Research Inst Nationwide Children'S Hosp

NIH Research Projects · FY 2025 · 2023-04

PROJECT SUMMARY/ABSTRACT Clamping and cutting the umbilical cord is the most common intervention in humans, occurring in 140 million annual births. To maximize expediency (manage 3rd stage of labor, initiate neonatal resuscitation), early cord clamping (ECC) is performed within ~30 sec of delivery. Recently, evidence has emerged on the health benefits of delayed cord clamping (DCC, waiting ~1-2 min before clamping). Among term neonates, multiple randomized controlled trials (RCTs) have shown that DCC transfers blood from placentas to newborns, resulting in less iron- deficiency anemia and improved neurodevelopmental (neuromotor) outcomes through 4 years, than with ECC. Despite advantages for healthy newborns, in view of their exclusion from previous RCTs, the best approach to cord clamping in higher-risk pregnancies, notably those complicated by a fetal diagnosis of critical congenital heart disease (CCHD), remains uncertain. Although one might assume that the benefits of DCC in low-risk new- born populations would translate simply to CCHD neonates, unique anatomic and physiologic differences in neonates with CCHD suggest that risks of DCC in this subgroup may differ from risks in neonates without CCHD. Thus, a treatment dilemma exists on the optimal cord clamping practice at birth among CCHD neonates. The proposed study, entitled CORD-CHD (Clamp OR Delay in neonates with Congenital Heart Disease) trial will be the first RCT to determine the effectiveness of DCC vs. ECC on postnatal and neurodevelopmental outcomes of CCHD neonates. Our preliminary data demonstrate that, among CCHD neonates, DCC results in lower global rank scores (GRS), indicative of better health outcomes, than ECC. GRS is a validated composite measure, based upon the worst outcome post-cardiac surgery or catheterization and reflects the need for complex inten- sive care. Given the absence of high-quality data, maternal outcomes will also be determined. We will leverage a network of sites with requisite infrastructures, established guidelines with high adherence rates and treatment fidelity, and track records of collaboration. Aim 1 is to test the hypothesis that, among CCHD neonates, DCC results in lower GRS (better outcomes) post-cardiac surgery or catheterization, based on a higher win-odds (win- ratio adapted to include ties), than with ECC. Aim 2 is to test the hypothesis that, among neonates with CCHD, DCC will result in better neuromotor outcomes at 22-26mos postnatal, based on a joint test of a bivariate outcome (Developmental Assessment of Young Children Second Edition motor score and the Hammersmith Neonate Neurological Exam) than with ECC. As a secondary objective, we will test the hypothesis that among CCHD neonates improved neuromotor profiles (General Movement Assessment) at 3-4mos mediate improved neuro- motor outcomes at 22-26mos. Aim 3 is to precisely estimate the difference in the risk of maternal postpartum hemorrhage between DCC and ECC to evaluate safety among mothers who give birth to CCHD neonates. This trial will advance the care of CCHD neonates and provide the evidence called for by national and international organizations, creating a global impact on umbilical cord management among a vulnerable population.

