Children'S Research Institute

NIH Research Projects · FY 2026 · 2026-06

Neuroblastoma (NB) is the most common extracranial solid tumor in children, with high-risk patients experiencing 5-year survival rates of only 40-50% despite intensive multimodal therapy including retinoic acid (RA) maintenance treatment. While RA therapy promotes differentiation and prevents relapses, its efficacy is limited by resistance development, necessitating novel combination strategies. Proteasome inhibitors (bortezomib, carfilzomib, ixazomib) have shown promise in various malignancies by disrupting protein degradation pathways and promoting apoptosis, with our preliminary data demonstrating potent synergistic anti-tumor effects when combined with isotretinoin (13-cis-retinoic acid) across multiple NB cell lines and patient-derived xenografts. Notably, carfilzomib exhibits a synergistic anti-tumor effect with isotretinoin in NB preclinical mouse model. We hypothesize that proteasome inhibitors will potentiate RA therapy in NB by enhancing RA-induced differentiation and apoptosis. This proposal will systematically evaluate proteasome inhibitor-RA combination therapy through three specific aims using genetically diverse NB models that recapitulate key clinical biomarkers (MYCN amplification, TP53 mutations, ALK status). Because the complex tumor microenvironment, systemic toxicities, pharmacokinetics, and metastatic cascades of neuroblastoma cannot be adequately recapitulated by in vitro or computational alternative systems, the use of live vertebrate animal models is required to validate these therapeutic approaches prior to clinical translation. All proposed animal experiments have been fully approved by the Institutional Animal Care and Use Committee (IACUC) at the Children's National Research Institute (07/31/2025-07/31/2028). Aim 1 will assess tumor growth inhibition by evaluating all three proteasome inhibitors combined with isotretinoin in subcutaneous xenograft models, measuring anti-tumor efficacy, synergistic interactions, and mechanistic endpoints including apoptosis markers and pathway analysis. Aim 2 will determine survival benefit and anti-metastatic activity by advancing the most effective combination to intravenous injection models using luciferase-expressing cells, with primary endpoints of overall survival and metastatic burden assessed by bioluminescence imaging. Aim 3 will comprehensively assess toxicity and tolerability in healthy mice over 4 weeks, evaluating treatment-related mortality, organ toxicity, and safety parameters to establish therapeutic windows for clinical translation. This innovative approach represents the first systematic evaluation of proteasome inhibitor-RA combination therapy in NB, employing advanced methodologies including real-time metastatic assessment, comprehensive combination index analysis, and toxicological evaluation. Expected outcomes include identification of the optimal proteasome inhibitor-RA combination with >50% tumor growth inhibition, ≥30% survival improvement, ≥50% reduction in metastatic burden, and acceptable toxicity profiles supporting clinical translation. Success will generate definitive preclinical data for IND application and Phase I clinical trial initiation, offering new hope for children with high-risk NB and potentially benefiting patients with treatment-resistant malignancies.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT The transition from adolescence to adulthood is a critical stage of development characterized by significant changes in social-emotional behavior. One of the central brain structures modulating this transition is the amygdala. The development of the amygdala continues through adolescence, undergoing an expansion in size and neuron number into early adulthood. These changes enable healthy social and emotional development, and perturbations in amygdala development and maturation are linked a host of mental health disorders, most notably autism spectrum disorders (ASD) and the long-term behavioral consequences as a result of early life stress (ELS). However, the amygdala neuronal and circuit substrates underlying changes coincident with this major life transition remain little understood. In our published studies in humans and mice, we identified and characterized a unique population of immature neurons in the paralaminar nucleus of the amygdala (PL). While these neurons are born embryonically, they interestingly delay their maturation until adolescence when they differentiate into excitatory neurons. Thus, our discovery and characterization of PL neurons that undergo maturation coincident with adolescence revealed a novel mechanism of brain plasticity during a critical stage of post-natal development. Using the mouse as a model, the goal of our proposed studies is to understand the function of amygdala late-maturing neurons from adolescence to early adulthood and what drives their maturation. To test this, we will examine how PL neuronal responses change over time (Aim 1), the necessity and sufficiency of PL neurons in this transition (Aim 2), and the role inhibitory neurotransmission plays in their maturation and later function (Aim 3). Our proposed studies are also an essential step to understanding the role late maturing PL neurons play in neuro-atypical brain function associated with disorders of social cognition to which the PL has previously been linked, such as ASD and the long-term consequences of ELS.

