Children'S Hosp Of Philadelphia

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Characterizing neurocognitive risk parameters in children is critical to the study of developmental psychopathology and paves the way for novel treatment and interventions. Heightened threat sensitivity – the recognition, interpretation, and response to real or potential threat cues in the environment – is a strong neurocognitive predictor of anxiety risk. However, little is known about how heightened threat sensitivity develops and is maintained across time. The limited extant work suggests parental characteristics and behaviors influence children's anxiety risk and may shape the development of children's threat sensitivity. However, we lack knowledge about intergenerational influences on the transmission of heightened threat sensitivity. The current study uses a longitudinal intergenerational framework to identify factors that influence the neural, biological, and behavioral correlates of threat sensitivity across time and generations. The current project will be the first intergenerational study of the Philadelphia Neurodevelopmental Cohort (PNC), a racially-diverse cohort of ~10,000 participants assessed at age 8–21 between 2009-2012, with many participants becoming parents in the last 5 years. In 300 mother-child dyads (children aged 4-8 years), we use a multimethod assessment framework with psychiatric (clinical interview, self-report), behavioral (computer tasks), observational (parent-child interactions), neural (electroencephalogram: EEG), and physiological (electrocardiogram: respiratory sinus arrhythmia) measures to examine the pathways underlying longitudinal and intergenerational influences on threat sensitivity and anxiety. First, we leverage data from the original PNC to examine factors that influence the presence of a multimethod threat sensitivity construct in mothers, 10- years later, and examine longitudinal links between threat sensitivity and anxiety symptomatology. Second, we focus on the child's threat sensitivity and anxiety, investigating the intergenerational influence of maternal threat sensitivity and, in an available subsample, the influence of paternal/secondary caregiver (n=200) threat sensitivity, on the child's threat sensitivity and anxiety. The study also examines the role of environmental threat exposures (e.g., trauma, discrimination, and poverty) on individual differences in threat sensitivity, with the hypothesis that increased threat exposures will increase susceptibility to abnormal threat processes. Lastly, we investigate a possible mechanism underlying the intergenerational transmission of threat sensitivity: negative parental communication. We will examine real-time transmission of threat through parental communication (e.g., verbal threat promotion, expressed anxiety) across a series of parent-discussion tasks. This project aligns with NIMH programmatic goals by charting mental health symptoms and mechanisms of risk across the lifespan. Results from the multimethod approach will inform multisystem mechanisms of intervention and prevention at the level of the parent and child. Our proposed expansion of the PNC to a longitudinal intergenerational cohort is an unprecedented opportunity to transform knowledge on anxiety risk.

NIH Research Projects · FY 2026 · 2024-12

PROJECT ABSTRACT STAT3 gain-of-function (GOF) is a rare, childhood-onset monogenic disease that amplifies inflammatory cytokine signaling. In this rare, inflammatory disease there is a paradoxical increase in both viral infections and in the incidence of autoimmunity. In STAT3 GOF patients we find impaired cytokine production and proliferation in CD8 T cells. Seeking mechanistic insight, we have found increased levels of CD39 protein, which is encoded by the STAT3 target gene ENTPD1, in CD8 T cells. CD39, an ectoenzyme that partners with CD73 to hydrolyze extracellular ATP to adenosine, is a negative regulator of immune activation. Adenosine in turn binds to the adenosine 2A receptor (A2AR) on T cells, potently inhibiting proximal TCR signaling and effector cytokine production. In the setting of chronic STAT3 signaling, and the resulting inflammation and autoimmunity, we propose that the CD39/axis serves as a rheostat for reducing inflammation. Our central hypothesis is that amplified STAT3 signaling drives CD39 expression, which increases ATP hydrolysis, thus increasing extracellular adenosine and impairing CD8 T cell function by binding to the adenosine 2A receptor (A2AR), thereby impairing both potential anti-viral and actively pathogenic autoreactive CD8 T cells in the setting of chronic STAT3 signaling. In Aim 1, we will test whether increased CD39 expression in CD8 T cells from STAT3 GOF patients and mice drives immune suppressive adenosine signaling to impair CD8 T cell function. These studies will also determine the impact of JAK inhibition (upstream of STAT3, the best available therapy for STAT3 GOF patients) in both STAT3 GOF samples from patients and mice, as well as perturbations of the CD39/adenosine axis in a mouse model of STAT3 GOF. In each case, we will assess the impact of chronic STAT3 signaling on CD8 T cell effector function, purinergic metabolite levels and the transcriptional impact on STAT3 target genes, CD8 T cell effector and adenosine signaling networks by directly comparing sorted CD39+ CD8 T cells vs. CD39- CD8 T cells and their impact on co-cultured “responder” bulk CD8 T cells. In Aim 2, we will determine the impact of inhibiting CD39 or A2AR on the susceptibility to autoimmunity and viral infection in STAT3 GOF. Specifically, we will assess the impact of inhibiting the CD39/adenosine axis in the NOD mouse model of type 1 diabetes (T1D), focusing on the impact on function when the STAT3 GOF patient variant STAT3+/K392R is exclusively expressed in islet-antigen specific CD8 T cells. In addition, we will assess the impact of inhibiting the CD39/adenosine axis in acute LCMV infection in B6 mice with co-transfer of STAT3+/K392R antigen specific CD8 T cells and STAT3+/+ antigen specific CD8 T cells. Defining the role of the CD39/adenosine axis could lead to novel therapeutic options for the many disease states rooted in chronic inflammation.