NIH Research Projects · FY 2026 · 2023-04

Summary Heart disease in type 2 diabetes mellitus (T2DM) is directly related to the severity of coronary artery disease, which results in impaired coronary blood flow and increased risk of myocardial infarction (MI). T2DM patients are 2-4 times more likely to experience MI than non-diabetic patients. Although endothelial dysfunction and atherosclerosis are known to decrease coronary blood flow (CBF) in T2DM, the underlying mechanisms are not known. Adverse coronary resistance microvessel (CRM) remodeling is a critical mediator of T2DM-induced cardiovascular disease. Published studies from the Trask lab show that structural remodeling of CRMs occurs early in T2DM (db/db) mice and pigs with metabolic syndrome, leading to impaired CBF. While the mechanisms that govern CRM remodeling are unclear, our preliminary data point to impaired Jagged1 (Jag1)/Notch signaling. The Notch signaling pathway is known to facilitate communication between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs). We found that expression of Jag1 and Notch3 in CRMs of T2DM (db/db) mice is reduced, and that mice lacking EC-expressed Jag1, or Notch3-null mice had impaired CBF similar to T2DM (db/db) mice. Furthermore, EC-Jag1-deficient mice have evidence of inward CRM remodeling. In addition, we have shown a significant reduction in fenestrae in the of CRMs of diabetic mice and pigs, and in EC-Jag1- deficient mice, suggesting that heterocellular EC-VSMC communication at the myoendothelial junction (MEJ) maybe be disrupted in all models. Our recent studies identified Notch3 and Jag1 at the MEJ of normal CRMs. Based upon our collective preliminary data, our overall hypothesis is that reduced coronary blood flow in T2DM is driven by impaired Jag1/Notch signaling between ECs and VSMCs. We will test this hypothesis using an integrative approach, combining genetically-deficient mouse models, EC-VSMC co-culture techniques, single- cell transcriptomics, and transgenic/drug rescue experiments: The Specific Aims are: Aim1. Test the hypothesis that T2DM causes a disruption of Jag1/Notch signaling in CRMs and define this mechanism. Aim 2. Determine if aberrant Jag1/Notch signaling contributes to adverse coronary microvascular remodeling in T2DM using genetic and transcriptomic approaches. Aim 3. Test the hypothesis that activation of Jag1/Notch signaling can prevent and/or treat T2DM-induced coronary microvascular remodeling. These studies will be the first to demonstrate Notch signaling is central to CRM remodeling and impaired CBF, and that correction of this pathway may reverse adverse CRM remodeling and reduced CBF in T2DM.

NIH Research Projects · FY 2026 · 2023-03

Summary Hepatitis E virus (HEV) infection is a major cause of acute hepatitis worldwide and can often persist in immunocompromised individuals leading to significant morbidity and mortality. Currently, there are no FDA- approved vaccines or HEV-specific therapy in the U.S. Our long-term goal is to elucidate the molecular details of the HEV infectious cycle to aid in the rational design of HEV-specific prevention and treatment. HEV is an enterically transmitted positive-strand RNA virus with a unique life cycle: the virus is shed as naked particles into the feces but circulates as quasi-enveloped (eHEV) particles in the bloodstream. The dogma in the field has been that eHEV mediates virus spread in the infected host, and its biogenesis requires the viral ORF3 protein. It is proposed that ORF3 usurps the cellular endosomal sorting complex required for transport (ESCRT) machinery to acquire an envelope from the multivesicular bodies (MVBs). However, in cell culture, HEV can spread regardless of ORF3 expression, and clinical isolates bearing ORF3 start codon mutations have also been described. Thus, the release mechanism for HEV is likely to be more complex than previously thought. In HEV- infected polarized human hepatocyte cultures and human liver chimeric mice, ORF3 almost exclusively localizes to the apical/canalicular membrane. Moreover, our recently published work shows that ORF3 is required for apical but not the basolateral release of HEV from polarized human hepatoma cells. This application seeks to better define the mechanism for HEV release from polarized hepatocytes and to clarify the role of ORF3 in this process. Our central hypothesis is that ORF3 dictates apical release of HEV but is not required for basolateral release from polarized hepatocytes. We propose two specific aims to test this hypothesis using in vitro and in vivo models. Aim 1 will use a highly polarized human hepatoma cell line to elucidate the mechanism for HEV release from both the apical and basolateral sides of human hepatocytes. We will determine that ORF3 recruits HEV capsid and ESCRT components to the apical recycling endosomes (AREs)-derived transport vesicles to facilitate HEV envelopment and exit, and an ORF3-independent mechanism is responsible for HEV release at the basolateral surface that mediates virus spread. Aim 2 will investigate the HEV release mechanisms in a newly developed rat model of HEV infection. The role of ORF3, ESCRT, MVBs and AREs will be investigated using various viral mutants. The morphology and protein composition of HEV virions in the bloodstream will be characterized and compared to virions released from the apical and basolateral sides of polarized human hepatoma cells. The completion of this work will shed new light on the unusual HEV life cycle and clarify the role of ORF3 in HEV infection. The knowledge gained from this research will also have broad implications for hepatocyte biology and noncytolytic release mechanisms for both nonenveloped and enveloped viruses.