NIH Research Projects · FY 2026 · 2026-04

Abstract The Child Health Research Career Development Award (CDRCDA) Program was first established at Children’s National Hospital in 2000, and over the past 24 years, we have successfully trained 30 Scholars. The purpose of the program is to facilitate the development of successful basic, translational, and clinical research careers for junior faculty members in pediatrics across the T0-T4 spectrum. The rationale for the program is that while many opportunities exist to use molecular biology, biomedical engineering, and translational science to advance treatment of pediatric diseases, the comprehensive scientific knowledge and practical experience that are required to capitalize on these opportunities are often deficient among young pediatrician-investigators who have recently finished clinical training. The CHRCDA addresses this need by providing protected time for nascent scientists during their initial academic appointment. In our program, scholars: 1) take coursework in basic, translational, or clinical science areas relevant to their research; 2) learn state-of-the art laboratory and computational methodologies; 3) develop preliminary data under the supervision of established mentors that will lead to submission of independent NIH grant applications; and 4) learn to effectively advance accomplishments in basic, translational, and clinical research into improvements in child health. To accomplish these goals, the CHRCDA scholars spend at least 75% effort honing these skills under the mentorship of established mentors over a 3-4 year period. During this period, each of the above tasks will be addressed in a systematic fashion, including participation in a core curriculum in research methodology and biostatistics, training in responsible conduct of research, and performance of increasingly independent research under senior investigators. We fund 2-3 Scholars annually and match these scholars with senior mentors within four scientific affinity groups: neuroscience, molecular genetics, cancer and immunology, and biomedical engineering. The administrative structure includes a Principal Investigator/Program Director, a Training Director, an Executive Committee, and an external Advisory Committee. The outcomes of this program are measured by the products of the scholars’ subsequent academic careers: publications and independent external grant support. Recent innovations to our program include: expansion of funded research to include T2-T4 science with recruitment of a cadre of appropriate mentors, new pipeline programs to increase our pool of candidates including two R38 awards to fund research among pediatric residents and significant capital investments including the new Children’s National Research and Innovation campus. This administrative supplement is necessary to sustain the CDRCDA program during an unanticipated funding gap, ensuring uninterrupted support for scholars and continued program operations until a future funding opportunity is released.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY / ABSTRACT The goals of this R03 Award are to 1) identify food allergy beliefs and perceived treatment benefits/burdens among caregivers of children who pursue Xolair food allergy treatment and 2) determine the relationship of the uptake of Xolair food allergy treatment and caregivers’ psychosocial functioning. Food allergy affects up to 8% of children in the United States, with 45% of these children diagnosed with multiple food allergies.1,2 Over a third of children with food allergy experience >1 food allergic reaction a year.3 Caregivers consistently report experiencing intense fear about the chance of life-threatening food-induced anaphylaxis and food allergy anxiety,4–8 and have long advocated for a food allergy treatment that prevents anaphylaxis.9 A promising new form of food allergy treatment that may increase allergic reaction threshold for multiple food allergies, omalizumab, was FDA approved in February 2024.9 In a recent clinical trial, 67% of children with diagnosed food allergies who received Xolair via subcutaneous injection for 16 weeks demonstrated an increased reaction threshold to peanut and multiple other food allergens, meaning they may be protected against allergic reactions in response to accidental food allergen exposure.10 The clinical trial assessed caregiver food allergy-related quality of life, an important measure of overall food allergy well-being, but not the impact of Xolair food allergy treatment on fear of allergic reactions or food allergy anxiety,11 two critical factors to understand because they are factors that caregivers report motivate them to participate in food allergy treatment9,12,13—and therefore could greatly affect their decisions to pursue or abandon treatment. This new treatment also presents new decision points which require thoughtful shared decision-making with allergy care providers and may lead to unique food allergy-related stress and anxiety.14 We will augment the clinical trial’s quality of life findings and address crucial information gaps about caregiver fear of allergic reactions, food allergy anxiety, and decision-making using a behavioral health research framework guided by the Health Belief Model and the Shared Decision Making model. We will characterize food allergy beliefs, perceived treatment benefits/burdens, the decision-making process, and the relationship of Xolair treatment with food allergy-related fear, anxiety, and quality of life among 30 caregivers of children ages 5-11 years. We anticipate using data from this pilot study to inform a larger scale, multi-site trial in order to determine if patterns that emerge at our food allergy clinics are comparable with other food allergy clinics. Additionally, these data will provide crucial early-stage information about caregivers who pursue new food allergy treatment options, how they make treatment decisions, and the relationship of treatment with their food allergy-related fear and anxiety. We will use our data to inform the development of clinical and educational resources that will support families during the decision-making process. Our data will also clarify if behavioral interventions should be developed to support families while they undergo new food allergy treatments.

NIH Research Projects · FY 2025 · 2025-10

Project Summary/Abstract Disturbances in the molecular pathways that control lip and palate development during embryogenesis can lead to oral clefts, but knowledge of the regulatory interactions involved in modulating the expression of genes in these pathways remains limited. Because enhancers are critical to the spatiotemporal regulation of gene expression during embryogenesis, those that are active in craniofacial tissues during lip and palate development are likely to control the expression of genes relevant to oral clefts. The overall goal of the proposed research is to identify interactions between enhancers, transcription factors that bind the enhancers, and target genes of the enhancers in lip and palate development and oral clefts. Aim 1 is to identify the subset of enhancers that drive gene expression overall in human embryonic palatal mesenchyme cells. The transcription factors with binding site motifs that are enriched in the enhancers will be identified, and binding of the transcription factors within the enhancers in human embryonic palatal mesenchyme cells will be confirmed using assays of chromatin immunoprecipitation followed by sequencing. Aim 2 is to identify enhancers that regulate transcription specifically within human embryonic palatal mesenchyme cells, because such enhancers are more likely to be involved in craniofacial-specific processes during development. Enhancers that can distinguish between human embryonic palatal mesenchyme cells and other types of tissues and cells will be considered palate-specific enhancers. The palate specificity of a subset of the enhancers will be confirmed using in vitro assays.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY A growing body of published research links heightened maternal psychological distress (MPD) during pregnancy to an increased risk of adverse outcomes for the pregnant mother herself as well as for her offspring, including impaired brain development. The alarming increase in MPD over the last few years highlights the need to better understand how exposures during pregnancy affect brain development and child outcomes. Within a well-characterized cohort of maternal-offspring dyads, this study aims to characterize (1) the structural and functional brain trajectories of offspring with and without prenatal exposure to MPD using qMRI measures (2) neurodevelopmental trajectories of these offspring and (3) determine the enduring impact of elevated mental distress on parenting and attachment, and the potential contributions to offspring development.

NIH Research Projects · FY 2023 · 2025-08

PROJECT SUMMARY Opioids are medically used for safe pain relief and management. However, illicit opioid use has substantially increased across the US in the past decade, with further worsening during the COVID-19 pandemic, leading to a profound impact on human health. Specifically, opioid use disorder (OUD) during pregnancy poses an increased risk of pregnancy-associated maternal morbidity and mortality, fetal growth restriction (FGR) and related complications, neonatal opioid withdrawal syndrome, and long-term neurobehavioral effects. Some of these risks persist despite the use of safer opioids, such as buprenorphine and methadone, medications for OUD (MOUD) patients. Whereas current studies center mainly on transplacental opioid transport to the fetus and the adverse effects of opioids on infants, the direct impact of illicit and prescription opioids on placental development, differentiation, and function are largely unexplored. The placental floating villi mediate maternal- fetal gas exchange, nutrient uptake, waste release immune defense and the production of hormones and extracellular vesicles (EVs). These villi are covered by a layer of multinucleated, terminally differentiated syncytiotrophoblasts (STBs), which forms the feto-placental frontline that is directly exposed to opioids in the maternal blood. Subjacent to this layer are mononucleated, progenitor cytotrophoblasts (CTBs), which replenish the STB layer through the process of differentiation and fusion. Importantly, injuries to the STB and CTB layers are implicated in pregnancy-associated complications, including FGR and stillbirth. Here we seek to investigate opioid-dependent placental injury, focusing on the most critical and unique layer of placental trophoblasts. We will enroll participants with OUD, including illicit opioids and MOUD (buprenorphine, methadone), examine their pregnancy course and their children’s health through the first year postpartum. Using biospecimens from each participant, including maternal plasma and urine across the three trimesters, placental biopsies and fetal cord blood at delivery, we will employ multimodal cutting-edge technologies, including single-cell RNAseq, spatial transcriptomics, protein chip cytometry and placenta EV RNA profiling, and explore the molecular and cellular processes affected by opioids in the maternal-placental-fetal trio- ecosystem. To gain mechanistic insights into the functional changes in gene expression and EV cargo, we will use an array of model systems, including human trophoblast stem cells and cultured primary human trophoblasts, and mechanistically interrogate pathways underlying opioid injury. We will further correlate key molecular signatures with clinical assessment, including maternal gestational disorders, perinatal and infant neurodevelopmental outcomes. Together, our strategic plan, bolstered by our transdisciplinary team, enables us to address critically important knowledge gaps related to human placenta biology in opioid-affected pregnancies.

