Children'S Research Institute

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Background: Young men bear a disproportionate burden of HIV incidence in the U.S. Though pre-exposure prophylaxis (PrEP) use is increasing among young men at risk for HIV (YMRH), dropout from care is high, and YMRH are more likely than older men to contract HIV after discontinuing PrEP. Existing CDC-recommended evidence-based practices (e.g., motivational interviewing, personalized health education, linkage to couples HIV testing) can increase retention in care and use of PrEP and other effective HIV prevention methods among YMRH. Research is needed to facilitate their delivery in diverse clinic settings. Present Study: The proposed mentored patient-oriented career development award (K23) project will use implementation science methods to identify and evaluate strategies to implement these evidence-based practices (hereafter, “HIV Prevention Plus Care” or “HP+ Care”) with YMRH starting PrEP in two clinic settings. HP+ Care will include MI and personalized health education to promote retention in care and use of PrEP and other prevention methods. Specific aims are: (1) using the integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework, investigate factors influencing implementation of HP+ care for YMRH in the constructs of recipients (staff), context (clinics), and innovation (CDC-recommended evidence-based practices); (2) using Aim 1 data, identify appropriate Expert Recommendations in Implementing Change (ERIC) implementation strategies to deliver HP+ Care in two clinics; and (3) pilot the implementation strategies in two clinics to assess feasibility, acceptability, and appropriateness. Candidate: Andrew Barnett, Ph.D., is a faculty psychologist in the HIV program at Children’s National Hospital whose research focuses on promoting health, including HIV prevention, among adolescents and young adults. Mentoring: The primary mentor, Dr. David Huebner, is an expert in HIV preventive interventions for YMRH, and four co-mentors have complementary expertise in rigorous quantitative analysis methods (Dr. Barker); HIV prevention and PrEP engagement in clinic settings (Dr. Chan); leading multisite research investigations to enhance HIV care or prevent HIV (Dr. Brown); and applying implementation science methods to improve delivery of evidence-based practices in healthcare (Dr. Elwy). Training: Training activities will advance the following goals: (1) gain experience in conducting implementation science investigations to prevent HIV in healthcare settings; (2) expand knowledge of novel biomedical HIV prevention approaches, including PrEP on-demand, long-acting injectable PrEP, and other modalities currently under development; (3) gain expertise in methods for quantitative analysis of clustered data, including hierarchical linear modeling; and (4) advance professional development, research ethics, and grants management skills. Training will prepare the candidate to conduct NIH-funded independent investigations.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY During pediatric primary care and urgent care visits, parents serve as surrogate decision makers for their children, who themselves have evolving developmental contexts and roles in healthcare decision making. When multiple potential choices for care exist, pediatricians and families commonly engage in shared decision making (SDM), which involves collaboration between the physician and parent – as well as the child when developmentally appropriate – to make a healthcare decision. In SDM, the pediatrician elicits parents’ values and goals for their child’s care and engages them to make a healthcare decision that aligns with these values and goals. While there is strong evidence that SDM leads to increased patient satisfaction and improved health outcomes, many patients and physicians do not feel empowered to engage in SDM, and there is a gap in our understanding of the optimal use of SDM in primary care, particularly for well and sick visits among pediatric patients. Further, limited interventions have been developed and rigorously evaluated for use with parents and pediatric patients to facilitate SDM. Because children receive most or all of their healthcare in a primary care setting, it is imperative that we elucidate the factors that support and hinder SDM so that families may make informed decisions in these settings. The proposed project’s overall objective is to identify factors that facilitate SDM in pediatric primary care settings to inform a targeted family engagement intervention for pediatricians to facilitate shared decision making in real-world clinical settings. We will accomplish the project objective through a mixed-methods study with the following aims: 1) Identify baseline experiences, expectations, and determinants of shared decision making among parents in a pediatric primary care setting; 2) Explore pediatricians’ and parents’ perceived challenges and facilitators of SDM in real-world clinical settings; and 3) Develop and evaluate a targeted shared decision-making pilot intervention for pediatricians tailored to facilitate parent engagement in informed decision making in a pediatric primary care setting. This pilot study has the potential to generate contemporary parent-engagement tools to foster physician and parent comfort with facilitating discussions around shared decision making, and ultimately to empower parents to make informed healthcare decisions for their children that align with their values and goals for their child’s care. In the process, I will advance my training by developing 1) expertise in behavioral science and patient engagement, 2) advanced techniques in mixed methods design, 3) expertise in behavioral interventions and implementation science, and 4) leadership and professional development skills to translate my findings into clinical practice. In summary, this research will develop my expertise in mixed methods and behavioral interventions, enabling me to become an independent investigator capable of developing and translating novel shared decision-making interventions to real-world clinical settings, with the ultimate goal of promoting family engagement in informed decision making for children.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT: Approximately 1.6 million children access the healthcare system through Emergency Medical Services (EMS) each year in the U.S. Despite an absence of validated EMS triage tools, 30% of all children are left at the scene, while many low acuity children are transported to an emergency department (ED) unnecessarily. This non-standardized EMS approach results in both under-triage and over-triage of children. The use of EMS for non-emergent complaints is unsafe because it causes delays in EMS response times for other patients and exacerbates ED overcrowding. Current EMS triage tools were not designed to identify children who can be safely managed without emergent transport to the ED. There is an urgent need for a pediatric EMS risk assessment tool (similar to the Emergency Severity Index [ESI] ED triage score developed with support from the Agency for Healthcare Research and Quality [AHRQ]). The Pediatric Observation Priority Score (POPS) was developed to identify children at low risk of deterioration in emergency settings. POPS has been validated in EDs with moderate/excellent inter-rater reliability between different healthcare professionals and is used in some EMS agencies in the United Kingdom. The acceptability and accuracy of the POPS tool in EMS is unknown. The overall goal of this proposal is to refine and pilot-test the POPS tool for use by EMS clinicians. This will be achieved through the following specific aims: (1) identify factors associated with under- triage for children not transported by EMS; (2) optimize the acceptability, appropriateness, and feasibility of the POPS tool with clinical end-users; and (3) assess the refined POPS tool through simulation and field pilot studies. Aim 1 will be conducted in a multisite retrospective analysis linking EMS records and Medicaid Claims data (a high-risk population). The POPS tool will be refined by incorporating factors found to be associated with under-triage. Aim 2 will be addressed using a mixed-methods approach with EMS clinicians. The POPS tool will be refined and iteratively assessed before pilot testing. Aim 3 will involve assessing the refined POPS tool in simulations with EMS clinicians and a feasibility field pilot test linking POPS scores with patient outcomes. These studies will generate preliminary data on tool accuracy and under and over-triage rates, leading to a national effectiveness trial of the refined POPS tool. A validated pediatric screening tool would enable urgently needed studies of EMS innovations (including treatment in place, telemedicine, and integration of primary care) for children, an AHRQ priority population. The Principal Investigator, Dr. Caleb Ward, is an early career physician-scientist with a strong clinical background in pediatrics, emergency medicine, and EMS. This award will foster his development as a researcher with content expertise in large database analytics, multisite EMS research, and implementation science. A mentorship team with expertise in these content areas will support Dr. Ward as he completes these research aims and related career development activities to ensure his transition to research independence.

