Children'S Hosp Of Philadelphia

NIH Research Projects · FY 2025 · 2025-09

Rationale for Multiple PI Proposal This proposal focuses on activities and collaborations with an initial set of Common Fund DCCs and the CFDE-CC in response to the Engagement Opportunity “Engaging Common Fund Data Coordinating Centers to Establish the Common Fund Data Ecosystem (CFDE)” OTA-20-2005. Our proposed engagements span the 3 key areas defined in the OT EOA and include GTEx, LINCS, HUBMAP, and SPARC as well as the activities the Kids First DRC is leading as part of the NIH Interoperability Working Group to further the establishment of the Common Fund Data Ecosystem (CFDE). The four investigators collaborating on this proposal have distinct professional backgrounds, areas of expertise, and research tools at their disposal including leading the Kids First DCC/DRP and CAVATICA efforts. At the Children’s Hospital of Philadelphia, Dr. Adam Resnick is a cancer and neuroscience research scientist with expertise in pediatric brain tumors and Dr. Allison Heath is a computer science expert in large-scale data bioinformatics and compute infrastructure. These experts will work together to lead the CHOP project team. At Centre Hospitalier Universitaire Sainte-Justine, Dr. Vincent Ferretti develops bioinformatics software for both large-scale software development and computational genomics. At Seven Bridges, Dr. Jack DiGiovanna is an expert in cloud-based analysis platforms for bioinformatics that are scalable, collaborative, and reproducible. Responsibilities of Investigators All PIs will share responsibility for ensuring the ethical conduct of the project, upholding the scientific integrity of the project, administration, oversight and coordination of the project’s management. Dr. Adam Resnick will serve as the contact PI. He will be responsible for the overall strategy, determining the prioritization of scientific use cases, and ensuring that the project meets its goals of scientific impact. Dr. Heath will oversee and facilitate the completion of the technical milestones and deliverables across all CDFE engagements. Dr. Heath will also be responsible for the execution of interoperability strategies with CFDE and the NIH IC Stacks. Dr. Ferretti will supervise the KFDRC portal development team and will be responsible for all of their relevant deliverables, such as authentication with NIH RAS and visualization integrations with LINCS. Dr. DiGiovanna will supervise the CAVATICA development team and will be responsible for all of their relevant deliverables, such as GA4GH DRS integration and multi-cloud capabilities. Communication and Data Sharing The PIs will communicate weekly and hold monthly teleconferences with PIs at the other organizations to discuss the CFDE and all administrative responsibilities. In addition, PIs will meet in person with all personnel at least annually to assess progress and make major decisions about the direction of the program. If changes are warranted, PIs will work together to discuss those modifications and the redistribution of funds, if necessary. A publication policy will be established based on the relative scientific contributions of the PIs and key personnel. Dr. Resnick will serve as contact PI and be responsible for submission of progress reports, annual reports to the NIH and all other communication.

NIH Research Projects · FY 2025 · 2025-09

OVERALL PROJECT SUMMARY/ABSTRACT Invasive fungal diseases (IFD) are infections caused by opportunistic fungi that are ubiquitous in the environment and often prey selectively on vulnerable populations, including patients who are immunocompromised. Although rare, IFDs are associated with significant morbidity and short-term case fatality rates of more than 30%. Current diagnostic approaches are extremely limited, often requiring risky invasive procedures, and management is often prolonged and sometimes ineffective. In immunocompromised children, IFDs are rarer and even more complicated to diagnose and manage than those in adults. IFDs most often impact pediatric patients with serious underlying immune-compromising conditions (e.g., primary immunodeficiency, malignancy), meaning that diseases that would otherwise be cured or managed long-term often turn deadly with concomitant IFD. Despite this obvious burden, there is a dearth of research aimed at advancing diagnostic approaches and management protocols for pediatric IFDs, and a persistent absence of data on patient and caregiver perspectives of the impact of these infections. This lack of knowledge is a direct result of the rarity of these events and the patient populations they impact. The Rare Diseases Clinical Research Consortium outlined in this proposal, the Pediatric Fungal Network STudy of Rare Invasive Fungal DisEases in Immunocompromised Pediatric Patients (PFN-STRIDE), will leverage the existing Pediatric Fungal Network that is dedicated to studying fungal infections in pediatric patients. The PFN-STRIDE RDCRC overall objective is to further the foundational work of prior PFN studies to advance the diagnostic and management approaches for rare IFD in children. This objective will be accomplished through three linked clinical and translational research projects. The first, a natural history study, will generate foundational epidemiologic data on IFDs in immunocompromised children by capturing clinical and patient- reported outcome data. The second will create a central fungal pathogen biorepository for genetic sequencing and susceptibility testing to correlate with clinical outcomes recorded in the natural history study. The third will explore novel IFD diagnostics by applying artificial intelligence algorithms on CT and MRI imaging studies and -omics analyses on blood specimens from immunocompromised pediatric patients with IFD. Additionally, Administrative, Career Development, and Pilot/Feasibility Governance Cores will support the completion of the three projects, as well as engage trainees and junior faculty interested in developing careers and research portfolios in pediatric mycology. Collectively, the RDCRC projects and cores will yield evidence to change clinical practice and inform design of future clinical trials."

