunology: The Institute will seek innovative
immunotherapies to suppress or stimulate a
child’s own immune system to cure disease—in
many cases, eliminating the need for surgery.
n Systems Biology: The decoding of the human
genome will allow surgeons and researchers to
personalized surgery for every child based on
his/her specific genetic makeup.
n Pain
68 | Institute for Pediatric Surgical Innovation
These four initiatives will be guided using business
model principles of innovation management to
expedite discovery and bring new therapies to
children as quickly as possible.
At the announcement event, His Excellency
Ambassador Yousef Al Otaiba, UAE Ambassador
to the United States, said, “We know illness and
disease know no boundaries or borders. Medical
advances require cooperation, partnership,
resources, and determination. This new institute
will bring together the best minds in the field of
pediatric surgery, pain management, and medical
research all with a singular focus to initiate
breakthroughs and find solutions.”
The gift also will create eight fellowships in
pediatric surgical innovation. Named the Robert
Fellowships, in honor of longtime supporter Joseph
E. Robert, Jr., the two-year fellowships will allow
promising young surgeons and researchers to
study the innovation management framework and
apply it to surgery and research.
Through these efforts, the Sheikh Zayed Institute
for Pediatric Surgical Innovation aims to quickly
translate research to care, share new knowledge
and medical discoveries, and benefit children
across the country and around the world. n
highlighted NIH grants and awards
NIH Grants
nTUCHMAN. The Molecular Bases of Inherited Urea Cycles Disorders and
Center for Cancer and Immunology Research
nVANDERVER. Molecular Mechanisms in Vanishing White Matter Disease.
nD’ANGELO. Improving Minority Health in Washington, DC. NICHD.
nD’ANGELO. Adolescent Medicine Trials Network for HIV/AIDS. NICHD.
nDOME. Telomere Maintenance Mechanisms in Human Osteosarcoma. NCI.
nHILL. Children’s Oncology Group. NCI.
Ureagenesis Regulation. NIH/NIDDK.
Center for Neuroscience Research
nAGUIRRE. A Role for EGF Signaling in Oligodendrocyte Development and
Repair. NIH.
nHINDS. Family Decision Making in Pediatric Bone Marrow Transplant. NCI.
nLADISCH. Immunosuppressive Neuroblastoma Tumor Gangliosides. NCI.
nALFANO. Mechanism of Sleep Disturbance in Children with Generalized
nLADISCH. Role of Gangliosides in Tumor Progression. NCI.
nLUCHTMAN-JONES. Pediatric Hydrxyurea Phase III Clinical Trial - Clinical
nCORBIN. Development of the Basal Telencephalic Limbic System. NIH.
Centers. NHLBI.
nROOD. Creation of a PDGF-C Autocrine Loop by HIC1 Inactivation. NINDS.
nZEICHNER. NICHD Contract for the International and Domestic Pediatric
and Maternal HIV Studies. NICHD.
nZEICHNER. HIV Microbicides and the Vaginal Microbiome. NIAID.
nCOLBERG-POLEY. HCMV UL37 Proteins: Trafficking & Functional Diversity.
nCOLBERG-POLEY. Alteration of ER:mitochondrial Contacts by Human
Cytomegalovirus Infection. NIAID.
nDOME. Telomerase as a Therapeutic Target for Pediatric Cancer.
nHILL Genetic Characterization of the Pleuropulmonary Blastoma Family
Cancer Syndrome. Center for Genetic Medicine Research
nCHEN. Molecular Pathophysiology of FSHD Muscular Dystrophy via
Genome-wide Approaches. NIH.
nCNAAN. CINRG Infrastructure for Clinical Trials in Duchenne. DOD.
nFREISHTAT. Analysis of Immunity and Thrombosis in Acute Lung Injury.
nHOFFMAN. Functional SNPs Associated with Muscle Size and Strength.
nHOFFMAN. Genetics and Genomic Approaches to Lung Diseases and
Disorders in Washington, DC. NIH.
nHOFFMAN. Improved Diagnostics of the Muscular Dystrophies. NIH.
nHOFFMAN. Integrated Molecular Core for Rehabilitation Medicine. NIH.
nHOFFMAN. Wellstone Muscular Dystrophy Center: Children’s National
Medical Center (Admin Core). NIH.
nHOFFMAN. Toxicology Program for Exon Skipping in DMD. DOD.
nLEVY. Cytochrome oxidase inhibition in septic heart. NIH.
nNAGARAJU. Pathogenesis of Autoimmune Myositis: Role of MHC Class 1.
nONYEWU. 2008 UNCF/MERCK Postdoctoral Science Research Fellowship.
nPARTRIDGE. CINRG - Non-Hormonal Steroid Drug Development in DMD.
nPARTRIDGE. Role of the Nuclear Envelope in Muscle Satellite Cell Activity.
nPENA. Impact of Inflammatory Genes on Glandular Hyperplasia in Children
with Sinusitis. NIH.