NIH Research Projects · FY 2024 · 2024-07

Project Summary During adolescence the brain undergoes dramatic changes that coincide with a major transition in social- emotional behaviors and is a time of enhanced vulnerability for individuals with a host of neurodevelopmental and neurobehavioral disorders such as schizophrenia, depression, and anxiety disorders. One brain region that is a major driver of the behavioral transition during adolescence is the amygdala. The amygdala is critical for social-emotional behavior and altered developmental trajectories and dysfunction of the amygdala are hallmark features of many neurodevelopment and neurobehavioral disorders. Here, we focus on the role played by the transcription factor, Foxp2, in behavioral and circuit maturation of the medial subnucleus of the amygdala during adolescence in both males and females. Our focus on Foxp2 stems from our previous work and work in the field highly implicating Foxp2 gene function in social brain function and critical periods of neurodevelopment. These findings led to our hypothesis that Foxp2 is required in a sex-specific manner for the formation of social circuitry in the medial subnucleus of the amygdala during adolescence. To study the function of Foxp2 in behavior and circuit maturation during adolescence, we will use cutting edge CRISPR-Cas gene editing approaches to delete Foxp2 gene function in male and female mice specifically in the medial amygdala during adolescence. We will examine the consequences on social behavior and neuronal circuit function (Specific Aim 1), and using state of the art genomic profiling tools, uncover the correlate gene regulatory deficits underlying these behavioral and circuit deficits (Specific Aim 2). The overarching goal of this project is to generate a mechanistic understanding of the genetic control of social brain formation and social behavior during adolescence. As amygdala dysfunction is a prime feature of a host of social and emotional disorders, most of which show sex biases, this work is a critical step toward understanding how brain circuit dysfunction is linked to prevalent human disorders.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY The developing embryo has the remarkable ability to buffer insults, ensuring normal development in the face of genetic and environmental influences. But when these insults exceed a disease threshold - birth defects can result. Our goal is to elucidate how these buffering systems mediate the interplay between genes and environment and if disruption of these buffering systems contributes to structural birth defects in genetic syndromes. Resistance to perturbations is known as developmental robustness, and miRNA-mediated negative feedback loops potentially play critical roles in buffering genetic and environmental insults. Disruption of miRNAs results in increased sensitivity to environmental factors in model organisms; yet, whether the miRNA-mediated buffering mechanisms play a role in birth defects remains unknown. This proposal will investigate whether defective miRNA-mediated buffering drives the phenotypic variability in 22q11.2 deletion syndrome (22q11DS). 22q11DS is the most common deletion syndrome in humans, with variable features independent of the size of the deletion. It is well accepted that variability is due to the influence of genetic and environmental modifiers, but the identity of these factors still needs to be discovered. Preliminary data indicate that mouse models of 22q11DS exhibit abnormal vitamin A/Retinoic acid signaling regulation, and dietary supplementation of the maternal diet with vitamin A (within recommended levels for pregnancy) is a modifier of outflow tract (OFT) defects in a mouse model of 22q11DS. Furthermore, Dgcr8 is deleted in 22q11DS. Due to its essential role in synthesizing mature miRNAs, Dgcr8 is an exciting but unexplored candidate for mediating abnormal buffering of signal transduction pathways in 22q11DS. This proposal aims to test the hypothesis that maternal dietary intake of vitamin A is an important modifier of OFT defects in 22q11DS, potentiated by the altered capacity of the 22q11DS embryo to buffer changes in vitamin A intake. We propose that reduced buffering capacity transforms benign vitamin A exposures into teratogenic doses by failing to rapidly engage miRNA-mediated negative feedback mechanisms to buffer retinoic acid signaling. Moreover, Tbx1 is deleted in 22q11DS and implicated in congenital heart defects (CHDs) in 22q11DS. However, the haploinsufficiency of Tbx1 results in low penetrance of OFT defects. We propose that altered buffering capacity in 22q11DS amplifies RA signaling and reduces Tbx1 gene dosage below a threshold needed for proper OFT development. This novel mechanism for aberrant gene-environment interactions will be tested with two specific aims: To establish (1) how RA buffering is disrupted in 22q11DS; and (2) if reduced miRNA processing due to Dgcr8 haploinsufficiency mediates altered RA buffering and contributes to OFT defects in 22q11DS. Together, these experiments will provide a novel understanding of the mechanisms mediating gene-environment interactions. This new insight can directly translate to preventing structural birth defects in 22q11DS.

NIH Research Projects · FY 2024 · 2024-06

PROJECT SUMMARY Ornithine transcarbamylase (OTC) deficiency and N-acetylglutamate synthetase (NAGS) deficiency are inborn errors of metabolism that are caused by genetic defects in the urea cycle genes OTC and NAGS. Genetic defects in these genes can cause hyperammonemia, brain edema, and neurological injury that ranges from mild executive functioning deficits to profound intellectual and developmental disabilities and even death. OTC deficiency is the most common and the only X-linked urea cycle disorder (UCD) whereas NAGS deficiency is the only UCD that can be effectively treated with drug monotherapy. Because of the broad spectrum of neuropsychological sequelae associated with OTC and NAGS deficiencies, understanding their molecular basis and improving their early diagnosis are among NICHD high research priorities. OTC and NAGS deficiencies are most often diagnosed by DNA testing because biochemical testing may not always sufficiently differentiate between different UCDs. DNA sequence variants identified in these genes are not always deleterious, and the current ACMG (American College of Medical Genetics and Genomics) and AMP (Association for Molecular Pathology) standardized framework for the interpretation and classification of DNA variants relies on published or publicly available computational, functional, segregation, population, allelic and clinical data in order to classify a variant. Because such publicly available data is limited, the majority of known sequence variants in the urea cycle genes OTC and NAGS would currently be classified as variants of uncertain significance. Correct classification of such variants is necessary 1) to accurately diagnose and treat these disorders 2) for reproductive counseling of affected patients and their relatives and 3) to inform the design of diagnostic eligibility criteria for clinical trials of these disorders. To permit the correct assignment of pathogenicity of known OTC and NAGS variants by clinical diagnostic laboratories and by the NIH-supported ClinGen UCD Variant Curation Expert Panel, this project seeks to leverage the combined data from 3 sources: 1) the largest natural history study of UCDs conducted by the NICHD-funded UCD Consortium, 2) the largest US clinical UCD expert center, Children’s National Hospital and 3) the largest private OTC and NAGS dataset from the legacy Tuchman lab. The Tuchman lab was an academic laboratory that prior to 2012 served as the US reference center for clinical OTC and NAGS sequencing. The legacy database of this lab contains over 20 years of variant and unpublished clinical data from US patients with OTC and NAGS and their relatives. We propose to combine and disambiguate anonymized data from these 3 complementary datasets, and publish the data that fulfill segregation, population, allelic and clinical variant curation criteria. For each OTC and NAGS variant, we intend to submit these data into ClinVar, a publicly accessible database that aggregates information about genetic variants.