NIH Research Projects · FY 2026 · 2024-12

PROJECT ABSTRACT GC responses are steered toward pathogen-recognition and away from self-reactivity by T follicular regulatory (Tfr) cells. The molecular means by which Tfr cells exercise control are unknown. GCs are deranged and Tfr subsets are altered in lymph nodes excised from common variable immunodeficiency (CVID) patients. CVID is a genetic disease caused by mutations in immune critical genes like CTLA4, NFKB1, PIK3CD or PIK3R1 and diagnosed based upon poor vaccine responses and a proclivity for autoantibody production. The relevance of Tfr cell defects to CVID pathogenesis is unclear. The long-range goal of the proposed work is to determine how GCs are controlled in health and how governance loss promotes immune deficiencies and autoimmune diseases. The objective of this grant application is to establish which lineage lymph node Tfr cells belong to in humans and how lineage-specific Tfr cell developmental aberrations contribute to autoimmune pathologies. The working hypothesis is that the Tfr cell pool encompasses both “natural” nTfr cells that descended from Tregs and iTfr cells that are induced from T follicular helper (Tfh) cells. Whereas nTfrs express autoreactive T-cell receptors and enforce self-tolerance, iTfrs arrive weeks into a GC response to amplify affinity maturation and ultimately quinch the reaction. Based upon altered circulating iTfr to nTfr ratios in CVID patients, we anticipate counterpart cells in their paired lymph nodes will display altered frequencies, locations and repertoires. Our rationale is that by understanding which GC response elements are controlled by iTfrs and nTfrs, we can develop new diagnostic and therapeutic opportunities for patients with GC-dysfunction disease including, but not limited to, CVID. Our specific aims will test the following hypotheses: Aim 1: iTfr and nTfr cells can be clonally distinguished and functionally described in lymph nodes and blood from controls and CVID patients Aim 2: iTfr and nTfr cells can be localized within healthy and CVID lymph node sections and Aim 3: CVID Tfr defects and CVID-associated GC dysregulation can be reproduced in genetically edits tonsil organoids. The contribution is significant because the molecular underpinnings of human GC regulation are unknown are of great consequence to patients with autoimmune and immunodeficiency diseases. The proposed work is innovative because we propose defining protein and gene expression of single human cells in their native, tissue-resident spatial context with a suite of modern, high-dimensional technologies uniquely suited to our topic. Further, we are verifying our findings in rare excisional lymph node biopsies of CVID patients using high-dimensional imaging and disease modeling in genetically edited tonsil organoids.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT I seek to become an independent, NIH-funded academic allergist-immunologist and clinical research informatician invested in improving outcomes in pediatric allergy. To this end, I will utilize electronic health record (EHR) data to study developmental patterns of pediatric allergic diseases and harness this knowledge to develop clinically relevant allergy prediction models using artificial intelligence approaches. I am in my final year of fellowship in pediatric allergy-immunology at the Children’s Hospital of Philadelphia (CHOP) having completed MD-PhD and pediatric residency training. I possess a strong background in experimental and clinical immunology and have pivoted to clinical research informatics for my post-doctoral research work, as it is aligned with my long-term career goals. Despite my development of multidisciplinary collaborations that have led to several publications, I require dedicated training in bioinformatics, statistics, and epidemiology in order to successfully conduct research independently in this space. The K08 Mentored Clinical Scientist Development Award is the optimal means by which I can obtain this additional experience and training. My training plan includes formal coursework through certificate programs at Penn. I will complement this with hands-on training with an exceptional team of mentors (Dr. David Hill, primary mentor; Dr. Robert Grundmeier and Dr. Rich Tsui, co-mentors) and advisors (Dr. Alex Fiks, Dr. Jonathan Spergel, and Dr. John Holmes). My training will also greatly benefit from the first-rate clinical and research environments at CHOP/Penn. To complement my training plan, I have developed an integrated research proposal that will allow me to model the development of allergic diseases in children. There is considerable variability from child to child in the sequence and number of allergic conditions that they develop, an emerging concept in the allergy field termed allergic trajectories. The basis for these heterogeneous allergic trajectories is incompletely understood. To date, allergy epidemiology has been measured largely via patient questionnaires, which are susceptible to reporting and self-selection biases. EHR databases contain demographic and longitudinal clinical data and thus represent an alternative approach for the study of allergic disease risk factors; however, they have been scarcely used for the study of their trajectories and for the development of disease risk prediction models. Building on my published and preliminary work, I will use the multi-institutional Comparative Effectiveness Research through Collaborative Electronic Reporting (CER2) and CHOP primary care network EHR databases to test the hypothesis that heterogenous allergic trajectories exist that are differentially associated with specific clinical, demographic, and/or environmental factors. The aims of my study are (1) to determine the major pediatric allergic trajectories and their biologic and non-biologic risk modifiers using multivariable logistic regression and Cox proportional hazards testing and (2) to develop and test EHR-based allergy risk prediction models that consider clinical and demographic information using machine learning and exploratory natural language processing. Study results will be externally validated in the independent, multi-institutional PEDSnet database. This work will yield clinically relevant tools that are expected to inform personalized medicine efforts focused on preventing and predicting pediatric allergy. By completing the proposed research and career development plans, I will be well positioned to function as an independent physician-scientist investigator at the intersection of pediatric allergy-immunology and clinical research informatics.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY CD4+ T cells (TCD4) play critical roles in adaptive immune responses following antigen-driven proliferation and differentiation. By convention, proliferation is driven by two triggers: “Signal 1” in the form of peptides (epitopes) derived from extracellular antigens and displayed at the surfaces of antigen-presenting cells (APCs) by MHC class II molecules (MHCII), and “Signal 2” in the form of co-stimulatory molecules expressed by APCs in re- sponse to pathogen associated motifs (“stranger/danger”). Convention also holds that TCD4 differentiation is driven by cytokine environments at sites of activation (“Signal 3”), resulting in the emergence of one or more functional TCD4 subsets (TH1, TH2, TH17, Treg and/or TFH). Canonical Signal 3 is clearly important, but it is well established that strength of Signal 1 (“antigen dose”) can also govern TCD4 differentiation. However, studies making this point have largely involved purified proteins or synthetic peptides in in vitro settings, with outcomes varying widely with respect to the functionalities associated with low and high antigen doses. Extension of our work on MHCII-restricted presentation of influenza (flu)-derived epitopes could provide clarity in this regard. Specifically, we have established that MHCII epitopes can be generated not only from extracellular (“exogenous”) antigen but also intracellular (“endogenous”) antigen following antigen expression within the APC, and that en- dogenous vs. exogenous antigens drive far more potent TCD4 responses, with respect to expansion and, per preliminary data, functionality. Based upon these and other findings reviewed below, we propose the following model: 1) Extracellular antigens in various forms, not necessarily presenting a threat, are inefficiently converted to peptide:MHCII (p:MHCII) complexes via conventional (endosomal) antigen processing (a weak Signal 1), driv- ing limited TCD4 expansion and functionality. We define functionality as the average number of effector functions (cytokine production and cytolytic capacity) independent of subsetting conventions. 