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Obesity is a major modulator of lung immunity and is associated with poor outcomes in multiple inflammatory lung diseases including asthma. Notably, the pathological features of obesity-associated asthma (OAA) are distinct from non-obesity-related or “atopic” asthma: While atopic asthma is typified by type 2 inflammation and eosinophilia, OAA is characterized by type 1 inflammation and neutrophilia, indicating a change in innate immune activation with obesity. Yet, the underlying mechanisms by which diet-induced obesity alters innate immune cell activation in the lung are unclear. Previous research demonstrated that diets high in saturated fat have considerable effects on tissue-resident myeloid populations, including transcriptional and functional shifts toward a metabolically activated state in adipose tissue. As saturated long chain fatty acids become more prevalent in modern diets in the form of animal fats and preservatives, it is critical to determine their health consequences in other tissues. The broad objective of this proposal is to decipher the effects of a saturated fat-enriched diet on the lung in the steady-state and with an allergic stimulus. The central hypothesis is that the saturated 18-carbon fatty acid stearate promotes cellular membrane rigidity and induces pro-inflammatory cytokine secretion in a subset of lung-resident macrophages, which aggravates innate responses to an allergic airway challenge, including exacerbated neutrophilia and worse pulmonary function. Aim 1 investigates the steady-state profile of lung myeloid populations in mice fed normal chow or stearate-rich diets with or without myeloid-specific deletion of the enzyme required for stearate incorporation into the membrane. The experimental approaches are 1) single lung cell transcriptomic analysis for differentially expressed genes and gene sets and 2) flow cytometric cellular phenotyping for inflammatory activation, myeloid infiltration, and cytokine production in the lung. Aim 2 determines the consequences of diet-induced inflammation in the lung in the context of an innate immune challenge by leveraging a HDM/LPS model of OAA, assessing 1) protective effects of myeloid-specific deletion of the stearate-processing enzyme, and 2) in vivo tests of pulmonary function in mice. Together, these studies will provide insights into the impact of dietary saturated fatty acids on lung myeloid function and the development of OAA, elucidating the role of metabolic activation and transcriptional shifts in innate immune responses, thus paving the way for therapeutic interventions and a deeper understanding of the pathogenesis of obesity-related lung inflammatory diseases. Conducted within the resource-rich, multidisciplinary environment of the Children’s Hospital of Philadelphia, which is committed to training the next generation of scientific leaders, support of this proposal positions the fellow to gain comprehensive skills in immunology, metabolism, and advanced research methodologies. The proposed research strategy and training plan will foster critical thinking, leadership abilities, and scientific innovation, paving the way for the fellow's transition to an independent research career dedicated to addressing complex health challenges.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Despite their well-recognized increased risk of overweight and obesity, adults with Down syndrome (DS) have not traditionally been considered at increased risk for “cardiometabolic” conditions such as Type 2 diabetes (T2D) and atheromatous disease. Recent robust epidemiologic data from the UK Clinical Practice Research Datalink suggest adolescence and young adulthood are specific periods of vulnerability for T2D development in this population. Overweight and obesity are clear risk factors, but their intersection with both DS-related co-morbidities [obstructive sleep apnea (OSA), congenital heart defects (CHD), dementia, hypogonadism, cancer survivorship] and demographics [race/ethnicity, aging] recognized to confer increased cardiometabolic risk (CMR) remain undefined. An improved understanding of CMR as well as potentially cardioprotective factors in a large, diverse population of individuals with DS is crucial for defining screening practices and interventions that minimize patient burden while considering the relevance of both traditional T2D complications and the intersection of CMR with established DS- related co-morbidities. This study will leverage de-identified data from a large, Research diverse population of adults with DS captured in the TriNetX Network of multiple health care organizations to 1) describe the prevalence of T2D, dyslipidemia, hypertension, OSA as well quantify HbA1C and lipids (HDL, LDL, TC, TG) by 5-year intervals; 2) examine the relationships of T2D, atheromatous disease, and dyslipidemia with common co-occurring condition in adults with DS (history of CHD, overweight/obesity, OSA, psychiatric medication prescription, dementia, menopause, cancer survivorship) and demographics (age, sex, race/ethnicity), 3) explore microvascular complications in the subset of patients with diabetes and 4) quantify screening practices for co-occurring conditions in adults with DS. This large database effort performed in a diverse, national population of adults with DS will advance our understanding of the prevalence of CMR, vascular complications, and cardiovascular risk factors in DS, a critical step for developing screening guidelines and targeted interventions that minimize patient burden without compromising care. This work will serve as the foundation for a longitudinal study aimed at defining the relevance of T2D and CMR for individuals with DS and to develop interventions to optimize screening for co-occurring conditions.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The intestinal lining is supported via maintenance of a layer of intestinal epithelial cells, and in particular, intestinal stem cells (ISCs). ISCs are very sensitive to cell death in response to various injuries, including radiation, chemotherapy, or inflammation. In the face of ISC depletion, the epithelial layer can still efficiently regenerate due to the contribution of other cells that can re-acquire ISC activity when needed, termed “facultative” intestinal stem cells (f-ISCs). F-ISCs must possess two fundamental attributes: 1) injury resistance, and 2) the ability to re-acquire ISC activity. These attributes together ensure replenishment of the epithelial lining in response to tissue damage. Despite the critical importance of f-ISC activity in the regenerative response, little is known about its molecular basis. Emerging evidence implicates autophagy as a key player in this process. Genetic inactivation of autophagy leads to reduced regeneration after epithelial injury, and polymorphisms in autophagy genes are associated with susceptibility to Crohn's disease. Conversely, calorie restriction or fasting, which can induce autophagy, is associated with enhanced intestinal regeneration. Our recent publication showed that intestinal cells with high autophagic vesicle content are relatively resistant to DNA damage compared to ISCs in vivo. We also find that high autophagic vesicle content in intestinal epithelial cells, particularly differentiated secretory cells, is associated with enhanced organoid formation- an in vitro proxy for ISCs. These data suggest that high autophagic vesicle content can prospectively identify secretory cells that are f-ISCs in vitro, however, whether certain lineages are better “poised” to be f-ISCs and the mechanistic contribution of autophagy to both injury resistance and regeneration are critical knowledge gaps. The current proposal will use in vivo models and organoids from both mice and humans to define how autophagy contributes to cells that survive injury and re-enter the cell cycle to drive regeneration. Aim 1 will define whether autophagy, and specifically mitophagy, underlies DNA damage resistance of f-ISCs. Key findings will be confirmed in enteroids and colonoids from de-identified healthy human subjects. Aim 2 will define the extent to which autophagy-mediated f-ISCs utilize a TGF-mediated fetal gene expression program to contribute to tissue regeneration. Key facets of Aim 2 will be evaluated directly in human organoid lines. Our study will provide a significant conceptual advance in understanding how non-ISCs with high autophagy can repurpose themselves as f-ISCs to contribute to epithelial barrier restoration. In addition, these studies are highly impactful because they will directly translate key findings in primary human cells. Resulting data will form a basis for enhancing f-ISCs for clinical benefit in patients with GI diseases.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY- Elucidating Effector CD8 T-Cell –Kupffer Cell- Interferon Gamma Interaction in Pediatric Activated T-cell Acute Liver Failure The overall goal of this five-year proposal for a Mentored Clinical Scientist Research Career Development Award is for me to become an independent academic investigator in the field of liver immunology. After graduating from Tel Aviv University School of Medicine, I completed my pediatric residency at Children's Hospital at Montefiore. I then pursued fellowship training in Pediatric Gastroenterology and Transplant Hepatology at Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania (Penn). I joined the faculty of CHOP and Penn as an Attending Physician and Instructor in the Division of Gastroenterology. I continued my scientific training by completing a Masters in Translation Research at Penn 10/2024. During my fellowship, I developed a clinical and research interest in why dysregulated immune responses result in Pediatric Acute Liver Failure (PALF). My mentor for this award, Dr. Edward M. Behrens, is a physician-scientist with a longstanding track record of scientific innovation and providing exceptional training to mentees. As an internationally recognized expert in inflammatory disorders, Dr. Behrens's work complements my own, and we are poised for productivity. My scientific advisory committee includes scientists and physician-scientists with expertise in all aspects of the proposed work, from CD8 and macrophage biology to next-generation sequencing and spatial transcriptomics. Scientifically, this proposal focuses on the role of hepatic interferon-gamma (IFN-) response in the most common cause of PALF, termed Pediatric Activated T-cell Hepatitis/ALF (TC-PALF). TC-PALF is characterized by an elevated Th1 immune response with a hepatic IFN- transcriptional signature and an abundance of hepatic effector cytotoxic T lymphocytes (eCTL) expressing markers of tissue residence (CD8+, CD103+, perforin+) and macrophages. Under the guidance of Dr. Behrens, I previously discovered that hepatic parenchymal response to IFN- results in exacerbated liver injury in a mouse model of Hemophagocytic Lymphiohistiocytosis (HLH), a rare autoinflammatory disorder characterized by high circulating IFN- and PALF. However, how specific hepatic constituents respond to this cytokine in TC-PALF remains unknown. Based on prior literature and my preliminary data, my central hypothesis is that IFN- directly affects Kupffer Cell (KC) biology and drives liver injury in both murine and human TC-PALF, independent of its effect on intrahepatic and peripheral lymphocytes. The aims of this proposal are to establish: 1) the mechanism by which KCs respond transcriptionally and functionally to IFN- in a murine model of TC-PALF, and 2) the spatial relationship between IFN- responsive KCs, hepatocytes and eCTLs in both human and murine TC-PALF. This proposal will close major gaps in knowledge regarding the mechanism by which IFN- acts on hepatic parenchymal cells to develop hepatic-specific therapies and improve native-liver survival for patients. In accordance with my career development objective to become a field leader in liver immunology, my scientific proposal complements my current proficiency in cellular immunologic methods with training in advanced hepatocyte and macrophage biology and bioinformatic methods.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT In the United States, > 1500 children undergo hematopoietic cell transplantation (HCT) as life-saving treatment for malignancies, immunodeficiencies, inborn errors of metabolism, and multiple other conditions. HCT requires intensive high-dose chemotherapy and/or radiation followed by an infusion of hematopoietic progenitor cells with the goal of correcting cellular defects, repopulating chemotherapy-ablated marrow, or eradicating malignancy. Survival is limited by the development of pulmonary toxicity, which occurs in up to 40% of pediatric HCT recipients due to infectious and noninfectious inflammation. HCT recipients with lung injury have 40% mortality when invasively ventilated and > 60% mortality if meeting acute respiratory distress syndrome (ARDS) criteria. The molecular pathogenesis of lung injury after HCT is largely unknown, partly due to a lack of well-phenotyped cohorts that examine clinical and biochemical characteristics prior to development of lung injury. Our research group focuses on mechanisms contributing to the development of lung injury, and in a recent comprehensive biomarker analysis of pediatric ARDS we found that nucleosomes, composed of histones and cell-free DNA (cfDNA) released from dying cells, were strongly associated with mortality. Histones and cfDNA have been implicated as damage-associated molecular patterns (DAMPs, endogenous danger signals released that propagate inflammation) and are potential upstream contributors to severe lung injury. In this cohort, 12% of children (and a disproportionate 35% of non-survivors) had undergone HCT and possessed a distinct biomarker profile, with elevated nucleosomes, histones, and cfDNA at ARDS onset. Preliminary interrogation of the larger plasma proteome and the cfDNA methylome also revealed targetable pathways warranting focused investigation. Overall, our clinical, proteomic, and cfDNA characterization of pediatric ARDS suggested that the molecular signature associated with HCT was also associated with higher mortality. Therefore, we propose the Lung Injury in ONcologic Stem cell transplants (LIONS) study in 400 subjects undergoing HCT at the Children’s Hospital of Philadelphia. LIONS is a prospective longitudinal cohort study, with serial plasma collection pre-HCT and immediately post-HCT (between day -2 to +20 of HCT) that aims to characterize the molecular changes leading to lung injury. We hypothesize that elevated DAMPs pre- and post- HCT predict subsequent lung injury, and that subjects who develop lung injury have a distinct molecular profile. Aim 1 tests the utility of nucleosomes, and their component histones and cfDNA, to predict lung injury post- HCT. In Aim 2, we leverage novel nanoparticle-enriched mass spectrometry to perform deep unbiased proteomics to characterize the molecular signature of subjects that develop lung injury. Finally, in Aim 3 we characterize the contribution of cell-specific cfDNA, and of recipient-derived cfDNA in allogeneic HCTs, to the development of lung injury. LIONS is the first necessary step towards identifying the molecular signature and tissue targets of lung injury post-HCT, which remains a condition with high mortality and no directed therapies.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Children born extremely preterm (EP; <27 weeks gestational age (GA)) and very preterm (VP; 28 – 32 weeks GA)) are at high risk of having language-related deficits [1-5] compared to term-born control (TC) children. Little is known regarding the neural mechanisms that contribute to the substantial variation in the rate of language development in EP/VP children, with no explanation why some EP/VP preschoolers with delayed language ‘catch up,’ while others receive a diagnosis of language disorder at school age. The PI’s team has extensive experience obtaining brain function (magnetoencephalography (MEG)) and brain structure (magnetic resonance imaging (MRI)) data in infants and young children, with studies from the PI and others showing that variability in language development is due to between-subject variability in the maturation of neural-circuit activity, such as variability across children in their ability to rapidly encode auditory information (i.e., measured via the auditory M50 response latency [39]). Employing a longitudinal design and using multimodal neuroimaging (MEG and MRI), this R01 will identify neural mechanisms contributing to the heterogeneity of language trajectory in EP/VP children at 3, 4, and 5 years corrected age (CA), improving upon already identified clinical and socio-demographic risk factors. This R01 leverages the PI’s current TALK supplement study (3UG1HD068244-13S1), in which MEG, MRI, and language measures are obtained from EP (N = 60) and TC (N = 60) children at age 3 years (Time 1). For this proposed R01, follow-up brain imaging and language measures for these EP and TC children will be obtained at age 4 (Time 2) and 5 years (Time 3), and a new cohort of VP children (N=60) will be recruited and assessed at all 3 time points (3, 4, 5 years corrected age (CA)) to evaluate the specificity of findings across a broader spectrum of prematurity. Source localization is used to examine neural-circuit activity associated with auditory encoding and with receptive and expressive language processes in brain space. Study aims examine group differences in these auditory cortex and language neural measures as well as determine the degree to which the neural measures (single-time-point and rate-of-change) improve prediction of language trajectory and language outcome at 5 years CA, above and beyond clinical/socio-demographic risk factors. The proposed R01 has high impact and captures the maturation of language associated neural activity (local and network activity) that is associated with language ability (current and future). It is anticipated that the elucidation of neural risk factors will provide increased specificity with respect to the nature of variable language outcome in preterm preschoolers. Study findings will advance our mechanistic understanding of neural circuit contributing to language delay and late talking in preterm young children, the R01 study goals in line with the TALK Initiative goal “to create longitudinal datasets and identify optimal measures for differentiating developmental trajectories in late talking children across time.”