NIH Research Projects · FY 2026 · 2023-03

Project Summary PROJECT SUMMARY Although somatic mosaicism is a known cause of malformations of cortical development (MCD), it is still difficult to detect sparse somatic variants in patient tissue and study their molecular and functional effects. The long- term goal of this project is to unravel the cellular and molecular complexity of MCD and translate this knowledge into improved diagnostic and treatment opportunities for patients. The overall objectives in this application are to (i) improve somatic variant detection, (ii) identify transcriptional correlates of somatic variants, and (iii) test functional effects of somatic variants in relevant cell types. The central hypothesis is that somatic variants are enriched in particular cell lineages in MCD and that cell identity is an important determinant of a variant’s molecular and functional effects. The rationale for this project is that understanding somatic variation and its consequences at cell-type resolution will ultimately improve gene discovery for MCD and help advance the field toward targeted therapies for drug-resistant epilepsy associated with MCD. The central hypothesis will be tested by pursuing three specific aims: (1) Improve somatic variant detection in patients with focal cortical malformations, (2) Evaluate cell-type-specific transcriptional effects of somatic mutations, and (3) Functionally validate the cell-type-specific contribution of somatic mutations to disease features. Under the first aim, relevant cell types will be enriched from affected patient tissue and sequenced as a strategy to improve somatic variant detection. For the second aim, integrated single-nuclei genotyping and transcriptomic analyses of patient tissue will be used to evaluate gene expression signatures of somatic mosaicism. The third aim will leverage a novel transgenic mouse model of MCD to drive somatic variation in particular cell types and determine how cell identity contributes to specific components of disease. The research proposed in this application is innovative because it takes a new approach to gene discovery in MCD, leverages leading-edge techniques such as integrated single- nuclei genotyping/transcriptomics, and takes advantage of a unique mouse model generated by the applicant’s lab. The proposed research is significant because it is expected to yield new causal somatic variants for MCD and new knowledge of their molecular and functional effects in appropriate cellular contexts. Ultimately, such knowledge has the potential to provide new opportunities to develop or apply targeted treatments.

NIH Research Projects · FY 2026 · 2023-02

Abstract Respiratory syncytial virus (RSV) infection leads to 2.1 million outpatient visits and 58,000 hospitalizations for children under 5 years of age. In those 65 years of age or older, RSV accounts for an average of 177,000 hospitalizations and 14,000 deaths annually, with similar mortality rates to influenza. Human data suggest pre- existing atopy may have a protective effect on mortality and severity of influenza and SARS-CoV-2 infection, and mouse models have shown protection from influenza mediated mortality with pre-existing atopy; however, the mechanism of this protection remains unclear. Using the house dust mite model of atopy, we found being atopic before infection with mouse parainfluenza virus type-1 (Sendai virus; SeV, a murine virus closely related to RSV), prevented mortality to an otherwise lethal viral dose. This survival depended upon CD11c+ cells, which produced neureglin-1 (NRG1). NRG1 appears to protect airway epithelium from the viral insult. Two alarmins released in the house dust mite model, IL33 and TSLP, induced NRG1 production from CD11c+ cells. CD11c+ cells from atopic mice or exogenous NRG1 reduced viral replication in airway epithelial cells in vitro and NRG1 significantly reduced mortality in vivo. Based on our data, we propose the hypothesis that pre-existing atopy protects against respiratory viral induced mortality in an IL33-TSLP dependent process that drives CD11c+ cells to produce NRG1, which restores epithelial cell homeostasis and protects epithelial cells from viral infection. Using our mouse model and mouse and human airway epithelial cell cultures to test these hypotheses, we propose to: (I) Define the NRG1 producing cell(s) in atopic mice and determine the requirement for NRG1 in atopy mediated survival from normally lethal SeV infection. (II) Determine the effect of NRG1 on epithelial cell function and protection from a respiratory viral insult. Upon completion of this proposal, we will have identified and characterized the NRG1 producing cells in the atopic mouse lung, the requirement for these cells and NRG1 in mediating survival in SeV infected atopic mice, and the requirement for alarmins in the development of the NRG1 producing cells and subsequent survival from the viral infection. In addition, we will have mechanistically characterized the effect of NRG1 on epithelial cells and determined the potential for NRG1 as a therapeutic agent. These findings form the basis for future studies to explore therapeutic interventions to prevent mortality from respiratory viral infections, with great potential to change medical care for severe respiratory viral infections.