2) Abundantly produced en- dogenous antigens, reflecting active infection, lead to dense and sustained p:MHCII display at the APC surface (strong Signal 1). This strong Signal 1, signaling a potential threat, drives robust TCD4 expansion and functionality, thereby enhancing the TCD4 response and the prospects for a successful defense. Grounding our studies in mRNA-based vaccination, in combination with several technical innovations, we will test this model by: a) varying antigen location via microRNA-based targeting of antigen-encoding mRNA (Aim 1), and b) modulating strength of Signal 1 with respect to both density and half-life of surface peptide:MHCII complexes while holding other key parameters constant (Aim2). Impact on TCD4 functionalities will be assessed via flow cytometry and protection studies. The proposed studies could fundamentally revise the working models of threat perception and TCD4 differentiation, motivating novel approaches to modulating TCD4 in settings where their participation is advanta- geous or deleterious.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY Viruses harness host cellular functions to complete their infectious cycles. DNA virus infection introduces foreign viral genomes into the host cell nucleus which can activate kinase signaling pathways that are part of the cellular DNA damage response (DDR). Viruses have also evolved strategies to manipulate DDR signaling to promote infection, and this can be achieved through viral-encoded ubiquitin ligases which target cellular substrates with degradative and non-proteolytic outcomes. Herpes simplex virus type 1 (HSV-1) is a DNA virus whose infection is enhanced by both activation and manipulation of cellular DDR pathways. Previous studies have established that HSV-1 infection activates signaling through the ATM kinase pathway which benefits virus replication. The viral immediate early protein ICP0 is a multifunctional protein important for stimulating gene expression and overcoming host defenses during lytic HSV-1 infection. Among the known substrates for the ICP0 ubiquitin ligase are regulators of the DDR network. Our understanding of the interface between HSV-1, ICP0, and the host DDR pathways, has been constrained by prior knowledge from studies of DDR functions in response to damage of cellular genomes. We propose that the viral responses will be better informed by unbiased global approaches that define signaling networks and proteome changes specifically activated by virus infection. In this application we bring together multi-modal proteomics techniques in an integrative approach that will define ways that changes to the proteome by ATM-activated signaling and ICP0-mediated ubiquitination alter recruitment of proteins onto viral genomes to promote expression and replication. In extensive preliminary data, our global proteomic analysis of HSV-1 infected cells quantifies the landscape of phosphorylation within DDR pathways, identifies ICP0-dependent ubiquitination events induced, and informs on ways that these modify the set of host proteins associated with replicating HSV-1 viral genomes. Our data converge on a number of protein targets and complexes which we propose function as key regulators of viral gene expression and genome replication. Our complementary aims elucidate mechanisms by which phosphorylation and ubiquitination combine to promote viral replication. In Aim 1 we will define the intersection of phosphorylation and ubiquitination and determine their combined impact on the DDR during HSV-1 infection. In Aim 2 we will determine ways that ubiquitination and ATM-signaling promote HSV-1 infection by examining the proteins associated with viral gnomes to promote gene expression and replication. Integrating these global proteomic approaches will highlight mechanisms leveraged by HSV-1 to overcome repression of gene expression and facilitate productive infection. Understanding the cellular systems which control viral infection will ultimately advance translational research towards developing antiviral therapies and interventions to prevent infection.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY Type 2 immune responses provide protection against damaging parasitic helminth infection. Helminth infections, of which there are currently 1 billion world-wide, can cause tissue damage, generalized immunosuppression, malnutrition and anemia. While most helminths reside in the intestine, a critical stage of the life cycle of many helminths involves transit through the lung. Thus, anti-helminth type 2 immune responses are observed in the lung and GI tract. While type 2 immune responses can be advantageous during worm infection, in some individuals, immune cells inappropriately target innocuous allergens and drive devastating and potentially life- threatening allergic disease. Thus, understanding how type 2 immune responses are controlled may provide new therapeutic approaches for eradicating worm infection or treating allergic disease. This proposal details a novel regulatory circuit in a recently discovered subtype of IL-18 receptor expressing (IL-18R+) ILC2 cells in the lung. This regulatory circuit helps to prevent immune cell mediated lung inflammation as helminth larvae transit the lung. At the center of this regulatory circuit is the E3 ubiquitin ligase Cul5. Based on our preliminary data, we hypothesize that Cul5 limits IL-18R signaling in ILC2 cells in the lung to restrict IL-18R+ ILC2 numbers and recruitment of tissue damaging neutrophils. Information gained from these studies will broaden our understanding of functionally distinct ILC2 subsets and how they behave in different tissues, and aid the design of therapies that enhance or inhibit Cul5 activity. In Aim 1 we will determine how Cul5 expression in IL-18R+ ILC2 cells impacts the clearance of helminth larvae from the lung, recruitment of larvae killing neutrophils, and persistent lung inflammation. In Aim 2, we will determine how Cul5 regulates signaling downstream of the IL-18 receptor and features of the Cul5 ubiquitin complex important for this function, and in Aim 3 we test whether Cul5 regulation of ILC2 function is limited to the lung or also occurs at other mucosal barrier surfaces. With our combined expertise in ubiquitin ligase function, type 2 immune responses, neutrophils, ILC2 biology and N. brasiliensis infection, we are uniquely poised to uncover cytokine regulatory circuits in ILC2 subsets that will have a significant and long term impact on our understanding of how ILC2 cells initiate type 2 immune responses, and how regulatory circuits in these cells impact helminth clearance and immune cell mediated tissue damage. This information will aid future therapeutic targeting of Cul5 for treating helminth infection and allergy.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Inborn errors of metabolism (IEMs) are rare, devasting disorders arising from pathogenic variants in genes encoding enzymes of key biochemical pathways. The liver plays an important role in the pathogenesis of over 150 IEMs, often failing to metabolize a toxic metabolite that can injure secondary organs, such as brain. Liver transplantation is employed in some IEMs; however, its utility is limited by scarcity of donors and lifelong risk of post-transplant complications. To address the unmet medical need of IEM patients, we aim to develop a master protocol for the rapid development of personalized prime-editing therapies for severe, rare hepatic IEMs. We envision a platform regulatory framework where IND-enabling studies for a “leader” hepatic IEM prime-editing therapy also support programs for varied “follower” indications. The leader and follower therapies will differ only in patient-variant-specific guide RNA sequences. For our leader indication, we have selected phenylketonuria (PKU). In PKU, an autosomal recessive disorder, impaired phenylalanine (Phe) catabolism in the liver induces neurotoxic Phe accumulation. In our proof-of-concept studies, a single dose of an AAV8-based, R408W prime- editing therapy completely and durably normalized Phe levels in humanized PKU R408W mice. We will leverage our PKU R408W IND-enabling studies to accelerate development for our follower indications: ultra-rare, severe, neonatal urea cycle disorders (UCDs) and organic acidemias (OAs) that affect ≈1:20,000 births. Neonates with UCDs or OAs present with severe toxic accumulation of ammonia and/or organic acids. While liver transplantation can improve metabolic control, patients must grow to an appropriate size to receive a transplant. During this wait, most patients experience irreversible neurologic damage and episodes of life- threatening metabolic decompensation. We seek to develop just-in-time, personalized, liver-directed prime- editing therapies addressing the pathogenic variants identified through newborn screening at our large referral center. A platform regulatory approach is essential to develop therapies in time to meaningfully improve outcomes in this patient cohort who typically suffer significant early morbidity and mortality. Our primary objectives are to (1) establish a therapeutic platform, comprising a single prime editor and AAV delivery system, for numerous hepatic IEMs, and (2) streamline approvals through regulatory innovation, informed by stakeholder input and disseminated to the scientific community.