Anxiety Disorder. NIH.
nGAILLARD. Plasticity of Language Networks in Childhood Epilepsy. NIH.
nGALLO. Postdoctoral Training in Developmental Disabilities Research. NIH.
nGALLO. MRDDRC at Children’s National Medical Center Administration
Core. NIH.
nGALLO. Characterization of SOX17 As a Regulator of Oligodendrocyte Cell
Differentiation. NIH/NINDS.
nHAYDAR. Neocortical Neurogenesis and Mitotic Spindle Dynamics. NIH.
nJONAS. Neuroprotection with Serpins During Cardiac Surgery. NIH/NHLBI.
nKENWORTHY. Structural and Functional Neuroanatomy, Cognition and
Genetic Variation in Individuals with Autism. NIH.
nPACKER. Under St. Jude Children’s Research Hospital Contract. The
Pediatric Brain Tumor Consortium (PBTC). NIH.
nPACKER. Neurological Sciences Academic Development at Children’s
National Medical Center. NIH.
nCORBIN. Rescue of GABAergic Transmission Defects in the Amygdala
in the Fmr1-/- Mutant Mouse Model of Fragile X Syndrome. FRAAXA
Research Foundation.
nZOHN. Molecular Mechanisms Causing Spina Bifida and Exencephaly in
p381P-Mutant Embryos. March of Dimes.
Center for Molecular Physiology Research
nJOSE. ARRA Administrative supplement for 2R01 DK039308. NIH.
nJOSE. Calcium and Sodium Transport in Hypertension. NIH.
nJOSE. Dopamine-1 Receptor Defect in Hypertension. NIH.
nJOSE. Dopamine/Angiostensin Receptors in Genetic Hypertension. NIH.
nJOSE. GRK4 and Development of Salt Sensitivity. NIH.
nJOSE. Renal Dopamine Receptor and Regulation. NIH.
nJOSE. Renal Vascular Oxidative Stress in Hypertension. NIH.
nRAY. Iron and Vitamin E in Childhood HIV-Associated Renal Disease. NIH.
nRAY. BFGF Low Affinity Receptors and HIVAN. NIH.
nRAY. Pathogenesis of HIV-HUS in Children. NIH.
Center for Clinical and Community Research
nBatshaw. NIH, NCRR. 1 M01 RR020359-01 General Clinical Research
nBatshaw. NIH, NCRR. U54RR019453-05 Rare Disease Clinical Research
Center – Urea Cycle Disorders.
nROSE. Role of MUC5AC Mucins in Airway Asthma. NHLBI.
nBeers. OAPP/OPA, DHHS. Healthy Generations.
nTUCHMAN. N-acetylglutamate Synthase: Structure, Function & Defects.
nBeers. American Academy of Pediatrics. Developing an Intervention to
n TUCHMAN. N-carbamylglutamate in the Treatment of Hyperammonemia. NIH.
70 | Grants and Awards
Support Co-parenting in Adolescent Parents.
nBurd. National Science Foundation. Vision and RFID for Multimodal
Tracking of Working Teams.
nBurd. National Science Foundation. Multimodal Capture of Teamwork in
Collocated Collaboration.
nChamberlain. HRSA, MCHB. Chesapeake Applied Research Network for
nChamberlain. NIH, NICHD. Lorazepam for Status Epilepticus.
nChamberlain. MCHB, EMSC. Defining Quality Performance Measures for
Pediatric Emergency Care.
nCora-Bramble. NIH, NIMHD. P20MD000198 Washington DC-Baltimore
Center To Improve Child Health Disparities.
nHinds. NIH, NINR. Family Decision Making in Pediatric Bone Marrow
nHinds. NIH, NIAMS. PROMIS Supplement to Expand Testing of the
Pediatrics PROMIS Tools.
nHinds. Alex’s Lemonade Stand Foundation. Testing a Hospital Sleep
Hygiene Intervention.
nJoseph. NIH, NIMH. R01 MH072577 Violence Exposure and Teen
Mothers: A Multiethnic Study.
nLuban. NLC. NIH, NCRR. Science Education Partnership Award (SEPA).
nLuban. NIH, NHLBI. Washington Area Basic Translational Research
Program in Sickle Cell Disease.
nLuban. NIH, NHLBI. Transfusion Infections: Pediatric Prospective Study.
nMoon. NIH, NCRR. Factors Influencing the Racial Disparity in SIDS.