NIH Research Projects · FY 2026 · 2024-04

PROBLEM. Pediatric tumors represent a very heavy social and economic burden with profound emotional involvement not only for the directly affected children but also for their family and friends. Within pediatric tumors, neuroblastoma (NB) is of particular relevance, since it is the most common solid cancer in children outside of the skull and it still kills about 40% of patients diagnosed with the most aggressive forms. Therefore, there is a clear need to improve the treatment for this deadly disease. Development of more potent immunotherapies could improve outcome for these patients. PREMISE. Natural killer (NK) cells, especially when “activated” (aNK cells) mediate direct cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC). All cell types release extracellular vesicles called exosomes that contain biologically active components (proteins, DNA, mRNA, and non-coding RNAs including miRs) that can be delivered to recipient cells and influence their functions. Exosomes released by aNK cells, could increase the efficacy of chemoimmunotherapy in NB. Little is known about human aNK cell-derived exosomes, their therapeutic potential and role as biomarkers of response to chemoimmunotherapy in NB. Our group was the first to show that microRNAs (miRs) in aNK-derived exosomes are able to kill NB cells. OUR DATA. We can propagate and activate blood NK cells from normal donors and patients with NB using K562-mbIL21 artificial antigen presenting cells (aAPC) plus IL-2. We discovered that these aNK cells release large quantities of exosomes and that purified aNK exosomes are cytotoxic for NB cell lines. We also have preliminary evidence that aNK-derived exosomes contain miRs that contribute to the cytotoxic effect of aNK-exosomes. We also observed that children affected by NB responsive to chemoimmunotherapy, present markers of aNK activation in their blood. We hypothesize that aNK-derived exosomes kill NB cells through the exosomal transfer of MYCN-, AURKA-, TGFBR1- and TGFBR2-targeting miRs, and that these miRs can be exploited to develop an anti-tumor effect and implement the efficacy of chemoimmunotherapy for NB patients. We also hypothesize that specific circulating and exosomal miRs can be exploited as biomarkers of response to chemoimmunotherapy in children affected by NB. These hypotheses will be tested in the following Specific Aims: 1) To study cytotoxicity mechanisms and therapeutic efficacy of aNK- derived exosomes alone and combined with chemoimmunotherapy in NB; 2) To assess association of NK- exosomal miRs, circulating RNAs, and gene expression profiles with response in patients treated on chemoimmunotherapy regimens. SUMMARY. We focus upon a completely new immunotherapeutic strategy using human miR-enriched aNK exosomes. The results of this study will provide important information for producing highly cytotoxic aNK exosomes which could potentiate efficacy of existing chemoimmunotherapy. This study will also identify new exosomal RNA cargo able to stratify neuroblastoma patients for response to chemoimmunotherapy.

NIH Research Projects · FY 2025 · 2024-03

PROJECT SUMMARY / ABSTRACT The primary objective of this study is to evaluate the feasibility of a novel approach to ameliorating cognitive deficits in children and adolescents with sickle cell disease (SCD). SCD is an understudied, life-limiting disease affecting 100,000 individuals in the United States and over 300,000 newborns globally every year. Youth with SCD are at substantial neurological risk given their increased likelihood of overt stroke and silent cerebral infarct. However, even individuals without signs of cerebral infarct exhibit lower cognitive performance compared to healthy siblings due in large part to non-stroke, disease effects on the central nervous system. Disease-related cognitive issues are diffuse but often affect working memory function. Very few studies have examined therapeutic approaches to treating cognitive deficits in SCD; however, recent research supports the use of a home-based, eHealth working memory training program (Cogmed). In a randomized controlled trial, Cogmed training (i.e., repeated and adaptive working memory skills practice) resulted in improved working memory but adherence to the intervention was low. Early engagement with the training program emerged as predictive of better adherence. Therefore, in an effort to promote engagement, an enhanced version of the program was developed that incorporates social support components (e.g., multifamily Cogmed Kickoff events, social incentives, peer navigator support) and memory strategy training. The study will evaluate the following specific aims in a single-arm pilot clinical trial: 1) Assess the feasibility of Cogmed+ (Cogmed plus social support components and memory strategy training) in youth with SCD; and 2) Determine the effect of Cogmed+ on rates of treatment adherence. In this study, 50 youth ages 7-16 with SCD will complete a cognitive screening, after which 30 participants with working memory deficits will proceed to the Cogmed+ program. Participants will complete Cogmed on a tablet device from home 3-5 times per week for 5-8 weeks. Participants will attend weekly videoconference calls with a Cogmed coach who will review training progress and teach memory strategies during four coaching calls (weeks 2-5). Outcomes will be assessed by examining the number of Cogmed sessions completed and rates of attendance to Cogmed Kickoff events and memory strategy training sessions. Results will also be compared to a historical comparison group of youth with SCD who completed the basic version of Cogmed. Findings will provide critical data regarding a novel strategy for improving access to an efficacious treatment for youth with SCD. If such an augmented approach proves beneficial, resultant data will inform a randomized controlled trial to examine the effectiveness of a stepped care model that selectively delivers more intensive Cogmed treatment packages only as needed. This line of investigation, which balances practical access and resource considerations, could serve as a scalable care model and ignite efforts to address SCD- related cognitive impairment for the millions of people living with SCD globally.

NIH Research Projects · FY 2026 · 2023-12

The importance of science, technology, engineering, and math (STEM) to our daily lives has been heightened by the nature of the pandemic: from vaccines to computer programs that allow us to stay connected, the innovations that are integral to our daily lives are based in STEM. Further, as healthcare researchers, we recognize that the brain underpins the nature of the human experience and is involved with a wide variety of healthcare topics beyond the brain/spinal cord, including but not limited to oncology, trauma, sleep, hearing and speech, neurodevelopmental disabilities and general health/safety. Understanding how the nervous system interrelates with various STEM concepts, impacts neurodevelopment, and influences health outcomes is critical for building a capable workforce. The lack of career pathways for capable young innovators in brain-based STEM and health backgrounds signals a continued need for a focus on STEM literacy and competencies throughout K-12 education. Mentored Experiences to Expand Opportunities in Research version 3 (“METEOR v. 3”) will provide meaningful experiences for Washington, DC metro area high school students and STEM teachers-in-training with a specific focus on understanding the healthy and diseased brain, spinal cord, and peripheral nerves through a children’s health lens. METEOR v. 3 will engage participants in inquiry-based biomedical, behavioral, and clinical research in the setting of Children’s National Hospital and its’ Research Institute. We will provide a comprehensive program and curriculum, which will employ unique, research-based educational practices designed to stimulate interest and advance knowledge in neurosciences, neurobiology, behavioral health and related fields. These innovative hands-on experiences will stimulate the next generation of students and teachers to bring neurosciences to the forefront of STEM and health care research