NIH Research Projects · FY 2026 · 2023-02

Summary: Properly allocating metabolic resources is crucial for mounting energetically costly T cell mediated-immune responses. In addition, cellular metabolic programs interact with cell-surface receptor signaling pathways by providing metabolites as ligands. This proposal aims to understand the role of γ-aminobutyric acid (GABA) in regulating T cell inflammation and explore the potential therapeutic value of targeting GABA in animal models of inflammatory and autoimmune diseases. An integrated analysis of the extracellular metabolome, stable isotope traced metabolic pathway analysis, and metabolic transcriptome revealed that GABA is one of the most abundant metabolites produced through glutamine and arginine catabolism in CD4+ T effector cells. Expressing 4-amino- butyrate aminotransferase (ABAT) funnels GABA as an anaplerotic substrate into the tricarboxylic acid cycle to maximize carbon allocation in promoting TH17 cell differentiation. By contrast, the absence of ABAT activities in iTreg cells enables GABA exporting to the extracellular environment and acting as an autocrine signaling metab- olite to suppress T cell inflammation. Accordingly, genetically or pharmacologically ablating ABAT activity in T cells suppresses inflammation in vivo. Conversely, genetically ablating GABA(A) receptor in T cells deteriorates inflammatory responses. Hence, we hypothesize that GABA functions as a metabolic and signaling gatekeeper in coordinating carbon assimilation and receptor signaling response to governing CD4 T effector cell proliferation and inflammatory response. The aims of this proposal are to 1) decipher the molecular and signaling mechanisms that control GABA metabolism in T cells; 2) determine the outcomes of modulating GABA metabolism and receptor signaling in regulating the effector function of T cells; 3) develop and test complementary enzymatic, genetic, and meta- bolic strategies to modulate inflammatory response and autoimmunity in animal models of multiple sclerosis and rheumatoid arthritis. Collectively, the expected outcomes of this project are significant as it will reveal the funda- mental principles of the emerging connections between cell metabolism, immune signaling, and T cell differenti- ation. These studies are critical to developing novel approaches and therapeutic interventions that improve clin- ical outcomes of inflammatory and autoimmune diseases.

NIH Research Projects · FY 2026 · 2023-02

Abstract Clinical effectiveness research (CER) plays a central role in research related to emergency medical services for children (EMSC). It is the conscientious use of the best available evidence in evaluating interventions, broadly defined as medical treatments, health policies, or practice patterns, which could lead to improvements in health care quality and patient outcomes. Observational data are more often used in the evaluation of healthcare systems or complex clinical practice than randomized controlled trials (RCTs), due to practical or ethical reasons. However, causal inference with observational data faces challenges: (1) Important covariates may be distributed differently between treatment options; (2) Conventional statistical analysis lacks control for unmeasured confounding. When the intervention is dichotomous, propensity score based adjustment is widely used to reduce the confounding bias introduced by observed covariates, through matching, stratification or weighting. Matching is a popular choice among researchers, as it creates data structures similar to RCTs, is easy to interpret, and robust to misspecifications in outcome modeling. But there is a critical methodological gap hindering the use of matching design when there are multiple (more than two) treatment options. This is due to the lack of good matching algorithms to generate well matched sets and the increased complexity of post-matching inference. Our overarching goal is to develop a statistically valid matching design (referred to as PMD) and subsequent causal inference procedures for use with complex observational healthcare databases, where there are multiple treatment arms or treatments over multiple time points. Specific aims: (1) Devise an innovative PMD for studies with multiple treatment arms or treatments over time; Develop causal inference strategies for PMD based on the potential outcome framework and sensitivity analysis strategies for assessing the unmeasured confounding effect; (2) Evaluate causal mortality impact of severe TBI (sTBI) patients who received trauma care at different type of trauma centers (PL1-level 1 pediatric, AL1-level 1 adult, and ML1-level 1 mixed trauma centers; PL2- level 2 pediatric, AL2-level 2 adult, and ML2-level 2 mixed trauma centers); (3) Assess the effectiveness of 4 Tier 1-2 medical management/therapies (ICP monitoring, head CT scan, cerebrospinal fluid drainage, decompressive craniectomy) on sTBI patient mortality; (4): Evaluate compliance with a Centers for Disease Control and Prevention (CDC) head CT guideline for mild TBI (mTBI) patients by different types of hospitals. This study is expected to fill a critical gap in EMSC research by extending the commonly used dichotomous matching design to complex observational studies with multiple treatment groups. This project is significant and our proposed methods are innovative as they include both observed confounding adjustment and unmeasured confounding assessment. We envision that this general-purpose methodology will be widely applicable and can benefit government agencies, policy makers, and social and health science researchers, where observational data are often utilized for comparative outcomes research and program/policy evaluation.