nMoon. Bill and Melinda Gates Foundation. Bedtime Basics for Babies.
nMoon. AHRQ. Factors Affecting the Racial Disparity in SIDS.
nO’Connell. HRSA. EMSC Targeted Issues Grant: Evaluating Parental
Presence During Resuscitation.
nStreisand. NIH, NIDDK. R01 Parenting and Control Among Young
Children with T1 Diabetes.
nStreisand. NIH, NIDDK. Prevention of Self Care Deterioration in Early
Adolescents with Diabetes.
nTeach. NIH, NIAID. Inner City Asthma Consortium.
nTeach. CDC under DC Government. CDC P0149282 Surveillance of ED
Visits for Asthma in the District of Columbia.
nTuchman. NIH, NIDDK. N-acetylglutamate Synthase: Structure, Function
and Defects.
nTuchman. NIH, NICHD. N-carbamylglutamate in the Treatment of
nTuchman. NIH, NIDDK. The Molecular Bases of Inherited Urea Cycle
Disorders and Ureagenesis Regulation.
NIH Career Development and Institutional Grants
K Awards
nAdeline Vanderver, MD, received a Mentored Clinical Scientist Development
Award for research in Molecular Mechanisms in Vanishing White Matter
Disease. (K08)
nBrian Rood, MD, received a Mentored Clinical Scientist Development Award for
research in Creation of a PDGF-C Autocrine Loop by HIC1 Inactivation. (K08)
nCandice Alfano, PhD, received the Mentored Patient-Oriented Scientist
Development Award for Mechanisms of Sleep Disturbance in Children with
Generalized Anxiety Disorders. (K23)
nCynthia Ronzio, PhD, received a Mentored Research Scientist Development
Award for work in physician communications with African-American
patients. (K01)
nIvor Horn, MD, received a Mentored Clinical Scientist Development
Award for research in Physician’s Communications with African American
Patients. (K23)
nJohn Van Den Anker, MD, PhD, was awarded the Midcareer Investigator
Award in Patient-Oriented Research for work in Optimizing Pain Treatment
in the Preterm Infant. (K24)
nLeticia Ryan, MD, received the Mentored Patient-Oriented Scientist
Development Award for research in the Analysis of Bone Health in
African-American Children with Forearm Fractures. (K23)
nLjubica Caldovic, PhD, received a Mentored Research Scientist
Development Award for work in Molecular Regulation of Ureagenesis. (K01)
nNazrat Mirza, MD, ScD, received the Mentored Patient-Oriented Scientist
Development Award for research in Low Glycemic Load Diets in Latino
Children at Risk for Type 2 Diabetes. (K23)
nRachel Moon, MD, was awarded the Midcareer Investigator Award in
Patient-Oriented Research for work in determining the Factors Influencing
Racial Disparity in SIDS. (K24)
nRichard Levy, MD, received a Mentored Clinical Scientist Development
Award for research in Cytochrome Oxidase Inhibition in Septic Heart. (K08)
nRoberta Debiasi, MD, received a Mentored Clinical Scientist Development
Award for research in Apoptotic Signaling in Viral Myocarditis. (K08)
nRobert Freishtat, MD, MPH, received the Mentored Patient-Oriented
Scientist Development Award for research in the Analysis of Immunity and
Thrombosis in Acute Lung Injury. (K23)
Child Health Research Center Development Award
nKevin Buckley, MD, received a Child Health Research Center (CHRC)
Development award for work in TCR avidity and its Effect on T-cell
Repopulation in Lymphopenic Hosts.
nSusan Sparks, MD, PhD, received a Child Health Research Center (CHRC)
Development award for work in Glycosylation and Muscular Dystrophy.
Pediatric Clinical Scholars Award
nAn Nguyen Massaro, MD, received a Pediatric Clinical Research Center
(PCRS) scholarship for work in Predicting Outcomes in Patients with
Hypothermia-Treated Neonatal Encephalopathy.
nMadison Berl, MD, received a Pediatric Clinical Research Center (PCRS)
scholarship for work in Working Memory and Language in Children with
Genomics of Lung Career Development Awards (GLDA)
nDiego Preciado, MD, received a GLDA scholarship for work in Genomic
and Proteomic Profiling of Inducible Otitis Media Mucoid Metaplasia.
nDinesh Pillai, MD, received a GLDA scholarship for work in the Role of
Circadian Oscillator Gene Polymorphisms in Asthmatic Airway Epithelium.
nPerry Payne, MD, MPP, JD, received a GLDA scholarship for work in
Assessing the Impact of Ancestry-environment Interactions in Asthmatic
nSabah Iqbal, MD, received a GLDA scholarship for work in TLR4 and
ADAM33 Epigenetic Modifications in Asthma.