NIH Research Projects · FY 2025 · 2025-08

Focal cortical dysplasia (FCD) is the most common cause of surgically-remediable, pharmacoresistant epilepsy in children. FCD-related epilepsy often starts at a young age, placing children at risk of neurocognitive impairment and exposure to the side effects of antiseizure medications. Despite the regularity of FCDs, these lesions are often subtle which can lead to delays in detection; and even after detection, there are often long delays to epilepsy surgery. Current structural imaging and FCD pathological characteristics have failed to identify consistently those children at risk of developing pharmacoresistant epilepsy, and who would benefit from surgical intervention. Recent evidence has implicated that these focal lesions can cause widespread disruptions of distributed brain functional networks. Resting-state functional magnetic resonance imaging (rs-fMRI) is a validated, noninvasive imaging method that can identify stable functional networks across pediatric and adult subjects. Using advanced processing and statistical methods, these networks can be studied and compared quantitatively at the individual and group levels. This proposal tests the overall hypothesis that FCD-related epilepsy disrupts established cortical networks, and that the quantity and location of these perturbations determine which patients develop pharmacoresistant epilepsy. The aims of this research plan will identify 1) quantitative local, regional and remote network connectivity alterations and 2) network hub reorganizations associated with pharmacoresistance. This information will alter clinical practice by characterizing functional network markers of pharmacoresistance, allowing earlier identification and utilization of epilepsy surgery as guided by the 2021 NINDS Epilepsy Research benchmarks (IIA,C,IIIC). Nathan T. Cohen, MD (PI) is a board-certified pediatric epileptologist with clinical and research experience in advanced imaging of epilepsy. The proposed training plan will allow him to develop expertise in functional connectivity analysis, to master applied biostatistics, and to learn prospective and multicenter trial design. The candidate has organized a targeted mentorship team including William D. Gaillard, MD, and Chandan J. Vaidya, PhD whose expertise in functional imaging of pediatric epilepsy will allow him to achieve these goals. This K23 Career Development award will allow Dr. Cohen to transition to a line of independent investigation using functional imaging techniques to study the underpinnings of pharmacoresistance and the neurocognitive, behavioral, and psychiatric comorbidities of the epilepsies.

NIH Research Projects · FY 2025 · 2025-08

Disorders of consciousness such as coma occur often after cardiac arrest (CA). They complicate  recovery and prognosis. Currently, they have no treatment. To improve recovery of consciousness  and quality of life in CA survivors, we need new therapies. The proposed study focuses on CA-­ induced injury to a deep brain nucleus critical to consciousness – the thalamic reticular nucleus  (TRN). We have discovered that a subset of TRN neurons dies early after resuscitation in a rodent  model of pediatric asphyxial CA. TRN neuronal death increases in a front-­to-­back pattern which  overlaps with increasing expression of a T-­type Ca2+ channel Cav3.3. Cav3.3 enables TRN neurons to  fire rapid bursts of action potentials from a hyperpolarized state. TRN bursts occur in unconscious  states during anesthesia, sleep, absence seizures. Importantly, they also occur in 50% of comatose  CA survivors. Here for the 1st time, we will test the hypothesis that Cav3.3-­dependent bursts during  post-­arrest coma contribute to degeneration of TRN neurons. We will use our clinically realistic model  of severe brain injury in asphyxial CA to examine the effect of ethosuximide, an FDA-­approved T-­type  Ca2+ channel inhibitor, on TRN neurons. In Aim 1, we will combine EEG and in vivo multichannel  extracellular recordings of single TRN neurons to determine if post-­arrest ethosuximide prevents  bursting on EEG and in TRN. In Aim 2, we will determine if post-­arrest ethosuximide prevents CA-­ induced degeneration of TRN neurons and associated microglial activation. Our preliminary data  show biological plausibility and technical feasibility. The rigorous experimental approach employs  randomization, blinding, inclusion of sex as a biological variable and appropriate controls. Our  laboratory has extensive expertise with CA models and in vivo neurophysiology, ensuring successful  execution of the proposed experiments. This study will examine a novel translational approach to  protecting thalamic neurons which regulate consciousness from injury after CA. More broadly, it will  advance a paradigm in which post-­arrest neuronal activity not only marks injury severity but indeed  regulates evolving brain injury in CA survivors. Successful completion of this study will identify  Cav3.3 in particular and neuronal activity in general as targets for new therapies to improve  recovery of consciousness and neurologic outcomes after cardiac arrest.

NIH Research Projects · FY 2025 · 2025-07

The complexity of modern-day biomedical research (e.g., biomedical, behavioral, and clinical research) necessitates a team science approach. Yet few, if any, biomedical research training programs offer training on how to assemble, lead, and retain high-performing research teams. This lack of training risks hindering, if not derailing, the career of promising early-career biomedical researchers. The proposed research training program, called TEAMS (Together Everyone Achieves More in Science), will address this gap by training early-career biomedical researchers to assemble, lead, and retain high-performing, collaborative, and sustainable research teams. Leveraging the expertise of a multidisciplinary team of experts in team science, organizational management, biomedical research, mentorship, and communication, we will: (1) Implement TEAMS for five national cohorts of early career biomedical researchers; (2) Establish a peer network of TEAMS trained biomedical researchers (TEAMS-alums) to provide each other continued support and guidance throughout their career journey; (3) Evaluate the short, medium, and long-term outcomes of TEAMS through process and summative program evaluation methodologies. TEAMS will equip early-career biomedical researchers with team leadership skills and a peer network that will increase their success as biomedical investigators and strengthen the biomedical workforce.