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Compared to nations of similar economic status, the United States has a high rate of preterm birth and 12-15% of all newborns require admission to the neonatal intensive care unit (NICU). Both the outcomes and use of NICU care for all infants varies widely across hospitals and geographic regions, which contributes to inefficient care delivery and adverse health outcomes for all infants. One significant change in the delivery of perinatal care has been the rise of private equity, or investor-owned, ownership of both neonatal physician groups delivering care and hospitals that supply the NICU. In the United States, private-equity corporations are now estimated to own 25% of all hospitals, and in many specialties such as dermatology, obstetrics, and ophthalmology these groups have an increasing share of practices nationally. While studies have shown mixed impacts on adult outcomes, only one small study of private equity ownership in neonatology, the acquisition of 36 physician groups over an 8-year period, found higher payments to these groups without any change in outcomes. There have been no further studies of the role of private equity ownership on neonatal care. This study, then, is designed to examine how ownership of neonatal physician groups, hospitals that provide neonatal care, or the combination of both affect the outcomes and use of NICU care for newborn patients in the United States. To study this question, we will link data on private equity ownership of physician and hospital groups that we have complied to a unique population-based dataset of all births in 15 states over a 25-year time period that encompass over 40% of all births in the United States. Using a staggered difference- in-differences approach and previously validated methods we have used to identify private equity acquisitions, we will examine the following specific aims: (1) Determine the impact of private-equity ownership of physician groups, hospitals that provide neonatal care, or the combination of both on mortality, morbidity, and length of stay of infants born prematurely during the birth hospitalization; (2) Determine the impact of private-equity ownership of physician groups, hospitals that provide neonatal care, or the combination of both on the use of NICU care, length of stay, and morbidity of term infants with less severe indications for which admission to the NICU may be discretionary, such as hyperbilirubinemia requiring phototherapy and hypoglycemia; and (3) understand how changes in ownership differentially affect infants with public insurance compared to private insurance. At the end of this project, we will have assembled evidence for potential positive, or negative, effects of private equity acquisition of neonatal care services for stakeholders, and further understand the potential multiplicative effects of such acquisition of physician and hospitals for patients and their families.