NIH Research Projects · FY 2025 · 2023-12

Project Summary/Abstract: Septic encephalopathy (SE) constitutes a common form of encephalopathy with an associated 70% mortality rate, underscoring the need for a highly effective treatment. The pathophysiology of SE is linked to an energetic crisis in the brain combined with immune-mediated neuro-inflammation. Specifically, neural cells shift their energy generation from aerobic oxidative phosphorylation (OXPHOS) to less- efficient glycolysis. Energy deficiency in the brain leads to excess accumulation of reactive oxygen species (ROS) and subsequently to oxidative stress, inflammation, and neuronal cell death. Studies have highlighted a mesenchymal stem cell (MSC)-related improvement in energetics that is partially achieved by the transfer of bioactive molecules such as miRNAs and proteins carried by secreted extracellular vesicles (MSC-EVs). In our preliminary work using a murine model of SE, we showed that MSC-EVs administered intravenously restore cerebellar ATP and improve neuro-inflammation and Purkinje and granule cell viability. However, the mechanisms by which MSC-EV cargo exerts its protective effects on neuronal integrity in SE have not been studied. The goal of this application is to examine the therapeutic potential of MSC-EVs in SE using a mechanistic approach to connect EV cargo with the regulation of metabolic and immune pathways. By including a murine model of SE, we propose to examine whether specific members of the MSC-EV cargo (miRNAs and proteins) alter metabolic and immune pathways, leading to improved neuronal cell viability. We hypothesize that in SE, based on our previous work, MSC-EV cargo directly activates cerebellar OXPHOS-related and other metabolic pathways, improving ATP generation, neuro-inflammation, and neuronal cell death. We will study in vivo the MSC-EV mechanism of action by using inhibitors of MSC-EV miRNA and protein cargo members that are abundant in the utilized EVs. The practical implication of this effort includes the development of EV-based therapeutic protocols to alleviate the metabolic and immune abnormalities that can broadly affect neural cells in encephalopathy and other conditions that cause brain injury. The PI is firmly committed to a career in translational neuroscience research and his goals are strongly supported by his institution and the co-Is. He is currently a tenure-track Assistant Professor of Pediatrics with 75% protected time for research and recently funded by K12/STTR grants, and Children’s National Hospital has been providing him with bench and office space, and computer/software support. The current proposal includes a comprehensive research plan that will advance our knowledge in EV therapeutic properties using techniques such as liquid chromatography and mass spectrometry, ATP measurement using Seahorse© technology, RNA/miRNA sequencing and advanced cerebellar histopathology. This work will lead to an R01-level grant focusing on SE metabolism and EV therapeutics using MSC-EVs and more efficient engineered EVs.

NIH Research Projects · FY 2026 · 2023-12

The Health Excellence Academic Research in Pediatric Hospital Medicine (HEAR-PHM) will build capacity to address differences across the acute-care continuum by both delivering a health excellence research curriculum to pediatric hospitalists and supporting a research-focused academic workforce within Pediatric Hospital Medicine (PHM). Differences have been identified across the spectrum of care and conditions for the hospitalized child. Although responses to address differences in pediatric care need to be multi-factorial, key strategies include developing expertise in health excellence research and fostering a well-trained academic workforce. A dedicated focus on increasing researchers in the pediatric workforce has been identified as a national priority. Pediatric hospitalists are uniquely positioned to lead changes in inpatient healthcare delivery because their clinical practice spans multiple domains; PHM is a young subspeciality that has opportunities to address health differences for hospitalized children and needs specialized health excellence research training. To address this critical gap, we propose the Health Excellence Academic Research in Pediatric Hospital Medicine (HEAR-PHM) to build capacity to address differences across the acute-care continuum and support a well-trained academic workforce in PHM. HEAR-PHM program seeks to (1): Prepare PHM scholars to lead health-excellence research in the care of hospitalized children. We will equip scholars (PHM fellows and junior faculty) with a background in health-excellence research skills, and support completion of an impactful, rigorous capstone research project focused on child health excellence; (2). Enhance health excellence research in PHM. We will recruit early career pediatric hospitalist scholars across the country with an interest in advancing their careers in health excellence research; (3). Build a repository of health-excellence research resources to support the train-the-trainer model for PHM scholars. We will develop an online platform to support the health-excellence research lectures, develop a toolkit for scholars to train others, and provide opportunities for scholars to share their experiences and knowledge locally and nationally. Children’s National Hospital is well-position to lead this national program as it is one of the oldest and largest PHM programs in the country, and CNH has long-standing expertise in medical education, translational research, and community-based programs. HEAR-PHM program directors are national PHM leaders with strong reputation as educators and researchers, and program scholars will leave the program with enhanced health excellence research capabilities related to the mission of NICHD.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Traumatic brain injury (TBI) is the leading cause of death and disability in patients aged 1-44 years. While there is no treatment for TBI, one potential strategy is to harness the brain’s native capacity for cellular regeneration to replace lost cells. NG2-glia, the largest population of regenerative cells in the adult CNS, can proliferate and differentiate into multiple glial cell types; uncovering the molecular pathways regulating these NG2-glia processes is a key step to develop future therapies for TBI. The candidate previously found that cortical NG2- glia are regulated by the molecular circadian clock, a well-characterized 24-hr transcriptional-translational feedback loop, with a key contribution by the clock gene Bmal1. However, the mechanism by which the clock affects regenerative potential as well as the generalizability of this mechanism to other NG2-glia (e.g. white matter NG2-glia) are unknown. In this proposal, the candidate hypothesizes that the NG2-glia endogenous circadian clock directly governs molecular pathways to regulate regenerative potential, both in health and disease. He will test this hypothesis with the following aims: 1) Determine the clock-dependence of cortical and white matter NG2-glia proliferation and differentiation in the healthy brain and in response to TBI; 2) Identify the clock-dependent molecular programs regulating cortical NG2-glia proliferation in the healthy and injured brain; 3) Define the differential expression of BMAL1 target genes during basal and injury-induced cortical NG2-glia proliferation. Successful completion of these aims will identify the clock-dependent molecular pathways underlying NG2-glia regenerative potential that will serve as future targets to manipulate post-TBI cellular regeneration. Currently holding positions as Attending Physician in Critical Care Medicine at Children’s National Hospital and Assistant Professor of Pediatrics at George Washington University School of Medicine and Health Sciences, the candidate is committed to a career in academic medicine. With >75% protected time, as supported by his institution, the candidate will be guided by his primary mentor (Vittorio Gallo) and co-mentors (Kazue Hashimoto-Torii, Amita Sehgal, Regina Armstrong). He has access to laboratory space, supplies, and research funding to carry out the proposed project. His career development plan is comprised of hands-on training and didactics to accomplish his training goals, which includes technical and non-technical skills necessary for future independence. From a technical aspect, he seeks training in in vitro techniques, human post-mortem tissue evaluation, and omics sciences; there is a focus on the last, as his proposal uses translatomics and chromatin mapping, two approaches ideally suited for investigating the changes in NG2-glia molecular programs induced by the transcription factors comprising the circadian clock. Completion of his training plan will permit the candidate to conduct studies on a variety of scales, allowing him to fulfill the “bench to bedside” mantra that motivates him to tread the path of a physician scientist. Furthermore, he will have positioned himself as an investigator at a unique intersection of circadian rhythms, neurotrauma, and regenerative medicine.