NIH Research Projects · FY 2025 · 2025-06

ABSTRACT Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder caused by either deletion of 17p11.2 or mutations resulting in haploinsufficiency of the RAI1 gene located on 17p11.2. Common features of SMS include cognitive impairment, motor delays, impaired speech/language, a characteristic behavioral profile, and severe sleep disruptions. Recent preclinical studies have identified potential targets for therapeutic intervention in SMS. The central goal of our work is to facilitate future clinical trials by defining quantitative EEG biomarkers for SMS. Prior work has observed qualitative impairments in ~50-60% of SMS EEGs; this will be the first quantitative study of SMS EEGs. We will retrospectively analyze overnight EEGs containing periods of wake and sleep from children with SMS and age and sex-matched neurotypical controls. Using spectral analyses and other quantitative methods, we will complete two Aims: (1) Test the hypothesis that low-frequency brain rhythms are enhanced in SMS, and (2) test the hypothesis that sleep spindles are disrupted in SMS. This work will determine whether quantitative EEG analysis can detect SMS biomarkers that may then be validated prospectively prior to deploying in future clinical trial settings.

NIH Research Projects · FY 2025 · 2025-06

Next Generation T cell therapies for childhood cancers [NexTGen] Current treatments fail to cure many children with solid cancers. Recent advances in adult cancers such as checkpoint blockade and targeted small molecules have made little impact in childhood disease. Engineered T-cell therapies can achieve durable responses in refractory lymphoid cancers without long-term toxicity. These are precisely the characteristics required for new treatments for pediatric solid cancers. In contrast to hematologic malignancies, solid cancers are challenging due to a lack of targets, tumor heterogeneity, and hostile tumor microenvironment (TME). We posit that through advanced cellular engineering we can overcome these challenges. Our vision is that engineered T-cell therapy for childhood solid cancers will become routine within a decade. Our central hypothesis is that coupling of advanced cellular engineering along with progressive clinical development is the fastest route to developing effective T-cell therapies for pediatric solid tumors. In NexTGen, we combine detailed studies of primary tumors to discover new targets and understand how the TME subverts T- cell function. This, along with a closely coupled clinical development program will guide the progressive engineering of T-cells to result in transformative therapies. NexTGen is composed of 6 inter-connected work-packages (WPs) with work initially focused on pediatric sarcomas and brain tumors. AIMS: WP1: To identify suitable targets for engineered T-cells. WP2: To understand the TME in pediatric solid cancers. WP3: To develop receptors and other engineering components which target tumor cells and resist or modulate the TME. WP4: To evaluate the function of engineered T-cells developed in WP3. WP5: To translate approaches from WP4 and test them in clinical studies designed for maximal impact. Cancer Grand Challenges - Full Application - 2021 WP6: To promote data sharing across all WPs. METHODS: Target discovery (WP1) and TME studies (WP2) will utilize mass spectroscopy and chip cytometry respectively. Component engineering (WP3) will use protein engineering methods. To model engineered cell function, WP4 will mostly use intact tumor models such as immune PDXs. In WP5, clinical product generation will involve autologous closed system semi-automated manufacturing. WP6 uses standard and custom databases and data sharing platforms. USE OF RESULTS: Tumor target and TME data from WP1 and 2 will be uploaded to databases developed by WP6 for widespread distribution. Engineering components from WP3 and functional data from WP4 will be available for incorporation into therapeutic T-cell strategies by the entire community. Clinical study data from WP5 should lead to registration studies, improving cure rates and mitigation of long-term toxicity to realize our Vision.

NIH Research Projects · FY 2025 · 2025-06

Project Summary/Abstract Cerebral malaria (CM) is defined as an otherwise unexplained coma in a patient with Plasmodium falciparum parasitemia. The condition is common, primarily affects African children less than five years old, and has a large public health impact in endemic areas. Of the ~350,000 children diagnosed annually with CM, 15% die and 30% of survivors have neurological abnormalities at the time of hospital discharge. The mainstay of treatment is intravenous antimalarial drugs and supportive care. No adjunctive therapy has previously been proven effective in decreasing the high rates of mortality and morbidity in this condition. Our long-term goal is to establish feasible therapies that decrease death and disability rates in this vulnerable population. We will investigate 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, as a candidate adjunctive therapy for pediatric CM. We identified DON through a rational drug discovery process and tested its efficacy in several pre-clinical studies. Mice with experimental CM have radiographic and pathological abnormalities similar to those seen in human pediatric CM; DON administered to mice that are severely clinically ill rescues animals clinically, radiographically, and reverses abnormal histopathology. We will test DON’s safety and preliminary efficacy in human pediatric CM. To do so, we will first perform a dose escalation study of DON in healthy Malawian adults and adults with uncomplicated malaria, evaluating safety. After review, we will perform a randomized placebo-controlled double-blind safety and preliminary efficacy study of adjunctive DON in 70 Malawian children with CM. Participants in the first pediatric cohort (n=35) will receive lower doses of adjunctive DON or placebo. Doses of adjunctive DON administered to the second cohort of pediatric participants (n=35) will be informed by pharmacokinetic and safety data gathered from those previously enrolled. Our primary outcome is the proportion of participants with any Grade 3 or severe adverse events (SAEs). Concurrently with safety studies, DON’s preliminary efficacy in pediatric CM will be evaluated using brain magnetic resonance imaging (MRI), electroencephalogram (EEG), and transcranial Doppler (TCD). We hypothesize that Malawian children with CM who receive adjunctive DON will have no increase in mortality or rates of SAEs compared to participants receiving placebo. We hypothesize that children with CM receiving adjunctive DON will have biomarker changes (MRI, EEG, TCD) associated with improved outcome. In summary, this research is significant because the adjunctive therapy, DON, when used in a murine model of CM, reverses brain swelling, the most important risk factor for death in children with CM. If successful in subsequent human clinical trials, this would be the first adjunctive therapy with a demonstrable effect on decreasing death or disability in this patient population. We anticipate that with widespread dissemination of such a scalable intervention, the public health impact of this devastating infectious disease would finally decrease.