NIH Research Projects · FY 2025 · 2024-09

Project Summary The proposed study seeks to identify genomic features that explain epidemiological co-occurrences of childhood cancers (CCs) and structural birth defects (SBDs). We will import germline and genomics data from affected cohorts into the Common Fund Data Ecosystem (CFDE) Data Distillery Knowledge Graph (DDKG) project, an ongoing CFDE project that generated a comprehensively annotated graph database built with empirical data from 11 Common Fund projects with over 40 million data points and 300 million relationships, and which utility has been proven through successful applications of several complex use cases. Our goals for this proposal are first to expand and update the DDKG schema to support a broader spectrum of genomic data types and edge (relationship) weighting by evidence level. This expansion will expand the DDKG’s information capacity and better support machine learning applications on extracted data. Datasets chosen from this project are based on epidemiological observations on the relationships between congenital heart defects and neuroblastoma or hematological malignancies, and brain or CNS congenital defects and brain tumors. Data from representative cohorts with any or both selected CCs and SBDs will be obtained from the Kids First project as germline and tumor data. We will also incorporate genomics data from the NCI Molecular Targets Project into the DDKG, representing a comprehensive repository of childhood cancer genomics data produced by the lead principal investigator. We will analyze the DDKG data for predicted relationships between SBDs and CCs with strategies including topological link prediction methods, the Connect the Dots algorithm, dimensionality reduction methods (such as embeddings) with cluster detection, and machine learning with PyG’s support for Graph Neural Networks (GNNs) for heterogeneous graphs. User data delivery will be accomplished with the DDKG project’s pre-built tools, and by developing and refining innovative data delivery methods. This will enhance the accessibility of the project's findings and extend the utility of the DDKG for the broader research community. With the analysis of large-scale pediatric cohort genomics data, we seek to set a precedent for large-scale genomics data analyses using Common Fund Data while providing significant insights into the genetic drivers of CCs and SBDs, paving the way for future research and clinical applications. Other researchers can utilize the DDKG with our methodology developments, increasing the opportunities to reuse CFDE data.