NIH Research Projects · FY 2025 · 2023-09

Variations in sex traits (VST; also known as differences of sex development) are congenital conditions characterized by incongruence between genetic, gonadal, and/or phenotypic sex. Youth with VST often exhibit complex clinical presentations, including atypical genitalia, sexual/urological dysfunction, and fertility impairment. Interdisciplinary care is the standard of care for youth with VST given interrelated medical, mental health, and developmental care challenges which typically demand careful clinical decision-making and clear, coordinated communication between providers and youth. Many VST-related care decisions made during childhood and adolescence have life-long implications for sexual and urogenital functioning, fertility, quality of life, and mental health. Individuals with VST are at heightened risk for experiencing psychological trauma related to their care which often includes frequent genital exams and discussions of highly personal information with multiple care providers. Interdisciplinary care teams currently lack a standardized, youth-attuned means of obtaining information from youth to help guide personalized care and facilitate shared decision-making. There are no validated measures to capture the care preferences, needs, and care-related experiences of youth with VST, or the variations in VST outcomes experienced by common subgroups (e.g., those with/without interdisciplinary care access or neurodevelopmental disability). Therefore, this proposal, which builds on two NIH-funded pilot projects, finalizes the development, calibration, and validation of a VST self-report tool, called the VISTA, to capture youth needs and preferences and the unique stressors they face. AIM 1 expands and refines the pilot VISTA itemset to ensure item coverage, comprehension, and appropriateness for common VST subgroups (i.e., youth with neurodevelopmental disability; youth without interdisciplinary care access). AIM 2 recruits 600 youth and emerging adults (ages 11-26) with a broad range of VST diagnoses, half without interdisciplinary care access. Scale development research procedures, including latent variable modeling and differential item functioning, will produce subscales that function equivalently across youth. Convergent and discriminant validation will be tested with measures of mental health, medical stress/stigma, body image, and patient engagement in shared decision-making. Ecological validity will be evaluated with mixed methods follow-up interviews in a striated subsample of youth. Test-retest reliability will be assessed at one month. In AIM 3, variations in outcome will be examined across care access, geography, and neurodevelopmental conditions through sequential GLM models evaluating the independent and combined effects of the predictors. This proposal represents a critical step towards facilitating improved clinical practice for youth with VST.

NIH Research Projects · FY 2026 · 2023-09

This proposal details a 5-year plan to provide Dr. Rachel Margolis with the knowledge and skills to become an independent clinical and translational researcher focused on improving pediatric asthma outcomes. Research Plan: Socioeconomic and racial/ethnic differences persist in pediatric asthma, particularly among low-resourced, Black children in urban settings. Evidence demonstrates that psychosocial risk factors contribute to these differences. Maternal depression is one prevalent and potentially modifiable risk factor. While there is evidence that treating maternal depression may improve child health outcomes, mothers who are low-resourced face difficulties accessing depression treatment. Integrated care (i.e., the delivery of mental health care in a physical health care setting) has been associated with reduced maternal depression and improved child health in pediatric primary care. However, the feasibility, acceptability, and efficacy of embedding maternal depression treatment into a community-based asthma clinic needs to be demonstrated. Enhanced Brief Interpersonal Psychotherapy (IPT-B) is a promising depression treatment for low-resourced mothers that has proven efficacious among similar women when delivered in an obstetrics clinic setting, but it has not been studied in a pediatric asthma clinic setting. While these populations share similarities, there are substantive differences between the two settings that must be considered. Therefore, to maximize the success of Enhanced IPT-B in an asthma clinic setting, it is necessary to identify and address potential mother and provider-level barriers to integrated depression care. Stakeholder engagement with mothers and asthma clinic staff can facilitate the process of understanding and mitigating these barriers. Thus, the overall goal of this proposal is to integrate and evaluate maternal depression treatment in a community-based asthma clinic providing care to predominately low-resourced, Black children with asthma. The Specific Aims are to: 1) Engage stakeholders in determining the most effective and acceptable model for integrating Enhanced IPT-B for mothers into the community-based pediatric asthma clinic; 2) Determine the feasibility, acceptability, and preliminary efficacy of Enhanced IPT-B on decreasing maternal depressive symptoms in a community-based pediatric asthma clinic through a pilot RCT; and 3) Determine the preliminary efficacy of the intervention (vs. supplemented usual care) on improving child asthma outcomes. Training Plan: Through coursework and mentored research experiences with her multidisciplinary team of mentors/advisors, Dr. Margolis will develop advanced qualitative and mixed methods skills, learn clinical trial design with a focus on behavioral interventions for low-resourced and racial/ethnic minority families, and gain advanced implementation science skills. Dr. Margolis will emerge from her K01 training and research experience as an independent behavioral scientist.