NIH Research Projects · FY 2026 · 2025-05

Project Abstract Sickle cell disease is a genetic red blood cell disorder affecting approximately 100,000 individuals, primarily of African descent, in the United States alone. The presence of abnormal hemoglobin (hemoglobin S) leads to sickling of red blood cells and vaso-occlusion, resulting in acute episodes of pain. Acute pain, or “vaso- occlusive crisis” (VOC), is the most frequent cause of emergency room visits and hospital admissions in sickle cell disease, contributing to the high burden of health care costs for these patients. Opioids are the mainstay of treatment for a VOC. However, treatment with opioids runs the risk of both short and long term side effects such as itching, constipation, respiratory depression, opioid tolerance and addiction. Because of these often severe consequences, alternative treatment modalities to opioid therapy are urgently needed in this high-risk population. Nitric oxide, which is generated from the amino acid citrulline through the urea cycle, is a powerful vasodilator, and low nitric oxide levels play an important role in the pathogenesis of vaso-occlusion. Citrulline plays an important role in nitric oxide production in endothelial cells, and consequently may be able to ameliorate vaso- occlusion. We hypothesize that the introduction of L-citrulline to standard (opioid) therapy will shorten hospital length of stay and decrease opioid use. In this phase 2 clinical trial, patients with sickle cell disease will be randomized to receive either the study drug (intravenous citrulline) or placebo to determine if citrulline administration leads to improvements in pain and decreases in hospital length of stay. In addition, we will evaluate how the body reacts to the study medication by measuring tissue oxygenation, nitric oxide levels etc., while closely monitoring for side effects. To better assess how this new treatment might be tailored to meet individual needs, DNA will be collected to evaluate the link between genetic variation in the nitric oxide pathway and response to treatment with citrulline. The novel therapeutic option of intravenous citrulline has the potential to significantly decrease opioid use and improve clinical outcomes for hospitalized sickle cell patients suffering from vaso-occlusive sickle cell pain crisis.

NIH Research Projects · FY 2025 · 2025-04

PROJECT SUMMARY Transcranial direct current stimulation (tDCS) has clear translational potential for a wide range of clinical conditions, from post-stroke recovery to psychiatric and neurodevelopmental conditions. TDCS is a portable and relatively inexpensive form of neuromodulation, with an outstanding safety profile. However, the mechanisms underlying the effects of tDCS on brain and behavior have yet to be clarified, and relatively few studies acquire neuroimaging data during and/or after tDCS administration. We have acquired a substantial database (>225 sessions in >105 unique participants) of concurrent tDCS-functional MRI (fMRI) data targeting different cerebellar subregions, with cognitive and behavioral baseline measures, post-tDCS resting state and task fMRI, task performance data, and tDCS symptom ratings. The cerebellum interconnects with all major cortical networks, including the prefrontal cortex, and we and others have shown that targeted cerebellar neuromodulation can alter performance on a broad range of tasks (language, working memory, face recognition) and in different clinical populations (aphasia, autism, schizophrenia). That said, it is clear that there are individual differences in response to tDCS – while some participants have a robust improvement in performance, others show decreased performance or no measurable behavioral change. Multiple factors could drive these individual differences, including baseline task performance, resting-state brain connectivity, idiosyncratic task activation patterns, and anatomical targeting of the neuromodulation, to name a few. However, we do not know which (if any) of these factors are the most robust predictors of individual response. Our goal is to apply state-of-art machine learning algorithms to this unique, multimodal dataset to determine which factor(s) explain an individual’s response to tDCS. First, we will use individual participant’s structural MRI scans to model the peak electric field on a participant-by-participant basis. We will use these models and during-tDCS functional MRI data to determine the individual anatomical targeting of tDCS. Next, we will calculate the behavioral and neural effects of tDCS based on in-scanner task performance and activation patterns. We will extract metrics of baseline and post-tDCS resting-state connectivity in each participant. Then, we will use the curated dataset (electric field maps, cognitive performance, age, sex, resting state data, task activation, etc.) to determine which variables best predict the direction and size of the post-tDCS behavioral shift. While it has been hypothesized that anatomical targeting is a critical factor in individual response, it is also possible that baseline neural activation or even baseline task performance are the most predictive features. These are critical outstanding questions that, if answered, will accelerate the field toward more effective, better designed clinical trials. From a basic science perspective, this work will inform our understanding of how tDCS impacts both brain and behavior. Our goal is to conduct work that will transform the therapeutic efficacy of tDCS for neurological, psychiatric and developmental conditions.

NIH Research Projects · FY 2026 · 2025-04

ABSTRACT The maintenance of healthy skeletal muscle and its regeneration following acute injury involves precise regulation of the resident stem cell response by the surrounding muscle niche. Pediatric muscles respond quickly and are more proficient at regenerating from injury. The decline in regenerative capacity of geriatric muscle is widely studied, where the muscle niche is recognized to be a key contributor in the decline of the regenerative capacity of the muscle stem cells. However, the factors that support efficient regenerative capacity of pediatric muscle are less understood. The limited work in this area has focused on ex vivo examination of the intrinsic myogenic capacity of muscle stem cells but fails to capture the role of the muscle niche in driving pediatric muscle regeneration. An understanding of this is required as multiple degenerative muscle diseases, such as DMD, manifest from early childhood, where therapies that can maintain or further enhance pediatric muscle regenerative capacity can ameliorate the impact of this disease. The work proposed here aims to address this knowledge gap by building on our preliminary studies implicating the interplay of immune and stromal factors in the muscle niche for efficient regenerative myogenesis of pediatric muscle (Aim 1) and identify how these interactions are impaired in dystrophic that attenuates regenerative myogenesis and how targeting this holds therapeutic potential (Aim 2). We will make use of a combination of single-cell and spatial RNA transcriptomic analyses together with various DMD mouse models and patient samples to examine this process and validate our findings. Through use of these complimentary approaches the work here will provide basic insights into the regulation of healthy pediatric regenerative myogenesis with broad applicability to DMD and other pediatric onset degenerative muscle wasting diseases.