NIH Research Projects · FY 2025 · 2025-09

Rare tumors, while individually uncommon, account for 25% of cancer deaths. These cancers have been understudied, leading to less improvement in outcome than for common cancers. Obstacles to conducting clinical trials for patients with rare tumors are many, including limited biospecimens resulting in a lack of understanding of the biology and therapeutic targets, small patient numbers, and the need for novel trial designs. Additionally, most rare pediatric cancers occur in the adolescent and young adult population, and care for these patients is often fragmented between numerous pediatric and adult subspecialists. My role as a rare tumor clinical research specialist is to address each of these barriers at both the institutional and National Clinical Trials Network (NCTN) levels. Nationally, I serve as chair of the Children’s Oncology Group (COG) Rare Tumor Disease Committee, and study chair for three COG clinical trials. With R50 support, I will expand the availability of rare tumor clinical trials within COG, focusing on trials of immunotherapies and molecularly targeted and genomically informed therapies for rare cancers. This will include developing novel studies for patient populations never previously studied within COG, including thyroid cancer and melanoma. Importantly, I will continue to build partnerships with the adult NCTN groups to design trials that span the adolescent-young adult divide. Additionally, through leadership of rare tumor efforts for the NCI/COG Molecular Characterization Initiative and our institutional biobank, I will expand the collection and study of clinically and molecularly annotated biospecimens. At the Abramson Cancer Center, I will develop a pediatric-adult rare tumor program, built upon my leadership of the Pediatric Very Rare Malignant Tumor Program and role as institutional PI of the NCI-funded Pediatric Early Phase Clinical Trial Network (PEP-CTN). I will lead both NCTN and institutional trials that span the pediatric-adult age range. Through this program, I will increase enrollment to both NCTN and investigator-initiated precision medicine trials for both children and adults with rare tumors and develop a software tool enabling physicians to search for appropriate trials for their patients, regardless of whether they are open at the pediatric or adult hospital. Finally, I will mentor the next generation of rare tumor and developmental therapeutic clinical trialists to design and lead studies through COG/NCTN. Together, this award will substantially expand the pipeline of rare tumor clinical trials within the NCTN, increase participation in NCI-funded rare tumor clinical research across the age spectrum at ACC, augment both institutional and COG biobanks to enable the discoveries that will drive the next generation of national cooperative group trials, and develop the next generation of rare tumor leaders within the COG.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Multiple sulfatase deficiency (MSD) is an ultra-rare, fatal neurodegenerative disorder with emerging therapeutic options, including an AAV-based approach (Foundation for the NIH Bespoke Gene Therapy Program; PIs Adang and Ahrens-Nicklas). MSD is the result of dysfunctional sulfatase activation by the SUMF1- encoded formylglycine-generating enzyme (FGE). The resulting phenotype arises from the combined loss of all sulfatases. Our preliminary data suggest distinct phenotypes of MSD based on neurologic severity (severe and attenuated) that correlate with genotype and a novel biomarker of disease, glucosaminoglycan non-reducing ends (GAG-NREs). Because of its biologic similarity, we hypothesize that outcome measures employed in MLD and MPS clinical trials will be capable of capturing the impact of disease in this unique population. There is also a critical gap in our understanding surrounding the family's perspective of this ultrarare disease. The identification of patient-centric measures will be an essential step towards meeting the urgent needs of this rare disease community for future clinical trials. With our ongoing natural history study, we have the unique opportunity to address the critical need to (1) define patient-centric tools for measuring the burden of disease and defining clinical benefit and (2) validate the use of disease-specific scales in MSD for potential use as clinical endpoints in clinical trials. In Aim 1, the longitudinal performance of a panel of patient-centric assessment tools in 30 subjects will be captured. This includes the parent-reported measures including quality of life surveys and validated parent- reported assessments of functional abilities. This will be compared to standard provider administered outcome measures. As part of this aim, we will also create a rigorous study platform to support future research and regulatory needs. The expected outcome is a panel of objective measures that reflect patient and family perspectives on severity and importance that can be used as clinical trial endpoints in the upcoming MSD gene therapy trial. In Aim 2, existing tools developed for the single-sulfatase disorders will be applied to the MSD population. Within our prospective natural history cohort, we will compare the performance of these clinician reported outcome measures with more labor-intensive provider outcome measures and disease severity stratification by biomarkers and genotype. The expected outcome is the validation of additional outcome measures for clinical trial stratification. This work is significant because it will generate the tools necessary to define appropriate outcome measures to capture disease progression. These panel of measures defined in this project will be the foundation of imminent clinical trials. This work will form the basis of inclusion/exclusion criteria and selection of trial endpoints. Collectively, these efforts will form the components needed to design, conduct, and interpret clinical trials targeting MSD, a fatal and progressive disorder of childhood.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT TUBB4A-associated leukodystrophy (TUBB4A-LD) is a rare pediatric hypomyelinating disorder caused by sporadic mutations in the TUBB4A gene, which encodes β-tubulin 4A (Tubb4A) protein. Affected individuals experience significant motor development delay, abnormal movements, ataxia, spasticity, dysarthria, and cognitive deficits. TUBB4A-LD is a life-threatening diagnosis for which there is currently no treatment or cure. Promising therapies, such as antisense oligonucleotides (ASO) and in-vivo gene therapy, are nearing pediatric clinical trials, highlighting the urgent need for foundational tools to design patient-centric trials that are both safe and capable of evaluating treatment efficacy. Key challenges remain in clinical trial design and include gaps in (i) understanding the overall disease course, in particular systemic complications (e.g., cardiac involvement), and (ii) the lack of validated patient-centric clinical trial endpoints to ensure safety and measure efficacy in TUBB4A-LD drug candidate trials, respectively. We propose to address this urgent gap in clinical trial readiness by leveraging our partnership with disease/outcome experts, caregivers, and advocacy partners in the Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN). We will longitudinally map the systemic complications of TUBB4A-LD and develop a novel quantitative measure of systemic burden (TUBB4A-S) (Aim 1). This effort will guide clinical trial readiness by enabling determination of safe inclusion and exclusion criteria, identification of individuals at-risk of AEs as well as appropriate assignment of relatedness of AEs to disease. In addition, this work will also inform evidence- based clinical guidelines for TUBB4A-LD. Disease severity and complexity in TUBB4A-LD affected individuals will require patient-centric approaches to identify concepts of interest (COI) most meaningful to patients and families. Our team has already identified patient priorities and COIs. In Aim 2, we will identify and measure COAs able to capture patient-centric COIs, to define meaningful changes in COA measures with clear context of use (COU). The approach will be framed in accordance with guidance from the FDA as measures of health events and COI important to the patient community. Together, these efforts are expected to establish a sharable resource to validate clinical trial endpoints applicable to TUBB4A-LD candidate drug trials. Also, this work will create a knowledge base on systemic complications of TUBB4A-LD to define standards of care and inform clinical trial design including, trial eligibility, at-risk prediction and adverse event attribution.