NIH Research Projects · FY 2025 · 2023-09

Abstract Childhood cancer is the leading cause of disease-related death in children in the United States. The Children’s Oncology Group (COG), one of five clinical trials groups supported by the National Clinical Trials Network (NCTN), brings together more than 10,000 experts in childhood cancer representing diverse disciplines. More than 90% of the approximately 16,000 children and adolescents diagnosed with cancer each year in the United States are cared for at COG member institutions. The COG has nearly 100 clinical trials open, including trials to refine front-line therapy for childhood cancer, study novel approaches to patients with recurrent disease, advance understanding of cancer biology, and improve supportive care and quality of life for cancer survivors. The functioning of COG is dependent upon scientific oversight for protocol development that occurs centrally and oversight of clinical trial conduct that occurs locally at more than 200 member sites. Dr. Jeffrey Dome has been a steady and substantial contributor to the COG ever since its inception over 20 years ago at both the central and local levels. At the groupwide level, his major contribution has been his leadership of the Renal Tumor Committee. From 2006-2016, he served as chair of this committee, which entailed oversight of more than 6,000 patients enrolled on the Biology and Classification Study and four front-line therapeutic trials. He successfully guided the committee through the completion of the first generation of COG studies for childhood kidney cancers, resulting in clinical practice change across the country. He remains involved as an advisor to the current committee chair, member of the AREN1721, AREN1921, and AREN2231 study committees, associate vice-chair for publications and leader of the efforts to foster collaborations with international cooperative groups. Dr. Dome also serves on the COG Executive Committee, which advises the Group Chair on science and operations, and the COG Scientific Council, which reviews all the new concepts and major amendments before they are reviewed by the NCI steering committees. Future directions include opening three new COG renal tumor studies for favorable histology Wilms tumor, malignant rhabdoid tumor and bilateral Wilms tumor as well as furthering the study of novel biomarkers such as circulating tumor DNA. At the local level, Dr. Dome serves as the institutional Principal Investigator for COG studies at Children’s National Hospital, one of the largest and most active COG sites. Between 2018-2020, Children’s National had 379 COG clinical trial enrollments, including 115 phase 1 enrollments and 37 phase 2 enrollments. In 2020, Children’s National was in the 98th percentile of all COG sites for therapeutic enrollments. Future directions include improving the quality assurance and regulatory oversight infrastructure to accommodate the increasing complexity of COG trials. The NCI Research Specialist Award will provide an excellent mechanism to protect Dr. Dome’s time to continue to advance COG science.

NIH Research Projects · FY 2025 · 2023-09

The main objective of this NIH/NIDDK K26 is to recruit, retain, and mentor trainees into research career pathways that will ultimately help support our nation's biomedical and behavioral workforce goal of increasing the pipeline of diabetes researchers. Trainees under this award will include doctoral-level (graduate students) and post-doctoral (fellows) researchers who have an interest in children's type 1 diabetes (T1D) self-management, adherence promotion and glycemic control, and family-based self-care. Mentorship will take place at Children’s National Hospital (CNH), the largest and only exclusive provider of pediatric training and pediatric patient care in the greater Washington, DC region. CNH's location in the nation's capital means it has access to many nearby degree- granting universities and/or institutions of higher learning that are part of a research training network. This opportunity will provide trainees clinical-translational research training under the mentorship of a recognized and dedicated researcher, with a well-established track record of extramural funding in T1D research who has mentored a cadre of successful students, interns, fellows, and early-stage investigators. The mentor (Randi Streisand, PhD, CDCES) is an expert in children's health behavior theory and research methods, the science of behavior change, and their application to T1D adherence promotion and the prevention and control of T1D complications in childhood. Mentees will be sought from the fields of medicine, nursing, epidemiology and community/public health, pharmacy, health services research, and social/behavioral sciences. CNH's exceptional core training, research, and administrative facilities, along with those of our academic affiliate (at The George Washington University), will be leveraged to accelerate the tempo of mentees' experiences in the field of T1D research. Mentees will participate in a series of structured, didactic, and skill-building experiences. This training will be customized through individual learning plans, arranged by and with Dr. Streisand and multidisciplinary team members, that will deepen and enrich the mentees’ overall research experience. This mentoring relationship holds the potential to favorably alter the future research career trajectories of individuallys within the behavioral diabetes research workforce to improve clinical and public health outcomes.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract Growth impairment is a common complication of pediatric Crohn’s disease. Normalization of growth is a marker of disease control and successful Crohn’s disease therapy. Treatment strategies for improving growth impairment and final adult height are currently suboptimal. The impact of Crohn’s disease on growth is potentially mediated by many factors, including inflammation, genetics, microbiome, nutrition, and medications. The continued presence of growth impairment primarily reflects continued suboptimal treatment of the underlying inflammation characteristic of Crohn’s disease. We hypothesize that the inflammation characteristic of Crohn’s disease has greater negative effects on endocrine growth regulators (IGF-1 levels, sex hormone levels, and gonadotropin levels) in males and that these greater negative inflammatory effects help to explain the increased susceptibility to growth impairment in males. This hypothesis is based on our analyses of data collected from our completed prospective multicenter longitudinal study of sex differences in growth impairment (Growth Study Part 1). Our Part 1 data show that as bone age progresses, standardized height gain is lower in males. Our Part 1 findings suggest inflammation exerts a greater negative effect on hormone levels and growth in males, and indicate that sex-specific molecular pathways lead to growth impairment in children with Crohn’s disease. The primary pathway to growth impairment appears be the growth hormone/IGF-1 axis in males and the hypothalamic/pituitary/gonadal axis in females. Developing a sex-specific risk-based treatment approach for children with Crohn’s disease is essential. However, the specific molecular mechanisms causing sex differences in growth impairment remain poorly characterized. Here, we propose to expand and continue to follow our cohort to harvest information on the proteome (Aim 1) and genome (Aim 2) to provide new insights into growth impairment. These data will enhance our ability to determine the underlying mechanisms of sex differences in growth impairment (Aims 1 and 2) and develop robust sex-specific predictive models to identify high-risk patients (Aim 3). Part 2 of the Growth Study will generate essential data that will enable us to develop a highly needed sex-specific risk- based pediatric Crohn’s disease treatment approach, which will represent a major paradigm shift in clinical practice. Institution of appropriate personalized sex-specific risk-based medical therapies targeting the underlying inflammation (since improved growth results from improved disease control) is essential since only a very narrow therapeutic interval is available to intervene to improve growth before growth plates close.

NIH Research Projects · FY 2025 · 2023-09

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY During the COVID-19 pandemic, healthcare workers (HCWs) have had a more than 11-fold higher infection risk than the general population. Several risk factors for COVID-19 infection among HCWs have been identified, including the lack of personal protective equipment (PPE) and inadequate PPE use. Among these factors, the inadequate use of PPE has been associated with a one-third higher risk of infection. Given the high incidence of infection, there is a critical need to address the challenges of monitoring and promoting adherence with appropriate PPE use among HCWs. The long-term goal of this research is to reduce workplace-acquired infections in HCWs by improving adherence to appropriate PPE use in settings at high risk of transmission. The overall objectives of this proposal are to design, implement, and test a system (Computer-Aided PPE Nonadherence Monitoring and Detection—CAPPED) that (1) tracks the team’s PPE adherence using computer vision and (2) highlights episodes of potential PPE nonadherence on a video-monitoring system. Our central hypothesis is that continuous monitoring of PPE use by multiple HCWs is a complex, cognitively demanding, and error-prone task unaddressed by current methods for monitoring PPE adherence. The rationale for this proposal is that enhanced recognition of PPE nonadherence is a requirement for reducing transmissible infections in HCWs. Guided by preliminary data, the central hypothesis will be tested by pursuing two specific aims: (1) design and implement a computer vision system (CAPPED) for recognizing PPE nonadherence in a dynamic, team-based setting, and (2) compare human performance during simulated resuscitations using direct observation, basic video surveillance, and computer-aided monitoring (CAPPED system). For the first Aim, machine learning approaches will be applied to recognize the type of nonadherent PPE (headwear, eyewear, mask, gown, gloves) and the category of nonadherence (absent or inadequate). Under the second Aim, a customizable visual interface will be designed and evaluated for monitoring and spotlighting PPE nonadherence with a human-in-the-loop. The proposed research is innovative because it addresses the challenges of simultaneously identifying nonadherence with several types of PPE used by multiple individuals in a dynamic setting. This proposed research is significant because it is expected to reduce infection transmission to HCWs by tracking and eventually alerting them to nonadherent PPE use. The results of this research are expected to positively impact the workplace safety of HCWs by addressing the limitations of current approaches to PPE monitoring.