NIH Research Projects · FY 2026 · 2025-02

Pediatric patients with rare diseases experience high mortality with 30% not living to see their 5th birthday. Families are likely to be asked to make complex medical decisions for their child. Pediatric advance care planning involves preparation and skill development to help make future medical care choices. Children with rare disorders are a heterogeneous group, resulting in their exclusion from research. Available research on families of children with rare diseases lacks scientific rigor. Although desperately needed, there are few empirically validated interventions to address these issues. We propose to close a gap in our knowledge of families’ needs for support in a heterogeneous group of children with rare diseases; and to test an advance care planning intervention. The FAmily CEntered (FACE) pediatric advance care planning intervention is adapted to families with children who have rare diseases. Theoretically informed and developed and adapted by the principal investigator and key stakeholders, the proposed intervention will use Respecting Choices Next Steps Pediatric ACP™ for families whose child is unable to participate in health care decision-making. Our consultation with families of children with rare disorders and the National Organization for Rare Disorders (NORD) revealed that basic palliative care needs should be addressed first, prior to an advance care planning intervention. For the study to be able to meet this request, all families randomized to the intervention will first complete the Carer Support Needs Assessment Tool (CSNAT)© adapted by our team for use in pediatrics. In the CSNAT Approach, facilitators assess caregivers’ prioritized palliative care needs and develop Shared Action Plans for increasing informal social support. Thus, we propose an innovative 3-session FACE-Rare intervention, integrating two evidence-based approaches. We will evaluate FACE-Rare using a scientifically rigorous intent-to-treat, assessor-blinded, longitudinal, prospective, three-site, randomized controlled trial design. Family/child triads (N=160) will be randomized to FACE-Rare (CSNAT Sessions 1 & 2 plus Respecting Choices Sessions 3) or an enhanced information Treatment as Usual control group. All families will complete questionnaires at baseline and follow-up at 3-, 6- and 12 months. We will evaluate the effect of FACE-Rare on family quality of life (caregiver appraisal, psychological, spiritual). We will assess the palliative care needs of families at four time points. We will determine the intersection of child-sex, family-race, and household income on family caregiver quality of life and child healthcare utilization. We will explore the influence of urban vs. rural setting and religious coping on quality-of-life outcomes. We will use advanced statistical methods informed by statistical advice from rare disease investigators for clinical trials in small populations.

NIH Research Projects · FY 2026 · 2025-01

Despite enormous investments in research over the last 30 years, pediatric sepsis remains a leading cause of in-hospital death. Sepsis is defined as rapidly progressive, life-threatening organ dysfunction (OD) due to an immune dysregulation as a response to infection. In the U.S. over 75,000 children are admitted for sepsis annually with an associated mortality rate of 5 to 20%. Effective timely sepsis management (early/accurate diagnosis and appropriate treatment) is exacerbated by varying sepsis phenotypes resulting in high heterogeneity in sepsis presentations and responses. Sepsis phenotypes can result in significant variability in the immune response by disrupting metabolism and adenosine triphosphate (ATP) levels, affecting critical cellular functions including those needed to fight infections. The pathophysiology of sepsis is linked to an energetic crisis combined with immune-mediated inflammation. Specifically, cells shift their energy generation from aerobic oxidative phosphorylation (OXPHOS) to less-efficient glycolysis. Cellular energetic deficiency leads to excess accumulation of reactive oxygen species (ROS) and subsequently to oxidative stress, inflammation, and 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). Neonates and young children are particularly vulnerable to energy deficits during sepsis due to their limited energy reserves, higher metabolic rates, and immature organ systems. Early sepsis recognition and timely treatment with appropriate antibiotics, IV fluids and/or vasopressors can reduce mortality. Additionally, there is no therapy that directly targets the pathophysiologic changes of sepsis such as the concurrent disrupted energy-generating metabolic processes and immune dysregulation, especially in organs most affected by sepsis such as the brain and the lungs. To develop new therapeutic protocols for sepsis, our team has been investigating the use of MSC-EVs in alleviating sepsis-induced immune and metabolic dysfunction with encouraging results. In summary, I have established a program that aims to decrease sepsis mortality in the pediatric population by 1) using an AI-guided early identification tool, 2) performing sepsis phenotyping and a digital twin patient model to predict personalized treatment response and 3) developing a cutting-edge extracellular vesicle-based therapeutic protocol. I have made significant contributions to the scientific community by providing mentorship to trainees of all levels and service to professional societies, peer review panels and journal editorial boards. I’m committed to creating a robust scientific environment with the goal of decreasing sepsis mortality and potential long-term effects and improving the lives of many vulnerable children their families.

NIH Research Projects · FY 2024 · 2025-01

Project Summary: Pediatric patients with congenital heart disease (CHD) frequently require pharmacological interventions (e.g., inotropic agents) to stabilize and improve cardiac mechanical function after corrective heart surgery. However, the medications administered to hospitalized children have not been formally studied in this population - due to underrepresentation of pediatric patients in clinical trials. Indeed, postnatal development is a dynamic process, as cardiomyocytes undergo significant adaptations in cell structure, calcium handling, and contractile function. We hypothesize that cardiomyocyte maturity strongly influences pharmacodynamics, and that consideration of age-specific differences in inotropic drug response can improve clinical care by tailoring drug therapies to pediatric patients. This proposal will investigate driving factors of postnatal cardiomyocyte maturation, the physiological effects on electrophysiology and contractility, and the impact on myocardial response to inotropic agents. Specifically, Aim 1 will investigate age-specific differences in drug response on cardiac electrophysiology and excitation- contraction coupling. A juvenile guinea pig model will be used to measure electrocardiograms, electrophysiology metrics, optical action potentials and intracellular calcium transients, and left ventricular pressure during baseline conditions and following treatment with calcium, dopamine, or milrinone. Tissue samples will be collected for mechanistic analysis of developmental changes in gene and protein expression. Aim 2 will investigate postnatal development of human cardiomyocytes and the impact of age on drug response. To aid in the translation of our animal studies, I will collect human cardiac tissue samples from neonates, infants, and children undergoing corrective heart surgery at my institution. Age-dependent changes in gene and protein expression will be quantified. Calcium transients will also be recorded from live, human heart tissue slice preparations under baseline conditions and in response to inotropes. By providing data on pediatric heart development and drug responsiveness, the results of this study will have a significant impact on the cardiac research field, cardiac surgery, and critical care medicine. Further, this 3-year training plan will support my scientific growth, which builds upon the expertise of my Sponsor (Dr. Posnack: cardiac electrophysiology, pharmacology) and co- Sponsor (Dr. Ishibashi: pediatric cardiac surgery). I will also benefit from interactions with collaborators and a mentoring team, who will provide guidance in career development, the goals of this study, and experimental techniques (e.g., optical mapping, molecular biology). This proposal will advance my knowledge in cardiac physiology, pharmacology, and clinically relevant approaches – and support my future goal of independently leading a translational cardiac research laboratory.