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT The prevalence of chronic diseases such as diabetes, depression, and hypertension is increasing among young adults. If not properly managed in the preconception period, these conditions may contribute to worsening birth outcomes. However, early adults aged 19 – 34 years have the highest uninsurance rates in the US, and experience high rates of insurance status changes, sometimes called churn. Churn is associated with poor control of chronic conditions, low continuity of care, low self-rated health, and low prenatal care receipt. Uninsurance and churn in early adulthood limit access to health care during a critical time to improve pregnancy outcomes. Because Medicaid is relatively generous during pregnancy, it provides coverage for 40% of US births, including 90% for those who experience pregnancy-related churn. This grant will fill knowledge gaps about the relationship between preconception Medicaid enrollment and pregnancy outcomes. We will do so by leveraging two features of Medicaid policy. First, starting in 2014, the Medicaid expansion encouraged states to increase income thresholds for adult Medicaid eligibility, and was associated with increased coverage during early adulthood. State variation in adoption of Medicaid expansion allows comparison of otherwise similar individuals in Medicaid expansion states and non-expansion states to test whether increased coverage improved outcomes. Second, as in pregnancy, childhood Medicaid coverage is relatively generous, covering 40% of youth 18 years and younger. We will therefore use pediatric Medicaid claims to build and characterize of a cohort of individuals who grew up in low-income households. This will limit confounding by indication and will focus our analysis on individuals likely to be low-income in early adulthood, and thus most likely to benefit from the Medicaid expansion and to have observable Medicaid-insured births. Aim 1 will define patterns of Medicaid coverage in early adulthood and test whether these patterns are associated with state adoption of the Medicaid expansion. Aim 2 will test whether residence in a state that adopted the Medicaid expansion is associated with pregnancy outcomes for early adult women. We will use Medicaid claims from 17 – 18 year- olds with female sex to identify individuals likely to be low income in adulthood. We will define patterns of Medicaid coverage in early adulthood (through approximately age 25). We will test hypotheses using near-far matching and a differences-in-differences approach. This project innovates by conceptualizing Medicaid coverage over an extended preconception period, rather than in association with individual pregnancies, consistent with mechanisms through which long-term management of risk factors, including chronic disease, can most influence pregnancy outcomes. Findings will provide evidence to inform changes in Medicaid policy and systems of care to improve preconception health, aligning with NICHD's strategic plan to improve pregnancy outcomes, specifically Theme 3: Setting the foundation for healthy pregnancies and lifelong wellness and elucidating the role of the health care system in improving outcomes.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT The goal of this Mentored Clinical Scientist Research Career Development Award (K23) is to prepare Carolyn McGann, MD, Clinical Instructor and Attending Physician at the Children's Hospital of Philadelphia to achieve her long-term goal of becoming an independent global health scientist focusing on neonatal sepsis prevention. Her immediate goal is to acquire the mentorship, training and research experience needed to successfully compete for R01 grants aimed at interrupting the transmission pathways identified in this work. To achieve these goals and transition to independence, Dr. McGann and her mentors have developed a comprehensive career development plan based on the following: (1) intensive mentorship from a team with complementary expertise (2) advanced training in microbiome methods and epidemiology, and (3) an innovative research plan to use microbiome methods and spatial epidemiology to evaluate risk factors for neonatal colonization with sepsis-causing pathogens. Neonatal sepsis leads to nearly one million deaths annually worldwide, but the causes of neonatal sepsis differ by resource level. Low-and-middle income countries (LMIC) have a much higher burden of disease, but little is known about the transmission of sepsis-causing pathogens in these settings. Colonization with sepsis-causing pathogens precedes invasive infection and is an important step on the causal pathway of neonatal sepsis. Hospital environmental pathogen reservoirs have been identified. Neonates who require prolonged stays are more likely to become colonized, but little is known about transmission of sepsis-causing pathogens. Kangaroo care, or skin to skin contact with a caregiver, is known to protect against sepsis but the mechanism is unknown. Leveraging an existing cohort and biobank, Dr. McGann's research will fill this knowledge gap by identifying factors that promote or protect against neonatal colonization with sepsis-causing pathogens by examining the following exposures: (1) maternal rectovaginal colonization with sepsis-causing pathogens, (2) kangaroo care (day of onset and duration), and (3) proximity to an environmental reservoir of sepsis-causing pathogens. Dr. McGann's K23 proposal addresses a critical gap in knowledge about the mechanisms of neonatal colonization with sepsis-causing pathogens in LMIC. Her findings will provide preliminary data for future R01 proposals aimed at decreasing the risk of neonatal sepsis. Her career development plan outlines a clear path to gain the knowledge, skills and experience needed to gain independence as a global health research scientist and to become a leader in global health neonatology.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Human hematopoiesis requires a complex interplay of genes, transcription factors, and epigenetic modifiers that regulate lineage commitment and maturation. Trisomy 21 (T21), the chromosomal abnormality underlying Down syndrome, is associated with genome-wide gene dysregulation and baseline hematopoietic abnormalities such as polycythemia and thrombocytopenia. Transient abnormal myelopoiesis (TAM) and myeloid leukemia of Down syndrome (ML-DS) are related disorders unique to Down syndrome that arise from a megakaryocyte-erythroid progenitor with blocked differentiation. TAM and ML-DS are characterized by a megakaryocyte (MK) surface marker signature and mutations in the hematopoietic transcription factor GATA1, resulting in exclusive expression of the truncated GATA1s isoform. ML-DS is additionally characterized by “third-hit” mutations in regulators of epigenetics or chromatin structure, such as in the cohesin complex member STAG2. Individuals with germline GATA1s mutations without T21 develop cytopenia(s) without leukemic predisposition, emphasizing the role of chromosome 21-encoded genes, such as the transcription factor RUNX1, in the progression from T21 to TAM to ML-DS. However, the underlying mechanisms remain incompletely understood. This proposal employs a novel isogenic human induced pluripotent stem cell (iPSC) system to isolate the individual and synergistic roles of T21, GATA1s, RUNX1 isoforms, and STAG2 loss in hematopoiesis. My data suggest that T21 and GATA1s synergistically lead to enhanced megakaryopoiesis and cytokine-independent proliferation, a hallmark of myeloproliferative disorders, and that dysregulation of RUNX1 may contribute to this phenotype. STAG2 loss combined with T21 and GATA1s further enhances megakaryopoiesis and results in dysplasia. This proposal builds upon these data through two specific aims: 1) Determine how GATA1s and RUNX1 co-regulate megakaryopoiesis and 2) Determine how STAG2 loss further perturbs hematopoiesis in T21/GATA1s cells. The aims seek to produce medically relevant knowledge on normal and Down syndrome hematopoiesis by combining established and cutting-edge techniques in assessing chromatin architecture, MK biology, and transcriptional regulation. This proposal describes a 5-year training plan for the applicant, Dr. Kaoru Takasaki, to transition to an independent research career in pediatric hematology as a physician-scientist with expertise in the dysregulation of transcription factors and chromatin structure at the intersection between normal and abnormal hematopoiesis. She will be supported by two mentors, Dr. Stella Chou, an international expert on hematopoiesis, and Dr. Mortimer Poncz, a global expert in platelets and MKs, as well as an advisory committee with complementary expertise in epigenetics, chromatin structure, and iPSC disease modeling. Dr. Takasaki’s research and training will take place in the resource-rich environments of the Children’s Hospital of Philadelphia and the University of Pennsylvania that will provide an outstanding foundation to embark on an independent physician-scientist career.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Since its launch, the Gabriella Miller Kids First Data Resource Center (KFDRC) has constantly innovated and helped redefine the architecture, development and operations across all cores of work to optimize and provide opportunities for the research community to have impact in childhood cancer and structural birth defects. This has included collaborative partnerships across the NIH data commons landscape to ensure the FAIRness of Kids First data and enable rapid access of data in cloud-based platforms. In the coming year, the KFDRC will build on these innovations and successes to further empower sustained, scaled growth and impact. This will be a cross-coordinated effort across the Administrative and Outreach Core, the Data Coordinating Core and the Data Resource Core. The combined efforts of these cores will provide researchers the data, tools, and workspaces they need to further the mission of the Kids First program. The KFDRC will make significant contributions to accelerate community efforts not only to understand etiology and drivers of pediatric diseases, but also drive and enhance the interpretation and clinical decision support for better outcomes for children.