NIH Research Projects · FY 2026 · 2023-07

PROJECT SUMMARY The causes of most non-syndromic structural birth defects remain unknown due to their complex causes where genetic and environmental factors (GxE) interact to cause disease. Understanding how GxE converges to alter embryonic development is critical for devising preventive strategies to reduce risks. Recent work by the Zohn laboratory established a new mouse model to study the mechanisms underlying GxE interactions and congenital heart defects (CHDs). Extensive preliminary studies with this mouse model led us to formulate our central hypotheses: GxE converges to alter gene expression in cardiac progenitor cells to alter cell fate, and different genetic variants in critical genes can have divergent effects on GxE interactions. We propose two Specific Aims that use our GxE mouse models to illuminate how GxE interacts to cause CHDs. Our experimental design involves altering the vitamin A content of the maternal diet (Environmental factor) in mice carrying a mutation in Hectd1 (Genetic factor), a novel ubiquitin ligase discovered in the Zohn laboratory. We show that while neither heterozygous mutation of Hectd1 nor mild vitamin A deficiency results in CHDs, the combination of the two causes CHDs. Mechanistically we demonstrate that Hectd1 is required for vitamin A/retinoic acid signaling, yet how HECTD1 regulates signaling remains unknown. The aims of this project are 1) to determine how GxE converges to cause CHDs in our model and 2) to elucidate how HECTD1 regulates retinoic acid signaling utilizing an allelic series of truncated HECTD1 mouse lines that model human CHD-associated mutations. Interestingly, our preliminary studies indicate that distinct mutations in HECTD1 disrupt retinoic acid signaling differently. Successful completion of these aims will: 1) provide a deeper mechanistic understanding of how GXE interacts to cause CHDs by elucidating which critical developmental processes are disrupted in our GxE model; 3) reveal how HECTD1 regulates RA signaling; and 4) link our animal studies to human disorders by modeling patient mutations in mouse models and determining how these mutations differentially interact with maternal vitamin A intake. These studies will reveal the mechanisms of how GxE interaction alters the development of the heart and pinpoint critical targets for preventing birth defects.

NIH Research Projects · FY 2026 · 2023-07

SUMMARY The overall objective of this project is to develop a clinical system that fuses laparoscopic video and laparoscopic ultrasound for enhanced visualization and navigation of laparoscopic procedures. Real- time video acquired using a laparoscope remains the primary visualization and guidance modality in over 14 million procedures performed per year globally, but it shows the operating surgeon organ surfaces only. Laparoscopic ultrasound can show internal structures, but is often displayed on a separate screen, leaving the surgeon to perform a mental integration of the 2 modalities. This task is inefficient, subjective, and variable with expertise. Introduction of a needle in the surgical field for ablative procedures further increases the surgeon's cognitive load by needing to register multiple sources of information for understanding three-dimensional spatial relationships and for maintaining hand-eye coordination. The proposed real-time data fusion, which we refer to as augmented reality (AR), presents complementary information to the operating team in an intuitive way. Research, development, and clinical translation efforts preceding this proposed project have demonstrated the technical feasibility and clinical utility of the proposed AR visualization and navigation. The team has successfully developed research prototypes and used the most recent prototype in 11 human cases at 2 different surgical centers. This proposal is borne out of the real-world lessons from our clinical translation experience toward building a clinical system. The major areas of improvement include reducing system complexity and size and improving reliability and clinical viability. Children's National Hospital and Terason will collaborate to develop custom specialized laparoscopic ultrasound transducers and offer AR as a well-integrated advanced application on a commercial ultrasound platform. The specific aims for this project are to 1) develop custom tracked laparoscopic ultrasound transducers, 2) develop a commercial-grade ultrasound system with integrated tracking and AR technologies, and 3) conduct preclinical evaluation of the developed system. Our scientific premise is that comprehensive intraoperative visualization of normal and pathological anatomy and navigated guidance of ablation needles will improve the precision, safety, and efficiency of prevailing laparoscopic procedures, and expand their utilization. The proposed academic-industrial partnership is designed such that these benefits are realized through the development of a clinical system ready for routine use in the operating rooms worldwide.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY Urea cycle disorders (UCDs) are inborn errors of metabolism that affect approximately 1 in 35,000 people and are caused by genetic defects in one of the eight urea cycle genes. Genetic defects in any of the eight genes can cause hyperammonemia which is the primary contributor to disease pathophysiology, leading to neurological injury that ranges from mild executive functioning deficits to profound intellectual and developmental disabilities and even death. Hyperammonemia is most pronounced in deficiencies of the first three enzymes of the urea cycle: N-acetylglutamate synthase (NAGS), carbamylglutamate synthetase 1 (CPS1), and ornithine transcarbamylase (OTC). Because of the broad spectrum of neuropsychological sequelae associated with UCDs, understanding their molecular basis and improving their early diagnosis are among NICHD high research priorities. This application is from an existing UCD variant curation expert panel (VCEP), which submitted OTC specific variant classification rules to ClinGen’s Sequence Variant Interpretation Working Group for review and has been developing NAGS and CPS1 specific variant classification rules. We are seeking support for expert curation of almost 1,300 OTC, NAGS and CPS1 clinically actionable variants that have been deposited in public databases and reported in the literature. Establishment of a comprehensive, expertly-curated catalogue of OTC, NAGS and CPS1 variants is essential for accurate diagnosis of the three UCDs. We have assembled a VCEP that includes experienced genetic counselors and genetics trainees as variant curators, and members of the Urea Cycle Disorders Consortium (UCDC) as expert reviewers. UCDC is an international research collaboration of health professionals with specialized expertise in diagnosis and clinical care of patients with UCDs. In Aim 1, we will assign expert-reviewed clinical significance to OTC, NAGS and CPS1 variants in ClinVar, other public sources of disease associated sequence variants, and in published case reports. Variant will be curated in the following order: complete loss of function (null) variants, missense variants affecting residues critical for enzyme function, variants identified in multiple probands, NAGS and CPS1 variants in trans with existing pathogenic variants, variants affecting the same residues as existing pathogenic missense variants, then all other missense variants. In Aim 2, we will annually review the literature for new reports of patients with NAGS, CPS1 or OTC deficiency and new data regarding sequence variation in large populations. We will utilize the new evidence for reassessment of variants with potential for reclassification (e.g., uncertain significance to likely pathogenic or pathogenic, or likely benign to benign). Expert classification of OTC, NAGS and CPS1 variants will improve diagnosis and clinical actionability for variants with clear relationship with the disease. This will benefit patients, treating physicians and diagnostic laboratories.