NIH Research Projects · FY 2025 · 2024-09

Project Summary / Abstract Asthma is a leading cause of childhood morbidity and disparities nationwide and limited provider adoption of and patient adherence to the prevailing evidence-based recommendations for chronic management represent tractable areas for implementation focus. In their 2020 Focused Updates, the NHLBI codified a new paradigm of asthma management - single maintenance and reliever therapy (SMART) - as the preferred management strategy for moderate/severe asthma management. In addition to its efficacy and safety, SMART has demonstrated real-world effectiveness in international settings, likely due in part to better adherence to daily therapy and less inhaler confusion. However, SMART has not been widely implemented in practice in the US and there are no prior studies of its real-world effectiveness in US pediatric populations. In preliminary work, investigators identified several critical barriers to SMART implementation, including insufficient: (1) decision support/training for providers to identify and educate eligible patients at the point of care, (2) ongoing patient education on key components of SMART once prescribed, and (3) systems-level issues, such as negative reinforcement by providers unfamiliar with SMART and insurance denials. The proposed study is a type II hybrid effectiveness-implementation study that uses a cluster-randomized design within 18 pediatric primary care clinics in a large US pediatric health system whose demographics mirror US asthma morbidity statistics. Enrolled clinics will be randomized to one of two study conditions, to iteratively compare a real-world control condition and two successive implementation strategies: (Phase 1) electronic health record-based Clinical Decision Support integrated with clinician workflows plus provider and patient education outreach (referred to as CDS+), and (Phase 2) CDS+ combined with Population Health Management (PHM), which adds longitudinal caregiver/patient SMART education, social support, and health system/insurance navigation provided by an evidence-based asthma community health worker program and nurse care manager. Using this approach, the project’s specific aims are to (1) conduct a cluster RCT that sequentially compares the effects of first CDS+ alone and then CDS+ with PHM to usual care on visit-level SMART adoption (primary outcome), patient-level sustained adoption, and clinic-level penetration of SMART (secondary outcomes); (2) determine the real-world effectiveness of SMART in reducing severe asthma exacerbations in a predominantly Black cohort of children with poorly controlled asthma; and (3) assess mechanisms of successful SMART implementation and effectiveness using mixed methods. The findings of this study will inform broader national implementation and dissemination strategies for SMART by establishing an evidence base for SMART effectiveness in a racially diverse US pediatric population and through sharing of potentially effective clinical decision support enhancements or implementation manuals through existing national networks.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Endocrinopathies, sleep disorders, cognitive issues, cardiovascular conditions, sensory impairments, and ability differences not only impact the quality of life of individuals with Down syndrome (DS) and their caregivers but can intersect to magnify the threats of these co-occurring conditions. Moreover, individuals with intellectual disabilities face additional barriers surrounding healthcare access and their decision-making involvement that can jeopardize their health. The dearth of observational studies that richly detail co-occurring conditions, social determinants of health (SDoH), and the ableism individuals with DS experience represents a major challenge to providing clinical care to individuals with DS. Our long-term objective is to partner with clinicians, researchers, individuals with DS, and caregivers across the country to establish a diverse cohort of individuals with DS for comprehensive longitudinal phenotyping including multi-omics and to develop an infrastructure for intervention studies. This multi-center, multi-disciplinary collaborative team will engage individuals from infancy through young adulthood to undergo blood sample collection, imaging studies, qualitative interviews, questionnaire completion, sleep assessments, and remote physiologic monitoring while subsets will undergo additional specific procedures with the goal of rich longitudinal phenotyping across multiple systems: Endocrine: thyroid and gonadal function Cardiometabolic: lipids, inflammation, meal-related glucose excursion, insulin secretion & sensitivity Cardiovascular: blood pressure, arterial stiffness, and left ventricular mass and function Nutrition: anthropometrics, body composition, bone density, nutritional intake, and appetite/satiety Sleep: obstructive and central sleep apnea, hypoventilation, participant and caregiver sleep quantity and quality Physical Activity: sedentary, light, moderate, and vigorous activity Neurocognitive: caregiver reported and objectively assessed measures, peripheral blood Alzheimer disease markers, audiology, brain MRI, secondary analyses of sleep study EEG SDoH: family education, income, English proficiency, medical literacy, neighborhood characteristics Ethical Issues: decision-making involvement, experiences with ableism, and healthcare access Electronic Health Information: diagnoses, medications, procedures, labs, and imaging Multi-omics: genome, transcriptome, proteome, metabolome Procedures will be repeated at a cadence that depends upon baseline age (<15y, every 12-18 mo) or (>15-30y, every 24-30 mo), baseline results, pre-existing co-morbidities, and subsequent interventions. Community members will help inform study design and the specific procedures to be undertaken will be tailored to the abilities of individuals with DS and to minimize participant and caregiver burden.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Eosinophilic esophagitis (EoE) is a chronic, debilitating allergic disorder that is increasing in incidence worldwide, resulting significant health care and financial burdens. Current therapeutic approaches in EoE include dietary elimination and limiting inflammatory signaling using corticosteroids or biologics; however, there is increasing recognition of an EoE patient population failing to exhibit clinical and histological remission in response to these interventions. Disruption of esophageal epithelial tissue architecture and barrier function are hallmarks of EoE and achieving healing of the esophageal epithelial barrier represents a significant clinical challenge. Our own published work demonstrates that maintained epithelial remodeling is associated with symptoms in patients with histologically inactive EoE. Moreover, a recent study demonstrated that epithelium of inactive EoE patients fails to normalize at the cellular and molecular level. Despite the importance of esophageal epithelium in EoE pathobiology, we lack the comprehensive understanding of the mechanisms regulating esophageal epithelial homeostasis that is necessary to shape approaches for promoting epithelial healing in EoE. In a recent publication, we identified a CD73+ progenitor population within the basal zone of esophageal epithelium that is critical for tissue renewal. We further found that CD73+ basal cells are depleted in human subjects and mice with EoE inflammation, with the EoE-associated cytokines IL-4 and IL-13 causing a shift from CD73+ to CD73- basal cells in human 3D organoids. CD73 is a membrane-bound ectoenzyme that catalyzes conversion of extracellular adenosine monophosphate into the purine nucleoside adenosine. In the current proposal, we provide robust preliminary data adenosine (1) restores organoid formation, differentiation, and barrier integrity in esophageal keratinocytes with genetic depletion of CD73; and (2) improves epithelial differentiation in IL-13- treated organoids and a mouse model of EoE. Based upon our published and preliminary data, we hypothesize that esophageal homeostasis is mediated by CD73+ epithelial cells and dysregulated purinergic signaling contributes to EoE pathobiology, including epithelial remodeling. We will test this hypothesis by: defining the direct requirement of squamous epithelial CD73 in esophageal homeostasis and response to EoE (Aim 1); identifying the molecular mechanisms through which adenosine signaling supports esophageal epithelial homeostasis (Aim 2); and delineating how levels of CD73 and CD73-associated purines relate to clinical features of EoE patients (Aim 3). This proposal will illuminate the functional and mechanistic roles of CD73 and purinergic signaling in esophageal homeostasis. The proposed studies will also assess the therapeutic utility of restoring purinergic signaling in EoE models and the clinical significance of alterations in CD73 and purines in EoE patients, which may have implications for EoE therapy and clinical management.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY / ABSTRACT Autosomal recessive polycystic kidney disease (ARPKD) is a rare disease, affecting ~1,500 children and young adults in the U.S. In severely affected patients, ARPKD can present in the neonatal period with massively enlarged kidneys and pulmonary hypoplasia, but the clinical spectrum of ARPKD is highly variable. We now recognize that just ~50% of patients present perinatally, and many present later in childhood or even adulthood. ARPKD causes progressive chronic kidney disease leading to kidney failure, as well as congenital hepatic fibrosis, which can lead to intrahepatic bile duct dilatation, periportal fibrosis, and portal hypertension. Despite this high burden of morbidity, there are currently no FDA-approved disease-modifying therapies for ARPKD. Several drugs appear promising in animal studies, but only one small Phase 1 clinical trial has been completed. Barriers to conducting clinical trials in ARPKD include: (1) limited natural history data; (2) lack of defined clinical outcomes to serve as trial endpoints; (3) lack of validated prognostic biomarkers to identify patients at highest risk of progression; and (4) difficulty in recruiting sufficient numbers of patients who are eligible, able, and willing to participate in trials. The overall objective of this proposal is to accelerate clinical trials for ARPKD by creating PKDnet, a robust data resource to identify a research-ready cohort of children with ARPKD and efficiently collect high quality, large-scale natural history data and identify suitable endpoints and prognostic biomarkers to inform clinical trial design. Data will come from PEDSnet, a National Pediatric Learning Health System with >14 years of electronic health record data for >13 million children at 11 U.S. academic pediatric centers. To inform future trial design, we will also leverage the PEDSnet infrastructure to administer patient and family surveys to identify priorities for patient-reported and clinical outcomes and understand factors affecting willingness to participate in clinical trials. Once established, PKDnet will serve as a sustainable resource for ARPKD research that will allow ongoing analysis of longitudinal natural history data, provide valuable data to inform future clinical trial design, and facilitate future recruitment of patients into high-priority studies.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract: Whole brain synaptic density imaging with quantitative positron emission tomography (PET) has demonstrated critical insights into understanding of neurodegenerative disorders and epilepsy, especially in the setting of normal anatomical MRI. We propose to use quantitative whole brain PET with a novel synaptic density tracer to characterize the synaptic density changes in the setting of targeted radiation therapy in rodents and to correlate it to cognitive changes that occur after radiation therapy. While radiation therapy is a life-saving standard of care for treatment of central nervous system (CNS) malignancies in both adults and children, cognitive decline is one of the major complications and has been tied to multifactorial mechanism which includes loss of synapses, white matter damage, endothelial cell damage, and activation of neuroinflammatory markers within the hippocampus and pre-frontal cortex. Hippocampal sparing radiation therapy is the leading approach to preserve cognitive function in patients requiring radiation therapy. Unfortunately, even after hippocampal sparing radiation, over 50% of patients develop debilitating cognitive decline. With increase in long term survival of patients with CNS malignancies, there is a critical need to understand the mechanisms behind radiation induced brain injury, so that therapies can be targeted to prevent post-radiation cognitive decline. Currently there are no established drugs that prevent or treat the sequelae of radiation, nor are there biomarkers to monitor cellular damage. Availability of these could be used to modify treatment protocols prior to the development of severe cognitive decline. Characterization of whole brain dynamic changes in synapses and how they are related to white matter damage have not been evaluated up to now, because tools to study whole brain synaptic density have not been readily available. To characterize the mechanisms behind radiation induced cognitive decline, we will use a novel PET tracer that has been established to measure synaptic density and quantitative PET modeling for quantification of synaptic density in different regions of the human brain. We assembled a team of experts in fields of quantitative PET, rodent quantitative MRI, rodent radiation therapy, rodent neuropathology, and cognitive assessment to determine the time course of synaptic density changes in different regions of the brain and how it relates to pathological assessment of synaptic density, white matter damage, and neuroinflammation. The short term goal of this project is to characterize the hippocampal and extra-hippocampal synaptic density changes in rats after targeted half-brain radiation. The long term goal is to use this model to characterize the molecular mechanisms of radiation therapy induced CNS damage in human patients that must undergo radiation treatments for brain tumors. Completion of this project will characterize a novel non-invasive biomarker of radiation induced cognitive decline that can be translated into clinical trials and used for monitoring of synaptic density changes to personalize treatment.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable clinical responses in patients with B cell malignancies. However, approximately 50% of treated patients do not exhibit durable responses and CAR T cells for solid tumors have been largely ineffective. Poor T cell fitness, whereby T cells lose the ability to expand, persist, and mediate antitumor responses, is a major barrier to progress for the development improved CAR T cell therapies. Emerging research suggests poor fitness is associated with epigenetic changes that lock T cells into a dysfunctional state, and further, that epigenetic reprogramming is mechanistically important for overcoming poor fitness. This presents a unique challenge since existing epigenome engineering approaches 1) are associated with technical hurdles that limit feasibility and translatability, and 2) are either non-specific (e.g., epigenetic drugs that induce global chromatin remodeling) or exceedingly specific (e.g., dCas9-based methods that target 1 or a few genes) and are therefore suboptimal for inducing the extensive but pathway-specific epigenetic changes associated with changes in fitness. The goal of this proposal is to develop and optimize a new class of epigenetic reprogramming factors (ERFs) which can target hundreds, thousands, or tens of thousands of DNA regions in a pathway-specific manner. The ERF platform is modular and fully programmable, thereby enabling fine-tuning of the specificity, strength, and durability of epigenetic marks. We will leverage this technology to target T cell exhaustion and aging-associated dysfunction, which are characterized by stable epigenetic marks that limit T cell responsiveness. ERFs will be designed to prevent or reverse epigenetic signatures that manifest during exhaustion and aging, thereby augmenting CAR T cell fitness and antitumor function. The proposed work will advance the state-of-the-art in T cell reprogramming and provide a powerful approach to enhance CAR T cell potency for liquid and solid tumors. In addition to their translational potential, ERFs can also function as molecular tools to interrogate transcription factor biology, gene expression programs, and epigenetics, and therefore have important implications for basic human T cell biology. Ultimately, we envision an ERF toolkit whereby combinations of ERFs can be tailored to enhance T cell fitness in a patient- or disease-specific manner. Since chromatin remodeling underpins cellular reprogramming in other cell types and disease settings, we predict that ERFs will be broadly applicable to other therapeutic modalities and represent a paradigm shift in the growing field of epigenome engineering.