NIH Research Projects · FY 2026 · 2023-01

Abstract Duchenne muscular dystrophy (DMD) typically results from mutations in the DMD gene that disrupt the open reading frame, resulting in no dystrophin protein, whereas the milder Becker muscular dystrophy (BMD) typically results from mutations that allow expression of a partially functional dystrophin protein. This observation has led to the development of therapies intended to result in expression of internally-deleted, BMD-like dystrophin proteins. Despite the availability of four such commercial therapies for a subset of patients, and the transformative promise of microdystrophin gene therapies that are on the horizon, there are fundamental unanswered questions about the relationship of partial dystrophin expression to patient function—questions that bear on our ability to assess the benefits of therapies, to offer prognosis to families, and to guide approaches to retreatment in gene replacement therapies, among other issues. Furthermore, it will be critical to understand the distinctions between endogenous, lifelong expression of partially functional dystrophins, and therapeutic dystrophins delivered postnatally. Our long-term goal is to understand a fundamental question: How much dystrophin protein—and what kind of partially functional dystrophin, expressed at what time—is enough? Our objective in this project is two-fold. First, we seek to understand in finer detail the molecular parameters of dystrophin expression that result in phenotype amelioration. Second, we seek to develop methods for full-length dystrophin expression from the endogenous DMD gene, which is a possibility for a for a subset of patients, and has the potential for improved outcomes in comparison to microdystrophin. Our central hypothesis is that multiple mechanisms exist to account for variations in disease severity, and that understanding these mechanisms will lead to a better understanding of the durability and long-term benefits of dystrophin restoration therapies. Our rationale is that a detailed exploration of these mechanisms will lead to a better understanding of the long-term outcomes expected from novel gene therapies for DMD.

NIH Research Projects · FY 2026 · 2023-01

ABSTRACT This proposal addresses the nature of interferon (IFN)-based antiviral responses at the oral mucosal barrier, and the bacterial factors that impact their efficacy. IFNs are antiviral cytokines that are critical in limiting all aspects of viral infection. We found that Type III IFNs or IFN lambdas (IFN-λs) are preferentially expressed by oral epithelial cells, and IFN-λ-associated signaling confers robust, broad-spectrum, antiviral immunity at the oral mucosal barrier. Bacterial colonizers at barrier sites have the potential to modulate host susceptibility to viral infection. Consistent with this, we found that Porphyromonas gingivalis (Pg), which is associated with oral dysbiosis and periodontal disease, singularly and totally dampened all aspects of IFN signaling in response to viral agonists. The overall goal of this study is to characterize the effect of Pg-induced IFN-λ suppression on viral clearance and neutrophil function, as well as determine the relevance of IFN-λ suppression for Pg colonization. Our main hypothesis is that IFN-λ is preferentially induced at the oral mucosal barrier and confers antiviral immune protection without inducing inflammation. Further, we hypothesize that Pg disengages both homeostatic and inducible IFN-λ responses, thereby enhancing host susceptibility to oral viral infection and to chronic inflammation, as well as contributing to Pg persistence. These hypotheses will be tested in the following specific aims. Aim 1: Characterize the impact of Pg-mediated suppression of IFN-λ signaling on viral clearance in vivo. Aim 2: Determine the contribution of IFN-λ mediated regulation of neutrophil effector functions to tissue damage and persistent inflammation during oral viral infections. Aim3: Determine the role of inactivation of IFN signaling in Pg persistence during infection. This study will provide fundamental novel information on the role of Pg in the suppression of anti-microbial inflammatory responses at the oral mucosal barrier. Additionally, an increased understanding of the factors that provide antiviral resistance in the oral cavity is highly significant as a large number of viruses, including SARS-Cov2, can infect oral tissues and cause local and systemic disease.