NIH Research Projects · FY 2025 · 2023-06

Project Summary Phthalates are a type of plasticizer that are used to make rigid polyvinyl chloride (PVC) plastic flexible. In medical devices, phthalate levels have been reported to be between 20-80% of a product’s weight depending on the type of device; however, questions have arisen over their safety. The most common phthalate plasticizer used in PVC medical devices is di(2-ethylhexyl) phthalate (DEHP). Patients undergoing cardiac surgery involving the use of a cardiopulmonary bypass (CPB) circuit are exposed to significant levels of DEHP from blood products, circuitry tubing, bypass cannulas, and endotracheal tubes. Despite the immeasurable benefits of plastics – there is increasing concern over the potential health risks of phthalate chemical exposures. Accordingly, there is an urgent need to develop and adopt safer alternatives to be used in pediatric CPB. The proposed research project will address this need by evaluating the cardiotoxic effects of DEHP on the pediatric heart and investigating potential mitigation strategies to reduce exposure to toxic phthalate chemicals. Aim 1 will assess the direct effects of phthalate plasticizers on human pediatric cardiac electrophysiology and contractility. Aim 2 will determine the efficacy of potential mitigation strategies to reduce phthalate exposure and improve cardiac outcomes. The latter will include investigating the cardiac safety profile of commercially available DEHP- free alternatives and the utility of using cell washing to remove phthalate plasticizers from cardiopulmonary bypass fluids. The results of this proposal will largely be applicable to the fields of cardiology, with the potential to inform regulatory decision making over the use of phthalate plasticizers in medical device manufacturing. This is particularly important for medical devices that are used to treat vulnerable neonates and infants undergoing cardiopulmonary bypass. This application contains a three-year training plan that will further my scientific development, by building upon the expertise of my Sponsor (Dr. Posnack with expertise in cardiac electrophysiology and cardiotoxicity) and co-Sponsor (Dr. Ishibashi with experience in preclinical models and pediatric cardiac surgery). I will also benefit from a broader group of collaborators, who will provide insight into clinical relevance and experimental techniques. This training proposal will expand my scientific understanding of pediatric cardiovascular physiology, plasticizer toxicity, and clinically relevant models while supporting my future goal to lead a translational research laboratory at a top children’s hospital.

NIH Research Projects · FY 2026 · 2023-03

Project Summary Medulloblastoma (MB) is the most common malignant brain tumor in children. There are several subtypes of MB, and among them, the GLI2-amplified SHH-MB subtype has the worst prognosis and a poor survival rate; the 5- year survival rate is <30%. Moreover, the GLI2-amplified MBs are non-responsive to the only targeted treatment option available for SHH-MB, the SMO inhibitors. This leaves an unmet critical treatment gap, and there is an urgent need to identify novel targets to develop effective therapeutics. However, a deeper understanding of the cellular and molecular mechanisms driving GLI2-amplified MB tumorigenesis is currently lacking. With a focused goal to resolve this particular type of MB tumorigenesis, we recently generated an engineered mouse model of GLI2-driven MB. Using this model, we demonstrated that GLI2 is the critical driver of tumorigenesis and identified granule cell progenitors (GCPs) as the cells of origin. Interestingly, we have also found that GLI2 drives only Math1+ embryonic GCPs but not neonatal GCPs to form SHH-MB. Correspondingly, our scRNA-seq analysis revealed that the MAPK pathway is specifically enriched in embryonic but not neonatal Math1+ GCPs. Moreover, the MAPK pathway is activated in mouse and human GLI2-driven MB tumors, and a MEK/ERK inhibitor significantly delayed the growth of GLI2-driven MB in vivo. Based on these exciting preliminary data, we put forward a novel hypothesis that GLI2-driven MB originates from a specific cell population of Math1+ GCPs and in a particular spatiotemporal window during cerebellar development. Therefore, targeting MAPK/MEK/ERK pathway in the embryonic GCPs in a specific timeframe can effectively prevent GLI2- driven MB initiation and progression. In this proposal, we plan to use our new GLI2-driven MB transgenic mouse model to define the spatiotemporal window of tumorigenesis of GLI2-driven MB more precisely and establish whether MAPK/MEK/ERK signaling is required for GLI2-driven MB initiation and development. Furthermore, we will use GLI2-amplified MB patient-derived xenograft (PDX) models to evaluate the efficacy of MEK/ERK inhibitors in preventing tumor progression and examine the mechanisms underlying therapeutic resistance. We will pursue our ultimate goal to design novel therapeutics and achieve better treatment outcomes by targeting MAPK/MEK/ERK pathway and via identifying additional combinational therapeutic opportunities to fight against tumor relapse. Since aberrant expression of GLI2 occurs in a number of other tumor types, our studies will also set a precedent for all GLI2-driven malignancies.

NIH Research Projects · FY 2026 · 2023-02

Funded by one of the inaugural R38 awards from the National Heart, Lung, and Blood Institute (NHLBI), the Children’s National Stimulating Access to Research in Residency (CNStARR) Program is an existing mentored program of career development and research training. It has dramatically expanded our institution’s capacity to recruit and retain outstanding residents with demonstrated potential and interest in pursuing research careers in content areas of interest to the NHLBI with a special emphasis on asthma and airway diseases, congenital heart disease, and hematology and immunology. Each content area was chosen because of the depth and breadth of our locally available, committed, and highly experienced preceptors. Leveraging the existing collaborations between Children’s National Hospital (CNH) and George Washington University (GWU) such as their jointly held Clinical and Translational Science Institute, CNStARR will recruit residents in pediatrics from CNH and in internal medicine from GWU. Utilizing the existing infrastructure of the Children’s Hospital Research in Residency Program and as well as highly tailored and focused Individual Development Plans, CNStARR provides its scholars with both the didactic competencies and the transformative mentored experiences in basic, clinical, or translational research to prepare them as successful, independent clinician- scientists. The most proximate goal of CNStARR is to accelerate the transition of participants to subsequent mentored career development awards, particularly the “Stimulating Access to Research and Residency Transition Support,” the linked individual K38 mechanism from the National Institutes of Health, as well as other mechanisms such as T32 and F32 appointments, our institutional KL2 and K12 awards, or individual K- series awards. CNStARR scholars will join the future academic leaders in research areas of relevance to NHLBI. Ultimately, they will direct research teams, compete successfully for grant support, and add significantly to our understanding of the etiology and treatment of heart, lung, and blood disorders across the human life span.