NIH Research Projects · FY 2024 · 2024-09

Abstract: Pelizaeus Merzbacher Disease (PMD) is a rare X-linked hypomyelinating leukodystrophy caused by pathogenic variants in PLP, which encodes proteolipid protein 1 (PLP1) and the estimated prevalence is 1.9 per 100,000 male births in the United States. PMD affected individuals are currently anecdotally and empirically classified as severe (typically conatal in onset), classic or mild but understanding surrounding early determination of disease subtype remains a critical gap and cannot be predicted from genotype. An existing PMD validated Functional Disability Rating Scale enables stratification of PMD by severity, but due to its age dependence and significant floor effect, it is insufficient to discriminate severity in the context of clinical trials. As therapies emerge for PMD, there is an urgent need for tools to discriminate disease severity in PMD early in the disease course, which is often the optimum window for clinical trial enrollment. To address this urgent need for a clinically informed tool, our team has established a natural history study to collect data such as age at onset of disease and key medical events. We propose to use this deep existing natural history data in the context of a rigorous tool-development approach. The CHOP Leukodystrophy Center of Excellence (CHOP LCE) is uniquely suited to addressing this gap in clinical readiness for PMD. As the data integration core for the Rare Disease Clinical Research Network (RDCRN) funded Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN), the CHOP LCE has collected data on over 60 individuals affected by PMD across the severity spectrum and curated for phenotypic and genotypic characteristics. Our team will be able to leverage this data to support the development of an empirically developed PMD severity scale with face and construct validity (Aim 1). We will then validate this scale prospectively in a cohort of 30 PMD affected individuals defining its feasibility, reliability and criterion validity, and determine context of use for future clinical trials (Aim 2). This approach will yield a validated Clinician Reported Outcome (ClinRO) in the form of a PMD clinical severity marker, which can be used in the context of imminent clinical trials as a tool for cohort stratification and monitoring of longitudinal changes in disease severity.

NIH Research Projects · FY 2025 · 2024-09

Project Summary / Abstract Dr. Kavita Dedhia is an assistant professor in otolaryngology at the University of Pennsylvania (UPENN) and Children’s Hospital of Philadelphia (CHOP). She has clinical expertise in pediatric otolaryngology, specifically chronic ear disease. Dr. Dedhia has recently completed the Master in Health Policy Research program at UPENN through which she gained introductory skills in study design and statistics. Her long-term goal is to become an independent surgeon-scientist and international leader in pediatric otitis media research. This career development award serves as a vehicle to achieve this goal by focusing on gaining and refining the necessary skills to evaluate the effectiveness of surgical otitis media management and patient-centered outcomes. Otitis media is the 3rd most common reason for pediatric primary care visits, yet evidence for type of surgical management has been limited. Most studies lack sociodemographic and regional diversity, have high attrition and cross-over rates, and infrequent assessment of patient-reported outcomes. The aims outlined in this proposal will serve to improve evidence optimizing surgical otitis media management, through using the PEDSnet learning health system. PEDSnet is a clinical network consisting of electronic health record data from 11 of the largest pediatric institutions throughout the United States. Using PEDSnet, a clinical consortium of pediatric otolaryngologists will be formed to assist in carrying out the aims. Aim 1 will evaluate the effectiveness of adjuvant adenoidectomy and heterogeneity of treatment effect based on age and medical conditions at-risk for developmental delay through analyzing the PEDSnet dataset from 11 institutions. Aim 2 will be a prospective cohort study at CHOP that will account for patient and environmental factors not available within the PEDSnet dataset to assess adjuvant adenoidectomy effectiveness. Input for study design and data collection will be obtained from the pediatric otolaryngology consortium. This study will assess patient recruitment, retention, uniform data collection rigor, reproducibility, and estimate effect sizes for a larger scale multi-institutional study at all PEDSnet sites. To carry-out the abovementioned aims, the candidate has formed a strong mentorship team. Her primary mentor, Dr. Christopher Forrest, is the founder of PEDSnet and adept in utilizing the learning health system model in pediatric outcomes research. Her co-mentors are equally impressive: Dr. Gregory Tasian is an expert in pragmatic trials and has formed a pediatric urology clinical network for studying pediatric urological disease, Dr Yong Chen has extensive expertise in medical informatics, causal inference, and comparative effectiveness research; and Dr. Diego Preciado is a pediatric otolaryngology surgeon-scientist who is an expert on otitis media research. The proposed plan will allow the candidate to become proficient in informatics, causal inference, comparative effectiveness, advanced statistical analysis, and pragmatic clinical trials to allow for a successful career as an independent surgeon-scientist.

NIH Research Projects · FY 2025 · 2024-09

This new 2-year educational program aims to grow a national biomedical research workforce adept in medical device innovation and entrepreneurship. Through skill-building, mentorship, and networking, participants will be empowered to embark on careers translating new research findings and technologies, including artificial intelligence, into market-ready medical devices for children and adults. Eligible candidates will include graduate students in clinical, translational, or basic sciences and engineering (e.g., Master’s, PhD, MD/DMD/Nursing), postdoctoral fellows, research-oriented residents and clinical fellows, and faculty at academic institutions across the nation. Participants will learn a core curriculum supplemented with a mentored individual development plan to prepare for careers in medical device innovation (e.g., translational researcher, developer, co-founder, regulatory/safety/clinical evaluator) and a Capstone Project. Our program will be built on our free, open-source, interactive e-book, Academic Entrepreneurship for Medical and Health Scientists. Mentors and faculty for the program will include e-book authors and other nationally recognized experts in device development and entrepreneurship. Participants will benefit from support personnel and resources at Children’s Hospital of Philadelphia (CHOP) and University of Pennsylvania (UPenn) and our nationwide research and entrepreneurship networks. Four aims are proposed: (1) Aim 1 Awareness: Increase awareness of Academic Entrepreneurship (AE) as a career path and build foundational AE skills for medical device development. Multimodal sessions with storytelling and interactive cases will introduce AE career paths and associated core concepts to a wide audience. One-day sessions will be held in hybrid format (in-person and virtual) four times per year. Session recordings will be shared online for asynchronous viewing to increase accessibility. Our outreach partners have successful national networks which will be used to enhance our recruitment and dissemination efforts. (2) Aim 2 Action: Provide further personalized training to those wishing to pursue AE focused on medical device development. Aim 1 Awareness participants can apply to AE Aim 2 Action programming, which includes a 5-day bootcamp during which they will engage in established and innovative adult learning formats like case-based activities, team-based project work on real-life devices, and modified Fishbowl discussions. (3) Aim 3 Mentor: Mentors and mentees will co-create Individual Development Plans (IDPs) to guide a mentorship program that will last up to two years. (4) Aim 4 Network/Sustain: Provide mechanisms, including the novel Expertise Knowledge Platform developed at CHOP, for all participants and program affiliates to stay connected and create a robust, sustainable AE ecosystem that will continue after IPERT funding ends. Taken together, these four aims were designed to promote our long-term goal of ensuring a skilled pipeline of talented Academic Entrepreneurs to advance medical device innovation and improve national public health.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Suicide is the second leading cause of death in US youth. Suicidal behavior is complex and is influenced by a combination of multi-level distal and proximal environmental risk factors and lifestyle factors (i.e., exposome), and biological susceptibility. Adverse exposome is key to youth suicide risk, and yet there is variability and most youth who experience adversity do not attempt suicide. To better understand this variability, we need to develop reproducible tools to quantify adverse exposome, to understand how exposome contributes to disparities in risk among minority populations, and to better understand mechanisms of resilience in high-risk youth. Additionally, we need to integrate risk models of environment with biological measures that can improve our understanding of how environmental stress “gets under the skin” and increases suicide attempt risk. Allostatic load, the physiologic “wear and tear” of the body over time in response to environmental stress is a proposed framework to study mechanisms of exposome's effects on mental health and on suicide risk. While exposome and allostatic load were previously linked to suicide risk, no prior studies have integrated both in a common framework. Our proposal will provide the foundation to test how exposomic risk contributes to psychobiological stress burden in youth, improving our understanding of the emergence of suicidal behavior in adolescence. We will quantify aggregate environmental risk burden in a reproducible manner in five different youth cohorts that include >65,000 youth, of whom 25,000 youth have longitudinal data. We will use an exposome-wide-association-study (ExWAS) approach, which applies a data driven method to systematically study associations with an outcome (such as suicide attempt in this case) using large scale data of exposures and applying statistical methods to derive effect sizes of risk associations, accounting for multiple testing and collinearity among exposures. Thereafter, we will compute exposomic risk scores that represent the aggregated burden of risk exposures and apply these scores to address our aims. In Aim 1, we will test generalizability of exposomic risk scores in five different cohorts from different settings, including a clinical sample; test disparities in exposomic risk to suicide attempt and identify resilience factors that are clinically relevant for future interventions. In Aim 2, we will map exposomic risk to allostatic load measures and test their combined contribution to mental health and suicide attempt risk among youth. Last, in Aim 3, we will explore causal mechanisms of environmental exposures, resilience factors and allostatic load to youth suicide attempt risk by applying causal inference methods on longitudinal data. The expected findings will advance suicide research through developing methods that are critical for reproducibility in using environmental exposures' data; will inform suicide prevention efforts through identification of factors that contribute to disparities in risk and to resilience in high-risk youth; and will advance understanding of the biological processes that are associated with risk and resilience to youth suicide attempts in diverse samples.