NIH Research Projects · FY 2026 · 2025-09

PROJECT SUMMARY The rising opioid use rates have led to a significant increase in children exposed to opioids in utero, with adverse effects on both the placenta and developing brain. These effects include alterations in brain structures, including the cortex, hippocampus, and cerebellum. Affected children also have an increased susceptibility to neurodevelopmental disorders such as neonatal opioid withdrawal syndrome, as well as deficits in speech, cognition, and executive function. Despite these known effects, there are no neuroprotective treatments due to limited knowledge of the underlying molecular mechanisms. Here, we propose an innovative strategy to unravel the lifelong impact of prenatal opioid exposure on brain development. We will employ a well-characterized model of early-life morphine exposure to identify how opioid exposure during brain development disrupts the metabolic-epigenetic axis, potentially disrupting long-term cell type-specific maturation. In this model, previous bulk RNA sequencing has identified mitochondrial dysfunction, especially in the prenatal period. In other models of prenatal opioid exposure, mitochondrial dysfunction persists into adulthood and opioid exposure increases susceptibility to other brain injuries, like traumatic brain injury. Epigenetic patterns are frequently disrupted by metabolic anomalies. Therefore, we will explore the effects of opioid exposure on mitochondrial function and epigenetic regulation throughout the lifespan. In both the fetal and juvenile First, we will employ advanced in utero metabolic imaging with 4D-Oxywavelet MRI and molecular profiling to correlate mitochondrial dysfunction with single-nucleus joint transcriptomics and epigenomics in the placenta and different regions of the fetal brain (cortex, hippocampus, and cerebellum) after opioid exposure throughout gestation. Then, in exposure juvenile animals, we will perform brain region-specific mitochondrial function profiling in the cortex, hippocampus, and cerebellum. We will subsequently perform single- nucleus transcriptomic and epigenetic profiling in the same animals and brain regions. Both approaches will allow us to directly correlate the variability of metabolic disruption with cell type-specific molecular profiles, allowing us to dissect the interplay between metabolism and the epigenome in developmental opioid exposure at a resolution that has never occurred before. We hypothesize this approach will also provide insight into the potential biological underpinnings for the variability of neurodevelopmental outcomes seen from opioid exposure. By performing this comprehensive assessment of how the metabolic-epigenetic axis is disrupted by developmental opioid exposure, we will be able to identify novel, lifespan neuroprotective agents. Additionally, the approach is flexible and could be applied to study other prenatal exposures, including exposure to other substances, that disrupt the metabolic-epigenetic axis.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Chronic kidney disease (CKD) affects 35.5 million Americans and contributes to morbidity, reduced quality of life, and heightened cardiovascular mortality, disproportionately impacting women more than men. CKD disrupts ovarian hormone levels, often leading to menstrual irregularities and low estrogen, both of which can negatively impact bone health and increase already elevated risks for reduced bone mineral density and fractures. Estrogen and progesterone (E/P) therapy is effective in improving bone mineral density and reducing fracture risk in hypoestrogenic women without CKD, but its efficacy in CKD has not been studied. Additionally, E/P therapy is associated with an increased risk of venous thromboembolism (VTE) and thrombotic stroke in the general population. This risk may be more pronounced in the CKD population, particularly among those with higher baseline thrombotic risk, such as patients with systemic lupus erythematosus with nephritis or nephrotic syndrome. However, there are subpopulations of patients with CKD who may not have increased thrombotic risk beyond the general population and thus may benefit from E/P therapy for regulation of their underlying menstrual irregularities and for bone protection. This project addresses these critical evidence gaps by leveraging two large and complementary real-world data sources, the TriNetX Research Network and Merative MarketScan, to evaluate the risks and benefits of E/P therapy in adolescent and premenopausal women with moderate to severe CKD (stage 3-5D). TriNetX organizations, integrates electronic health records for >100 million patients from 80 major healthcare and the Merative MarketScan database includes longitudinal patient-level claims data for>273 million individuals throughout all US states and territories. Specifically, the study will use a stratified sequential analysis with propensity score matching to assess the impact of E/P therapy on improving bone health by reducing fracture risk (Aim 1) while evaluating its potential to increase the risk of thrombotic events (Aim 2). These two aims will provide robust evidence on the risk and benefit of E/P therapy in CKD care. As the first and largest study of its kind, it will inform clinical guidelines for safer, more effective E/P therapy use, ultimately improving reproductive and skeletal health outcomes in this high-risk population. The grant will also provide the applicant with advanced training in pharmacoepidemiologic research methods and mentorship to support her career development and transition to an independent physician-scientist focused on the impact of chronic disease on ovarian health in adolescents and young adults.