NIH Research Projects · FY 2024 · 2022-11

Project Summary The overall goal of this project is to expand the knowledge on the genetic basis and molecular mechanisms of Prune Belly Syndrome (PBS), a severe human multi-system congenital urologic anomaly with muscle and connective tissue deficiencies. Hallmark clinical features of PBS include the triad of 1) wrinkled `prune' belly due to hypoplastic or absent abdominal wall skeletal musculature, 2) megacystis secondary to bladder smooth muscle pathology, and 3) bilateral undescended testes. We discovered three gain-of-function missense mutations in the X-linked gene filamin A (FLNA) causing syndromic and isolated PBS. FLNA is an abundant intracellular actin-crosslinking protein that functions as a crucial mechanosensor, transmitting force bidirectionally between actin and integrins as well as binding and regulating other modulatory transmembrane receptors or signaling molecules. FLNA regulates cell shape, adhesion, gene transcription, hypoxic responses, embryonic morphogenesis, and cell contraction. To assess the role of Flna mutations on mouse development and function, we will study our Flna gain-of- function mutant mice that have a highly penetrant PBS-like phenotype when exposed to gestational hypoxia (Aim 1). Using state-of-the-art structural and biochemical techniques, we will characterize mutant FLNA protein structure and the impact on binding partners (Aim 2). As the mouse-derived Flna gain-of-function bladder smooth muscle cells have a dysmorphic, dysfunctional cell phenotype, we will subcellularly and molecularly define their cell form and function when exposed to environmental stress and stimulants (Aim 3). This multidisciplinary expert team with unique scientific expertise and advanced molecular tool sets will unite to identify FLNA-based critical regulatory mechanisms modulating detrusor smooth muscle function and dysfunction leading to PBS. This work may fill an important gap in our understanding of FLNA signaling and yield greater mechanistic understanding of detrusor myogenesis and detrusor underactivity, integrating signaling pathways, creating animal models of PBS, and potentially impacting future management of detrusor underactivity by guiding future rational therapeutic designs.