NIH Research Projects · FY 2025 · 2024-09

Patients who undergo cardiac surgeries to establish the Fontan circulation (FC) suffer from lifelong complications and early mortality. Engaging in physical activity (PA) may help to counteract these negative consequences. Youth with the FC engage in less physical activity (PA) than their peers and demonstrate decreased aerobic performance and lower skeletal muscle mass portending worse clinical outcomes. We now know that patients with the FC can safely engage in PA and improve their aerobic exercise performance in hospital-based exercise programs. Unfortunately, these programs are highly selective, costly, and inconvenient. Digital health applications can mitigate these barriers by remotely promoting PA beyond the point of care, especially with caregiver support. However, gaps in knowledge remain about whether a home-based digital intervention can 1) increase PA and 2) improve aerobic performance and increase skeletal muscle mass and muscle strength, in youth with the FC. Thirdly, it is not known how individual, family and neighborhood level factors influence the effectiveness of a home-based PA intervention. Thus, there is a critical need to develop and test innovative digital interventions to improve PA and clinical outcomes among all youth with the FC. The study team’s objective is to evaluate the efficacy of a digital intervention to increase PA and clinically relevant measures of physical fitness in youth with the FC. To accomplish this, the team proposes a randomized controlled trial with three specific aims. A wrist-worn physical activity tracker will be given to all participants, but they will be randomized to “enhanced usual care” (tracker plus standard encouragement to exercise) or a digital PA intervention for 6-months. The intervention arm will include: (1) personalized aerobic-based physical activity, (2) personalized resistance exercise sessions, and (3) financial and non-financial engagement strategies, targeting youth and caregivers. These intervention components will be delivered using an advanced mobile health informatics platform. Clinical assessments will be made at baseline, 6 months, and 12 months. Under aim 1, we will determine if the multi-component digital intervention increases PA levels in youth with the FC. Under aim 2, we will determine if the intervention leads to improvements in physical fitness outcomes (aerobic capacity, muscle mass, and strength). Finally, under aim 3, we will test whether medical, neurodevelopmental and/or sociodemographic factors, are associated with the efficacy of the digital intervention, using qualitative and quantitative approaches. It is anticipated that the digital intervention will significantly increase PA and improve physical fitness. Further, multi-level factors will be identified that associate with the efficacy of the intervention, thus providing the foundation for future implementation trials. These findings will lead to the integration of digital PA interventions for youth with a FC in the pediatric cardiology clinical setting.