NIH Research Projects · FY 2025 · 2024-09

Asthma disproportionately impacts under-resourced, Black, and Hispanic youth who experience higher asthma morbidity. These disparities are partially explained by social adversity experienced at multiple levels (child, family, community). Yet, these critical associations between social adversity and pediatric asthma are not fully incorporated into strategies to address morbidity among children which may exacerbate existing disparities, meaning such at-risk children experience decreased quality of life, higher school absenteeism, and decreased educational and employment achievement in late childhood and adulthood. In this proposal, Dr. Tyris’ objective is to advance the existing knowledge on social adversity and asthma morbidity with diverse methodologies that seek to better integrate social care (activities mitigating health-related adverse social factors) into medical care for children. She will pursue this overall objective through the following specific aims: Aim 1: Predict risk of hospitalization among DC children with asthma using multi-level social adversity indicators. A population-based machine learning model using the DC Pediatric Asthma Registry (n= >19,000) and social adversity, clinical, and demographic data will be developed to predict risk of asthma-related hospitalization and to identify which variables are most predictive of children at highest risk for hospitalization. Aim 2: Characterize caregiver perspectives of mechanisms to address modifiable family-level variables that impact child asthma morbidity. A community advisory board will be established to conduct longitudinal focus groups and engage with caregivers of children frequently hospitalized for asthma to refine family-level approaches to address social adversity and enhance recruitment and retention issues for a pilot RCT. Aim 3: Determine feasibility and acceptability of an integrated social care intervention of individualized assistance and adjustment strategies among caregivers of children with asthma. Dr. Tyris will conduct a pilot randomized controlled trial to determine if using addressing social adversity in routine asthma care with assistance (helping resolve social adversity) and adjustment (modifying health care to overcome social barriers) will be acceptable to caregivers and feasible to implement. The outlined career development plan, including the proposed aims, will enable Dr. Tyris to gain advanced training and knowledge in four key areas: machine learning methods for risk prediction, stakeholder-engaged intervention design, clinical trial design and execution, and integrated social and medical care interventions. She will leverage the expertise of Dr. Tyris’ mentors (Drs. Teach and Parikh) and advisors (Drs. Trujillo Rivera, Hinds, and Gottlieb) and the robust, supportive research environment at Children’s National Hospital and George Washington University. Successful completion of this career development and research proposal will facilitate Dr. Tyris’ overarching career goal to become an independent and federally funded investigator who creates, implements, evaluates, and effectively translates stakeholder-engaged solutions designed to mitigate social adversity, reduce health disparities, and improve care and outcomes for children with asthma.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT The transition from adolescence to adulthood is a critical period of development characterized by significant changes in social-emotional behavior. One of the central brain structures modulating this transition is the amygdala. The development of the amygdala continues through adolescence, undergoing an expansion in size and neuron number into early adulthood. These changes enable healthy social and emotional development, and perturbations in amygdala development and maturation are linked a host of mental health disorders, most notably autism spectrum disorders (ASD). However, the amygdala neuronal and circuit substrates underlying changes coincident with this major life transition remain little understood. In our published studies in humans, and our unpublished work in mice, we identified and characterized a unique population of immature neurons in the paralaminar nucleus of the amygdala (PL). While these neurons are born embryonically, they interestingly delay their maturation until adolescence when they differentiate into excitatory neurons. Thus, the PL is well positioned to play a key role in the behavioral changes that are associated with the transition from adolescence to maturity. The goal of our proposed studies is to understand the role of amygdala late-maturing neurons in the circuitry, neuronal responsivity and behavioral transition that occurs during adolescence. To test this, we will examine the dynamic circuit changes in input connectivity (Aim 1), neuronal responsiveness (Aim 2), and the role the PL plays in the behavioral transition (Aim 3) from adolescence to early adulthood. Our discovery and characterization of PL neurons that undergo maturation coincident with adolescence suggests a novel mechanism of brain plasticity during a critical stage of post natal development. Our proposed studies are also an essential step to understanding the role late maturing PL neurons play in neuro-atypical brain function associated with disorders of social cognition such as ASD and the long-term consequences of early life stress.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY / ABSTRACT Type 1 diabetes (T1D) is one of the most common chronic illnesses of childhood. The involved treatment regi- men, including daily insulin administration/pump management, frequent blood glucose checks, and careful tracking of food intake, places a high stress burden on patients. Adolescence is a risky time for T1D management given a marked decline in treatment adherence. Over 80% of adolescents with T1D have glycemic control that does not reach target levels (A1c 7.0%), and one significant risk factor is the increase in negative affectivity, including depression and anxiety symptoms. Elevated depression and anxiety symptoms affect 40% of teens with T1D. Our preliminary data support the notion that negative affectivity contributes to diminished treatment adherence and worsening of glycemia, partially through the effects of negative affectivity on stress-related behavior such as maladaptive eating behavior. The use of novel, targeted interventions, tailored for the developmental needs of adolescents with T1D and the particular burdens of coping with their chronic illness, that are translatable and able to be disseminated into clinics are needed. Our pilot work adapted, with the collaboration of stakeholders, a 7-week, group mindfulness-based intervention based on Learning to BREATHE, BREATHE-T1D, and a health education comparison condition, HealthEd- T1D, for adolescents with T1D. This pilot study demonstrated the feasibility and acceptability of participation in both groups with the ultimate goal of improving glycemic control via improvements to mood and therefore less disordered eating, avoidant coping, less impulsivity, and better self-care. The primary goal of the current proposal is to conduct a full-scale efficacy trial of BREATHE-T1D as compared to HealthEd-T1D across two sites, Children’s National Hospital in Washington, DC and the University of Colorado in Denver. The study will be a pragmatic clinical trial with another primary aim to conduct a pilot feasibility study of implementation of a group-based intervention for negative affect via an in-clinic screening and program referral process consistent with the Fit to Context Framework’s Design Phase. The feasibility and acceptability of the screening and referral process will be assessed via documentation of screening rates as well as qualitative interviews and implementation survey measures with clinic staff and providers. This goal is to evaluate the screening and referral process into the program within the ultimate setting in which it will be delivered, if efficacious. The result of the current study will be a feasible and acceptable clinic screening and referral process across multiple clinics and an efficacious group-based, virtual intervention tailored for adolescents with T1D designed for the settings in which it will ultimately be implemented. The multidisciplinary and multi-site study team contributes complementary areas of expertise in adolescents with T1D, behavioral intervention development, negative affectivity and maladaptive eating behavior, adolescent mindfulness-based intervention, culturally- relevant care, qualitative data analysis, and dissemination and implementation.