NIH Research Projects · FY 2025 · 2025-08

Vascular malformations (VMs) result from abnormal overgrowth of blood and lymphatic vessels that are commonly driven by somatic variants in growth and proliferation pathways. Complex VMs are destructive, proliferative disorders with high morbidity and mortality. VMs are incurable and limited treatments exist. Advancing Rare Disorders-Vascular mAlformation Research Network with CaNVAS (ARDVARC) is our proposal for a distinct program that builds upon an established clinical trial consortium (CaNVAS) that focuses on VMs. ARDVARC has the overarching goal of supporting clinical trial readiness by developing a strong infrastructure for clinical trials, strengthening existing academic and commercial partnerships, fostering new collaborations, and promoting expertise across the workforce. The CaNVAS consortium was created by pediatric hematologists and oncologists to address the paucity of prospective muti-centered trials for VMs. CaNVAS consists of 23 academic medical centers with expertise in VMs and clinical research. These CaNVAS sites will serve as the infrastructure for ARDVARC. ARDVARC will focus on 3 categories of rare, complex VMs: PIK3CA overgrowth spectrum disorders with VMs, complex lymphatic anomalies, and extra-cranial arteriovenous malformations. Each of these diseases meets the criteria for rare diseases and has high morbidity and mortality, limited information on natural history, lack of effective treatments, and limited numbers of disease experts. ARDVARC will work as an interdisciplinary research team (patient advocacy groups, clinical, translational, basic, and health services scientists) with the RDCRN to enhance clinical trial readiness through the clinical projects and cores described here. Our specific research aims include two clinical projects that aim to address two major deficiencies in this field that impeded clinical trial readiness. Project 1 will establish the first U.S.-based centralized and accessible natural history registry and biorepository resource for the study of complex VMs. Project 2 will develop and validate VM-specific health-related quality of life patient-reported outcome measures for children to be used in future trials as key clinical endpoints. The Pilot Project core will develop a formal process for evaluating and prioritizing study proposals related to innovative interventions and endpoint assessments. The Career Enhancement Core will support the development of a sustainable workforce with expertise in research and clinical care of complex VMs. The Administrative Core is responsible for the overall administration and operation of this RDCRC. ADRVARC will be led by a group of expert researchers and patient advocacy group representatives to improve clinical trial readiness for complex VMs, with the long-term goals of improving clinical outcomes and identifying cures.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT: OVERALL The overall goal of the Advancing Craniosynostosis (ACT) Rare Diseases Consortium is to advance diagnosis, management, and treatment of the 5 types of syndromic craniosynostosis (CS): Apert, Pfeiffer, Crouzon, Muenke, and Saethre-Chotzen. ACT is a highly collaborative, patient-centric, translational, and clinical rare disease consortium. We have assembled a team of multi-disciplinary clinical investigators enhanced by interactions with an external advisory committee and patient advocacy groups. ACT is comprised of 15 investigators with world-leading expertise in genetics, craniofacial surgery, biostatistics, bioinformatics, data science, psychology, and clinical trials from 4 academic pediatric centers around the United States: Children’s Hospital of Philadelphia, Children’s Hospital Los Angeles, Seattle Children’s Hospital, and Boston Children’s Hospital. In addition, we will partner with PEDSnet, a PCORnet clinical research network of 11 leading pediatric hospitals that also include high volume craniofacial centers. The ACT Rare Diseases Consortium will carry out 2 Clinical Projects (CPs), each a prospective multi-site observational study. CP1 will carry out comprehensive longitudinal study of syndromic CS natural history measuring morphologic, neurocognitive, psychological and patient reported outcomes. CP2 will carry out observational comparative cohort study of 3 main types of surgical techniques and timing used to treat cranial vault constriction and increased intracranial pressure in the index operation, and the different surgical techniques and timing used to treat midface dysmorphologies in syndromic CS. In addition, we will operationalize 3 Cores to fulfill the multi-faceted mission of ACT to advance syndromic CS rare disease studies. The Administrative Core will provide an organizational nucleus for committee meetings, compliance oversight, patient registry of medical information, data, analyses, and samples; and communication within ACT and among Rare Diseases Clinical Research Network (RDCRN)-wide activities. The Pilot/Feasibility Governance Core will identify, recruit, vet NIH policies and launch pilot projects that leverage ACT RDC to study key problems in syndromic CS. The Career Enhancement Core will develop clinical research training, team integration, and professional development programs. The near-term deliverable of ACT will be to assemble the infrastructure and personnel to carry out the prospective multi-site studies that will yield the highest-level clinical evidence to inform future comparative studies and clinical treatment standards. The long-term impact of ACT is to significantly improve the health of children with CS through establishing best clinical practices, patient advocacy, piloting novel studies and training the next generation of craniofacial clinicians through ACT and RDCRN.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY/ABSTRACT Acute respiratory distress syndrome (ARDS) is characterized by acute onset of diffuse, bilateral pulmonary edema and severe hypoxemia not fully explained by cardiac failure. ARDS affects nearly 45,000 children in the United States annually, representing 10% of mechanically ventilated children in pediatric intensive care units (PICUs), with an associated mortality rate of up to 20%. There are no specific pharmacological therapies for ARDS, and supportive care remains the mainstay of treatment. In children, a lack of therapies is further compounded by uncertainty in management, as guidelines are extrapolated from adult ARDS, with uncertain applicability. However, pediatric ARDS possesses a distinct epidemiologic and outcome profile, necessitating studies specific to this population. Lung-protective ventilation with lower tidal volumes and driving pressures (defined as plateau pressure minus positive end-expiratory pressure) is the backbone of ventilation strategies in adults, with variable adoption in pediatrics. However, pre-clinical and observational clinical data suggest that the tidal volume and driving pressure limits extrapolated from adults are too restrictive for children. As lower tidal volumes and driving pressures are associated with worse oxygenation and ventilation, overly restrictive lung-protective ventilation may contribute to prolonged ventilation via worse gas exchange in pediatrics with no improvement in outcomes. In a re-analysis of adult ARDS cohorts, our group demonstrated that driving pressure is the most significant causal effector of mortality. By contrast, oxygenation (measured as PaO2/FIO2) was primarily implicated in children. Unfortunately, observational studies are intrinsically confounded, as higher tidal volumes and pressures are used in sicker children with greater baseline risk for poor outcomes. Furthermore, as pediatrics uses different ventilator modes, plateau pressures are rarely measured and ΔP (peak pressure minus positive end-expiratory pressure, a close approximate of driving pressure in pediatric modes) is substituted. Thus, a randomized trial comparing specific ventilation strategies is sorely needed in pediatric ARDS, with post-randomization ventilator protocols congruent with current pediatric practice. Herein we propose the Pediatric ARDS MAnagement (PARMA) trial, a phase 2A trial of high versus low ΔP ventilation in pediatric ARDS conducted at the Children’s Hospital of Philadelphia (CHOP). Additionally, we will use electrical impedance tomography (EIT) to quantify lung aeration. Given the low prevalence of pediatric ARDS and low mortality rates, PARMA will be analyzed in a Bayesian framework, utilizing a composite primary outcome that combines time to hypoxemia resolution and mortality. We specifically will test the efficacy of a high ΔP (25 cmH2O) versus low ΔP (15 cmH2O) ventilation on time to resolution of ARDS (alive and PaO2/FIO2 > 300), hypothesizing faster hypoxemia resolution (Aim 1), and improved lung aeration (Aim 2) with high ΔP. PARMA addresses a critical knowledge gap in pediatric mechanical ventilation, and will directly inform the design of a subsequent definitive trial of different ΔP strategies in pediatric ARDS.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Acute brain dysfunction (ABD) during sepsis occurs in 30% of children and is associated with a seven-fold increased risk of mortality. Survivors who experienced ABD during sepsis are more likely to have both functional morbidity and a reduction in health-related quality of life. However, there is a critical knowledge gap about the prevalence of new neurocognitive morbidities for sepsis survivors. With 100,000 children in the United States and 25 million children worldwide experiencing sepsis each year, new neurocognitive morbidities can have a lasting impact on their development. Our overarching goal is to identify the prevalence of new neurocognitive morbidities up to 12 months after hospital discharge and to determine if acute brain dysfunction during sepsis is a modifiable risk factor that can be targeted to improve these outcomes. This K23 proposal leverages the robust research infrastructure and resources at the Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania (UPENN). We propose a prospective longitudinal study of 180 school-aged sepsis survivors to evaluate the prevalence of new neurocognitive morbidity at 3 months after discharge, including the association of ABD during sepsis with new morbidity (Aim 1), the trajectory of neurocognitive recovery through 12 months for children with and without ABD during sepsis (Aim 2), and the association of high anticholinergic exposures during sepsis to ABD during sepsis (Aim 3). Neurocognitive status will be assessed at 1-, 3-, 6- and 12-months following discharge using two validated, caregiver-reported measures: PedsQL Cognitive Functioning Scale and the Behavior Rating Inventory of Executive Function. Additionally, in Aim 2, a subset of children will return for formal in-person, performance-based neuropsychological evaluation at 12 months to characterize neurocognitive function compared to age-matched normative data. In Aim 3, we will test the association between anticholinergic exposure with ABD during sepsis in the CHOP Sepsis Registry (6,500 patients) using a validated score to quantity the cumulative anticholinergic exposure. Many medications used to treat sepsis have unanticipated anticholinergic effects and high anticholinergic exposure has previously been associated with delirium (a form of ABD) and mortality in other pediatric critical illness. Identification of potential modifiable risk factors for ABD is imperative to target treatment strategies that can be implemented to improve outcomes. We have assembled a diverse, experienced, and multi-disciplinary mentorship and collaborative team that includes expertise in neurocritical care, long-term outcomes, neuropsychology, pediatric sepsis, and biostatistics. This team will guide the candidate through a rigorous training plan involving research conduct and career development training in neurocognitive domains and measurements, longitudinal study design with optimization of follow-up, and advanced biostatistical methods. Finally, the candidate will gain the necessary mentorship and training in clinical research and patient-centered outcomes to mature into an independent clinician-scientist studying neurocognitive outcomes secondary to ABD during sepsis.