NIH Research Projects · FY 2024 · 2024-09

Patients who undergo cardiac surgeries to establish the Fontan circulation (FC) suffer from lifelong complications and early mortality. Engaging in physical activity (PA) may help to counteract these negative consequences. Youth with the FC engage in less physical activity (PA) than their peers and demonstrate decreased aerobic performance and lower skeletal muscle mass portending worse clinical outcomes. We now know that patients with the FC can safely engage in PA and improve their aerobic exercise performance in hospital-based exercise programs. Unfortunately, these programs are highly selective, costly, and inconvenient. Digital health applications can mitigate these barriers by remotely promoting PA beyond the point of care, especially with caregiver support. However, gaps in knowledge remain about whether a home-based digital intervention can 1) increase PA and 2) improve aerobic performance and increase skeletal muscle mass and muscle strength, in youth with the FC. Thirdly, it is not known how individual, family and neighborhood level factors influence the effectiveness of a home-based PA intervention. Thus, there is a critical need to develop and test innovative digital interventions to improve PA and clinical outcomes among all youth with the FC. The study team’s objective is to evaluate the efficacy of a digital intervention to increase PA and clinically relevant measures of physical fitness in youth with the FC. To accomplish this, the team proposes a randomized controlled trial with three specific aims. A wrist-worn physical activity tracker will be given to all participants, but they will be randomized to “enhanced usual care” (tracker plus standard encouragement to exercise) or a digital PA intervention for 6-months. The intervention arm will include: (1) personalized aerobic-based physical activity, (2) personalized resistance exercise sessions, and (3) financial and non-financial engagement strategies, targeting youth and caregivers. These intervention components will be delivered using an advanced mobile health informatics platform. Clinical assessments will be made at baseline, 6 months, and 12 months. Under aim 1, we will determine if the multi-component digital intervention increases PA levels in youth with the FC. Under aim 2, we will determine if the intervention leads to improvements in physical fitness outcomes (aerobic capacity, muscle mass, and strength). Finally, under aim 3, we will test whether medical, neurodevelopmental and/or sociodemographic factors, are associated with the efficacy of the digital intervention, using qualitative and quantitative approaches. It is anticipated that the digital intervention will significantly increase PA and improve physical fitness. Further, multi-level factors will be identified that associate with the efficacy of the intervention, thus providing the foundation for future implementation trials. These findings will lead to the integration of digital PA interventions for youth with a FC in the pediatric cardiology clinical setting.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT Aicardi Goutières (AGS) is a severe autoinflammatory disease that predominantly affects the brain, leading to severe cognitive and physical disabilities. Although this disease is genetically heterogeneous, all genotypes lead to multi-system excessive type 1 interferon (IFN) activity. How the systemic inflammatory response in AGS leads to predominant central nervous system (CNS) injury is not entirely understood, which limits development of effective and targeted therapies for this destructive disease. In this study proposal, we aim to uncover the “driver” cell in either the peripheral or CNS immune system or at brain vascular interfaces that converts genetic mutations into progressive, IFN-mediated neuronal and oligodendrocyte injury. Using the first rodent models with AGS patient mutations that confer neuropathology, paired with new viral targeting approaches and immune chimeric models, we will test which cell(s) promote(s) neuropathology. We will use these approaches to further interrogate which compartment requires rescue for AGS treatment. This proposal leverages the unique expertise of three separate laboratories at the University of Pittsburgh (Wang) and Children’s Hospital of Philadelphia (Bennett and Vanderver) to dissect, for the first time, the distinct populations of cells driving AGS neuropathology and treatment.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Insufficiency of the placenta due to conditions such as hypertension, diabetes, and fetal congenital heart disease can lead to chronic in utero hypoxia. Chronic hypoxia increases the risk of neurodevelopmental disorders by disrupting the "placenta-brain" axis. Furthermore, the effects of chronic hypoxia on the developing brain include disrupted energy metabolism and epigenome disruption, also called the metabolic-epigenetic axis. Rodent models of prenatal hypoxia are useful for studying the complex relationship between the placenta, brain, and epigenome. We developed 4D in utero Oxy-wavelet MRI (4D-uMRI) technology for simultaneous structural and temporal mitochondrial dynamics assessment. We applied this technique to elucidate the variable metabolic dynamics of multiple models of prenatal injury. We have additional expertise in modeling prenatal brain injury and analyzing the effects of injury on the molecular phenotype of the developing brain through single nucleus multi-omics. In this proposal, we will leverage our combined expertise to study the effects of chronic hypoxia on the placenta, brain, and epigenome. Our team has expertise in neuroscience, imaging, pathology, and placental biology. This study allows us to derive a comprehensive understanding of the correlation between metabolic profiling and molecular phenotype. We will compare normoxic litters to animals exposed to 11% inspired oxygen from embryonic day 14.5 to 17.5. In Aim 1, we will use 4D-uMRI studies to determine to examine the relationship between placental structural anomalies and brain structural and metabolic dysfunction from chronic hypoxia. The study will provide insight into whether there is a direct relationship between the extent of placental insufficiency and brain metabolic disruption and growth parameters. In Aim 2, we will assess the brain's metabolic response to hypoxia to test the relationship between the extent of metabolic dysfunction and disruption of the transcriptome and epigenome through single nucleus multi-omic sequencing. The study proposes an innovative approach to testing the correlation between the extent of metabolic disruption and molecular phenotype. Together, these experiments will allow us to recognize novel correlations between structure, function, and molecular disruption to discover novel targets for treating the neurodevelopmental deficits from chronic hypoxic brain injury.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Well-established psychosocial interventions for children with or at-risk for ADHD include behavioral parent training at home and behavioral classroom management interventions at school, both of which show strong meta-analytic evidence of effectiveness. These approaches involve adults using antecedent- and consequence-based interventions to create contexts in which children are more likely to succeed. Moreover, the home-school relationship is critical for children's success in school and home, and interventions aiming to promote family-school collaboration are effective at improving outcomes of children with ADHD. However, caregivers need implementation supports to implement evidence-based antecedent- and consequence-based interventions with fidelity, and caregivers often have difficulty accessing behavior therapy in community settings. Preliminary data from our ongoing work developing and pilot testing implementation strategies for teachers in partnership with the School District of Philadelphia suggests an additional need for caregiver-facing implementation strategies to support behavioral intervention and home-school communication. Schools are a promising setting in which to provide early intervention for mental health challenges and to increase access to mental health care. Furthermore, stronger integration between home- and school- based interventions has the potential to meaningfully improve child outcomes. Therefore, we propose to develop implementation strategies for caregivers (Supporting School Success [SSS-C]), disseminated through schools and designed to address the specific needs of caregivers, to support caregivers of children with or at-risk for ADHD in implementing evidence-based behavioral interventions and home-school communication approaches. These caregiver-facing implementation strategies will be designed in coordination with the teacher-facing implementation strategies (SSS-T). To prepare for a large-scale R01 Hybrid Trial, we will address two specific aims: (1) Develop and field-test caregiver-facing implementation strategies (SSS-C); (2) Pilot test SSS-C, together with the existing SSS-T implementation strategies to prepare for a large-scale Hybrid Trial. During Aim 1, we will use an iterative, community-partnered approach to develop SSS-C, refine it in partnership with a Stakeholder Advisory Board based on feedback from try-outs with caregivers, and make final adjustments based on a field pre-test. During Aim 2, we will conduct a small-scale randomized pilot trial with 40 children and their caregivers and teachers, and will collect implementation outcomes (i.e., acceptability, appropriateness, feasibility, caregiver and teacher fidelity) and child outcomes (i.e., ADHD symptoms, functional impairment, academics, student- teacher relationship). We will also mixed methods to examine the hypothesized mechanisms, based on the Theory of Planned Behavior, of the caregiver- and teacher-facing implementation strategies.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY - OVERALL Kidney stone disease (nephrolithiasis) is characterized by painful, recurrent symptomatic events and is rising disproportionately in youth. Structural and scientific barriers have impeded strengthening the evidence base for management of pediatric kidney stone disease. The overarching objective of the Personalizing Outcomes of Nephrolithiasis in Youth (PONY) P20 Center is to generate knowledge that improves outcomes for youth with nephrolithiasis through an intentional and focused initiative to accelerate the research careers of early-stage investigators and thereby enhance the benign urology research community. To achieve this mission, this proposal strengthens partnerships among Dr. Gregory Tasian (PI at Children’s Hospital of Philadelphia, Dr Jonathan Ellison (early-stage investigator at Children’s Wisconsin), Dr. David Chu (early-stage investigator at Lurie Children’s Hospital of Chicago), and Dr. Jing Huang (biostatistician at Children’s Hospital of Philadelphia). In the proposed PONY P20 Center, we address critical structural and scientific barriers that have impeded strengthening the evidence base for management of pediatric nephrolithiasis. We will accomplish our objectives by leveraging the resources generated by Dr. Tasian’s research program, in particular the robust infrastructure of the Pediatric KIDney Stone (PKIDS) Care Improvement Network and data generated by the NIDDK-supported Urinary Stone Disease Research Network. Central to the PONY P20 Center is the PKIDS Care Improvement Network, which will support the Research Project and provide the means to disseminate the knowledge generated by the research directly into real-world care. In Aim 1, we will generate new knowledge responsive to patient-identified gaps in kidney stone research by conducting two distinct but complementary research studies that use data from PKIDS trial, the Prevention of Urinary Stones with Hydration (PUSH) trial, and the STudy to Enhance uNderstanding of sTent-associated Symptoms (STENTS). In Aim 2, we will accelerate the research careers of early-stage investigators in benign urology. The Administrative Core will create opportunities for Drs. Ellison and Chu to lead the execution of the Research Project through operational and logistical support as well as data access. PKIDS will also provide the scientific environment to support the R01 applications led by Drs. Ellison and Chu that will arise from the Research Project. In Aim 3, the PONY P20 Center will enhance the benign urology research community. We will share our expertise in stakeholder (particularly patient and caregiver) engagement with members of CAIRIBU other benign urologic researchers. We will participate in existing CAIRIBU forums by contributing our lessons learned on stakeholder engagement in clinical investigation, patient-centered trial design, and conceptual innovations in learning health systems. Overall, the PONY P20 Center will generate knowledge that addresses critical priorities identified by youth with nephrolithiasis and accelerates the career of early-stage investigators who will be leaders in benign urological research.