NIH Research Projects · FY 2025 · 2024-09

Viral infections are common and can be severe in immunocompromised patients, including those undergoing hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT). Virus-specific T cells (VSTs) have been effective in prevention and treatment of viral infections in patients post HSCT or SOT, but are inactivated or eliminated by immunosuppressive therapies including alemtuzumab, which limits their application and efficacy. We have demonstrated that CD52 knockout via CRISPR/Cas9 can be performed in CMV-specific T cells with maintenance of antiviral specificity. The overarching goal of this proposal is to study the impact of CD52-knockout on the function of multivirus-specific T cells, including antiviral specificity, cytokine profile, and cytotoxicity, as well as the persistence and safety of CD52-KO VSTs in vivo. In this study, we will address the following specific aims: 1) To establish the biological activity of multivirus-specific CD52-KO T cells in comparison with non-edited virus-specific T cells, and 2) To determine if CD52-KO enables T cell persistence and efficacy in the presence of alemtuzumab in vivo. To evaluate CD52-KO as a preventative cellular therapy, we propose to optimize CRISPR/Cas9 editing of rapidly-expanded multiviral T cells (targeting cytomegalovirus, Epstein-Barr virus (EBV), and adenovirus) from healthy donors, followed by extensive characterization of the phenotype and function of CD52-KO VSTs versus mock-edited VSTs, including surface markers, cytokine profile, single cell RNA-sequencing, and T cell receptor sequencing. Using a mouse model, we will evaluate the persistence and safety of CD52-KO VSTs in the presence of alemtuzumab. To assess function in vivo, we will test CD52-KO or mock-edited VSTs against EBV-lymphoblastoid tumors in mice, in the presence or absence of alemtuzumab. Finally, we will perform off-targeting analyses of the lead single guide RNA candidates by in silico and orthogonal testing of CD52-KO and mock-edited VSTs. We hypothesize that CD52-KO will have negligible impact on VST phenotype and function, and will enable persistence and activity in the presence of alemtuzumab in vivo. Completion of this study would provide a novel antiviral therapy which could reduce virus-associated morbidity in HSCT, and will develop a pipeline for production of a next generation of gene-modified VSTs to enhance efficacy in immunocompromised patients.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Placement of orthopaedic implants, such as guidewires and screws, is a common surgical task, and accurate placement is critical to the success of a range of orthopaedic procedures. However, the rate of screw misplacement is highly variable, with one study showing a 14% misplacement rate in the spine. While screws are often placed during open surgery, allowing direct visualization of bones, there is a growing trend toward percutaneous screw placement. The most studied procedure has been pedicle screw placement, where a meta-analysis showed that a significant percentage of screws are misplaced and that image guidance can improve placement accuracy. Misplaced screws can put adjacent nerves, vessels, and joints at risk of injury, leading to complications and revision surgery, which are often invasive and costly. The goal of this R01 proposal is to develop, evaluate, and prepare regulatory paperwork for first clinical studies of a new technique for guiding implant placement in orthopaedic surgery. The technique combines recent advancements in a low-profile robot with emerging methods for image reconstruction and registration using a low-dose 3D cone-beam tomosynthesis (CBT) system. Our long-term goal is to provide a complete solution for precision implant planning, placement, and verification while minimizing radiation exposure to the patient and surgical staff. This new methodology would allow surgeons to accurately place implants with fewer images, reduce radiation exposure, and provide verification of device placement in the operating room (OR), with opportunity for immediate revision. Our specific aims are to: 1. Develop a surgical navigation workstation based on the open-source software package 3D Slicer to integrate a low-profile guidance robot with 2D and 3D imaging for trajectory planning and robotic guidance of screw placement. 2. Develop and translate low-dose CBT for SCFE by identifying imaging protocols, optimizing reconstruction quality, and segmenting target structures using combined model-based and deep-learning techniques. 3. Develop and translate a 3D to 2D image registration and guidance system that exploits the rotating source to work off of a static C-arm gantry pose and track surgical instruments with respect to anatomy. 4. Integrate the technology developed in Specific Aims 1-3 and evaluate in phantom and cadaver studies. Modify as necessary to achieve less than 3 mm end-to-end targeting error. 5. Pursue an IDE submission to the FDA for first-in-human use in future work.

NIH Research Projects · FY 2025 · 2024-08

The overarching goal of this proposal is the development of the candidate into an independent investigator in the field of immune modulatory cell therapy for critically ill children, particularly those post hematopoietic stem cell transplant (HSCT). With her clinical and research background in pediatric critical care and T cell immunotherapy, she is ideally positioned to fully realize the benefits of an NIH Mentored Career Development Award. This research proposal seeks to establish the safety and preliminary efficacy of adoptive immunotherapy with donor-derived SARS-CoV-2-specific T cells (CST) for prophylaxis against SARS-CoV-2 infection in patients post HSCT by conducting an FDA- and IRB-approved phase I clinical trial (NCT 05141058) and to develop CSTs genetically engineered to maintain antiviral activity in the presence of the commonly used lymphodepleting agent, alemtuzumab. The specific aims of the proposal are: 1) to determine whether infusion of donor-derived CSTs safely enhances antiviral immunity to SARS-CoV-2 in patients early (<4 months) post HSCT, and 2) to genetically engineer CSTs to retain antiviral activity in vitro in the presence of alemtuzumab. Together, these aims will establish the safety and preliminary efficacy of CST prophylaxis in the post HSCT population and lay the foundation for a “next generation” of virus-specific T cells (VST) engineered to resist immunosuppressive peri- transplant drugs. In addition, they will develop the candidate's expertise in T cell immunobiology, high throughput sequencing, gene editing, and early phase clinical trials. The candidate has assembled an outstanding advisory team who are highly qualified to guide her in the pursuit of her career and research goals. Her primary mentor and co-mentor, Drs. Catherine Bollard and Michael Keller, are world-renowned experts in immune modulatory cellular therapy and T cell immunobiology. Dr. Matthew Porteus, a pioneer in the field of gene therapy, will guide her work developing genetically engineered CSTs. In addition, Dr. Patrick Hanley, Director of the Good Manufacturing Processes Laboratory at Children's National Hospital, will oversee production of the CST product (IND 27588); Dr. Rick Jones will advise and oversee trial conduct at Johns Hopkins Medical Institutions (JHMI); and Dr. Wei Li will provide bioinformatic support for both CRISPR and high throughput sequencing experiments. A selection of focused coursework and seminars will facilitate investigator independence by the end of the award period. The candidate will benefit from a superb academic environment and extensive resources available through the Center for Cancer and Immunology Research, the Genetic Medicine Research Center, and the Clinical and Translational Science Institute at Children's National, as well as from in-person training in gene editing in the Porteus laboratory. In summary, this proposal describes a plan that is relevant, feasible, and will provide the necessary mentorship and training to promote the candidate's development into an independent clinician scientist in the field of cellular immune modulatory therapy.