Grants and Awards | 71
Intramural Research Awards
Research Advisory Committee Award
nChristopher Spurney, MD, received a RAC Faculty scholarship for work in
Determination of miRNA Expression Profiles in the Cardiomyopathy of
Dystrophin Deficient mdx Mice.
nJeff Lukish, MD, received a RAC Faculty scholarship for work in the Safety
and Efficacy of Ovarian Tissue Cryopreservation in Young Females with
nMary Rose, PhD, received a RAC Faculty scholarship for work in IL8-
induced Post-transcriptional Regulation of the MUC5AC mucin gene.
nMatthew Sharron, MD, received a RAC Fellows scholarship for work in
Mechanisms of Granzyme B-platelet Induced Lymphocyte Apoptosis in
nNancy Bauman, MD, received a RAC Faculty scholarship for work entitled
"Propanolol vs Prednisolone for Infant Hemangiomas – A Clinical and
Molecular Study."
nRoberta Debiasi, MD, received a RAC Faculty scholarship for work in
G-Protein Coupled Receptor Signaling in Viral Myocarditis.
nRobert Yim, MD, received a RAC Fellows scholarship for work in Macrolide
Effects on Mucin Expression in CF Respiratory Epithelial Cells.
nStanislav Vukmanovic, MD, PhD, received a RAC Faculty scholarship
for work entitled A Novel Role of HLA Class I in the Pathogenesis of
Inflammatory Disorders.
nSteven Zeichner, MD, PhD, received a RAC Faculty scholarship for work in
HIV Activation through Selective Knockdown of Ikappa Bepsilon.
nYaser Diab, MD, received a RAC Fellows scholarship for work in storage
of Small Volume Apheresis Platelet Concentrates for Neonatal Use—
Comparative in vitro Study.
nYetrib Hathout, PhD, received a RAC Faculty scholarship for work in the
Study of Astrocytoma Secretome.
Avery Scholar Award
nDiego Preciado, MD, received an Avery scholarship for work entitled
“Molecular Mechanisms of Cigarette Smoke Induced Pro-Inflammatory
and Mucin Gene Activation in Otitis Media.”
nIrene Zohn, PhD, received an Avery scholarship for work entitled “P381P
in the Regulation of Mesoderm Developmental and Neural Tube Closure.”
nSasa Radoja, PhD, received an Avery scholarship for work entitled
“Regulation of Lytic Granule Exocytosis by Protein Kinase C delta.”
72 | Grants and Awards
Children's National Medical Center, located in Washington, DC,
is a proven leader in the development of innovative new
treatments for childhood illness and injury. Children’s has been
serving the nation's children for more than 135 years. Children’s
National is proudly ranked among the best pediatric hospitals in
America by US News & World Report and the Leapfrog Group.
Children’s Research Institute, the academic arm of Children’s
National Medical Center, encompasses the translational, clinical,
and community research efforts of the institution.
Edwin K. Zechman, Jr.
President and Chief Executive Officer
Mark L. Batshaw, MD
Chief Academic Officer,
Children's National
Director, CRI
Jacqueline D. Bowens
Vice President and Chief Government
and External Affairs Officer
Gaetano R. Lotrecchiano, PhD
Program Director, Academic Services
For more information, visit
Managing Editor
Jennifer Leischer
Corinne Ahrens
Sarah Wagoner
Design and Production
Marcotte Wagner
Office of Academic Services
Gaetano R. Lotrecchiano, PhD, Program Director
111 Michigan Ave., NW
Washington, DC 20010
Reprinted with permission,
Lloyd Wolf
Copyright © 2010 by Children’s National Medical Center. All rights reserved. The bear logo and Children’s National Medical Center are
registered trademarks. The names of the other organizations within the Children’s National Medical Center system are service marks of
Children’s National Medical Center and/or its affiliates.
A member of the Children’s Miracle Network.
Children’s does not discriminate on any grounds prohibited by applicable law, including race, color, religion, age, sex, national origin or ancestry,
sexual orientation, marital status, status as a disabled or Vietnam veteran, or as a qualified disabled individual.
Cert no. SW-COC-002142
Copyright © 2009 by Children’s National Medical Center. All rights reserved. The bear logo and Children’s National Medical Center are
registered trademarks. The names of the other organizations within the Children’s National Medical Center system are service marks of
Children’s National Medical Center and/or its affiliates.
A member of the Children’s Miracle Network.
Children’s does not discriminate on any grounds prohibited by applicable law, including race, color, religion, age, sex, national origin or ancestry,
sexual orientation, marital status, status as a disabled or Vietnam veteran, or as a qualified disabled individual.
Cert no. SW-COC-002142