NIH Research Projects · FY 2025 · 2025-08

Abstract Maintaining factor VIII (FVIII) in the normal range is critical for normal hemostasis. Deficiency of FVIII results in the bleeding disorder hemophilia A (HA) and excess FVIII confers prothrombotic risk. While the impact of serine protease cleavage on FVIII function has been extensively studied, the contribution of proteolysis on plasma FVIII levels is largely unexplored. Further, we demonstrated that the significance of proteolytic inactivation of activated FVIII (FVIIIa) has been underestimated. The overall objective of this proposal is to comprehensively investigate the proteolytic mechanisms that govern FVIII regulation before and after activation. Factor VIII circulates in plasma with its carrier protein von Willebrand factor (vWF). Prior to activation, FVIII levels in plasma are impacted by endothelial stimulation (where FVIII is synthesized and stored) and binding to vWF, which regulates FVIII clearance. We generated preliminary data in multiple model systems that support proteolysis of FVIII contributes, in part, to plasma FVIII concentration. A major goal of this application is to understand how proteolysis of FVIII or FVIII/vWF modulates plasma FVIII concentration, which will be investigated in Aim 1. Following activation, downregulation of FVIIIa function occurs through spontaneous dissociation of the A2-domain and cleavage by activated protein C (APC). Kinetic analysis suggests that A2 dissociation surpasses the rate of APC-mediated proteolysis leading to the general conclusion that APC minimally, if at all, contributes to FVIIIa inactivation. However, we demonstrated that a FVIII variant resistant to APC cleavage exhibits a 4-5 fold enhanced hemostatic effect and poses a greater prothrombotic risk in vivo compared to wild-type FVIII (FVIII-WT). Thus, our findings underscore the physiological relevance of APC inactivation of FVIIIa, challenging established mechanistic concepts entrenched in the field. This may be partly attributed to experimental constraints of studying FVIIIa inactivation in vitro. For example, purified system analysis of the kinetics of APC cleavage of FVIIIa have been predominantly studied on FVIII that underestimates the rate of APC cleavage of FVIIIa or the challenge of accurately modeling macromolecular interactions that impact FVIIIa inactivation. Another major objective is to comprehensively elucidate the mechanism underlying the proteolytic inactivation of FVIIIa that will be investigated in Aim 2. Our research will provide new mechanistic insight into FVIII biology, physiologic FVIIIa regulation and inform FVIII associated prothrombotic risk. These findings will directly inform the safety and efficacy of our and others’ work that aims to overcome current limitations of HA gene therapy limitations by using rationally engineered gain-of-function FVIII variants that bypass mechanisms of FVIIIa regulation.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The lung mesenchyme consists of heterogeneous cell types that are critical for lung development, architecture, and maintaining homeostasis in the mature organ. Alveoli mature during the final days of gestation and early postnatal life through a process called alveologenesis, which involves secondary septation—morphological changes in alveoli that create additional septa and increase the surface area for gas exchange. Postnatally, myofibroblasts rapidly expand and contract the lung tissue, facilitating secondary septation. However, the mechanisms regulating myofibroblast development, expansion, and transient existence remain poorly understood. In this proposal, we will leverage a novel murine model targeting neonatal alveolar myofibroblasts to test the hypothesis that these cells are specified by a morphogen gradient of bone morphogenetic protein (BMP) signaling in the embryonic lung. This signaling drives their clonal expansion in the postnatal lung, followed by the activation of intrinsic apoptotic pathways that lead to their decline after alveologenesis. Our specific aims for this proposal are (1) to utilize a novel lineage reporter mouse for alveolar myofibroblasts to study their expansion and activation of apoptotic pathways; (2) to investigate how the divergence of airway and alveolar myofibroblasts occurs around the embryonic endoderm in a BMP-dependent manner; and (3) to determine the necessity and sufficiency of alveolar myofibroblasts in driving secondary septation following neonatal lung injury. These studies will provide new insights into myofibroblast plasticity, molecular drivers of myofibroblast dynamics, and identify pathways that could enhance alveolar septation.

NIH Research Projects · FY 2025 · 2025-08

SUMMARY Medical care advances have extended life expectancy in individuals with Down Syndrome [DS]1, but substantial gaps in our understanding of the underpinnings, emergence, progression, and intersection of co- occurring conditions in DS hamper surveillance and management recommendations. A major obstacle to addressing these gaps is the limited availability of a trans-disciplinary, collaborative work force with expertise and practical knowledge of working in the clinical research setting with individuals with ability differences including persons with DS. The goal of this trans-disciplinary training program (PROGRAM TO ADVANCE RESEARCH AND TRANSDISCIPLINARY TRAINING IN THE CARE OF PERSONS WITH DOWN SYNDROME, PARTNERS) is to foster the development of a new generation of investigators from diverse disciplines and backgrounds to pursue research in youth and adults with DS. This program will pursue a “whole-person” curriculum that considers clinical, social, legal, ethical, and research issues and perspectives related to persons with DS. These efforts are intended to supplement ongoing training for health professional and graduate students, medical residents, post-doctoral fellows, and early-career investigators. To achieve this goal, training will include a week-long in-person short course at the Children's Hospital of Philadelphia and will be supplemented by on-line materials and a year-long, monthly one-hour virtual meetings and mentorship. The week-long course will consider 1) DS and its related co-occurring conditions, 2) ethical, social, and legal issues surrounding research with the vulnerable population of persons with DS, 3) engagement with patients with DS and caregivers of diverse backgrounds, 4) strategies for managing data (REDCap) and pursuing scientific rigor, and 5) special considerations surrounding data analyses and interpretation; when possible, hands-on experiences will be included. Additionally, 1) discussions with youth and adults with DS and their caregivers and 2) small group sessions to provide feedback on emerging and ongoing DS-specific research projects as well as career development will be included. Each presentation will highlight knowledge gaps in DS research and existing datasets (including the NIH INCLUDE Data Coordinating Center) that can be leveraged to address such gaps. The occurring disabilities, in their commitment faculty include 1) clinicians with expertise in care fo individuals with DS and their co- onditions, 2) clinica l researchers conducting research in youth and adults with DS or intellectual 3) experts in huma rights and disabilities, 4) established mentors and 5) physicians with expertise medical education as well as clinica research staff with hand-on experienc engaging individuals with DS and caregivers/support providers. Together these instructors have the varie expertise, resources, and to training the next generation of investigators to advance research in persons with DS. R25 PARTNERS r c n , l e d