NIH Research Projects · FY 2024 · 2022-11

Heart disease and heart failure remain the leading causes of morbidity and mortality worldwide. Adult mammalian heart demonstrates limited regenerative potential. Numerous measures, such as stimulating preexisting cardiomyocyte proliferation by activating cell cycle, have been attempted previously to induce heart regeneration, although only modest effects have been achieved to date. Adult cardiomyocytes need to undergo dedifferentiation first before proliferation, if not simultaneously. In fact, adult zebrafish heart regeneration is accomplished through both dedifferentiation and proliferation. Chromatin state and remodeling is often associated with numerous physiological or pathological processes including organ development, aging, and cancer. However, it is unclear whether epigenetics dictates cardiomyocyte proliferation capacity, or, whether harnessing epigenetics in adult cardiomyocytes stimulates proliferation. Through a comparative transcriptomic analysis of murine embryonic day (E) 14.5 hearts (proliferation active) and adult hearts (proliferation inert), we identified a number of chromatin remodeling factors including histone deacetylase 7 (HDAC7) that are enriched in E14.5 hearts but missing in adult hearts. HDAC7 belongs to Class II HDACs, which have specific tissue distributions and shuttle between the nucleus and cytoplasm in response to signals. Studies have shown that knockout of HDAC7 compromises vascular integrity during heart development, while overexpression of HDAC7 induces tumor growth and epithelial proliferation. However, the potential role of HDAC7 in cardiomyocyte proliferation is undetermined. In our preliminary studies, upon knocking down of HDAC7 in cultured neonatal mouse cardiomyocytes (NMCMs), we found that cardiomyocyte proliferation was significantly decreased. By contrast, overexpression of HDAC7 in NMCMs resulted in significant cardiomyocyte dedifferentiation and increased proliferation. Further, overexpression of HDAC7 in adult cardiomyocytes in vivo significantly induced cardiomyocyte proliferation and improved cardiac function after myocardial infarction. Based on these novel and exciting preliminary findings, we hypothesize that HDAC7 is both necessary for cardiomyocyte proliferation and sufficient to reactivate postnatal cardiomyocyte proliferative and regenerative potentials. Three aims are proposed to test our central hypothesis. Aim 1: To determine the mechanisms by which HDAC7 promotes cardiomyocyte proliferation; Aim 2: To determine whether HDAC7 is required for cardiomyocyte proliferation; Aim 3: To test whether HDAC7 overexpression promotes adult cardiomyocyte proliferation and improves heart function after myocardial injuries. We intend to achieve these goals by using a synergistic approach of mouse genetics, developmental and molecular biology, and biochemistry. Results of these experiments will establish a novel and rigorous therapeutic strategy for promoting heart regeneration and pave a new path to effective heart repair in humans.

NIH Research Projects · FY 2025 · 2022-09

Pain management is a top priority during pediatric burn dressing changes. Although virtual reality (VR) for pain management during burn care has been studied in clinical trials for more than 2 decades, there is still no evidence of the effectiveness of smartphone VR for pain management during the care transition from medical settings to at-home burn care. This study’s long-term goal is to use innovative, patient-centric smartphone VR to improve patient experience and outcomes. Based on our published findings that our innovative VR Pain Alleviation Tool (VR-PAT) could result in a clinically meaningful reduction in pain (47.1% overall pain reduction) among 90 pediatric burn patients treated at our hospital outpatient clinic, the overall objectives are to (i) determine VR-PAT effectiveness for pain management and opioid medication use reduction during at-home burn care, and (ii) to identify potential facilitators and barriers that could affect wide use of VR-PAT. The central hypothesis is that VR-PAT can induce clinically meaningful pain reduction (>30%) during repeated at-home burn dressing changes. The rationale is that a determination of the VR-PAT effectiveness at reducing pain and opioid medication use, safety, and patient/family engagement is likely to offer a strong scientific framework by which a smartphone VR can be implemented widely and easily by families at-home. Two specific aims : 1) Evaluate effectiveness of VR- PAT for pain management and opioid pain medication reduction during at-home burn care; 2) Examine continuous engagement of patients and caregivers with VR-PAT during repeated at-home burn dressing changes. A two-group randomized clinical trial will be implemented among a total of 200 pediatric burn patients (6-17 years old). Patients and caregivers from both the intervention group (VR-PAT) and control group (standard care) will complete their daily burn dressing changes at home. Overall pain and worst pain will be measured using a standardized pain Visual Analogue Scale (VAS) during each burn dressing change for 1 week. Area under the curve for child reported overall pain (AUC-VAS) and morphine equivalent total dose of pain medications (AUC-OC) will be integrated to calculate composite pain score intensity and opioid consumption (PIOC) score as the primary outcome for Aim 1. For Aim 2, adverse events, VR experience and engagement will be measured in the VR group to specifically address challenges in designing mHealth interventions that the U.S. National Academy of Medicine (NAM) identified as needing more research. This project is innovative because it not only tests an innovative smartphone VR to optimize patient’s experience and outcomes during at- home care but will also develop a novel composite pain assessment statistical method for broader burn research. The proposed research is significant because it is expected to provide strong scientific as well as practical justifications for implementing smartphone VR for pain management during at-home burn care. Ultimately, such knowledge has the potential of offering smartphone VR as an effective and safe non-pharmaceutical pain management approach during care transition from medical settings to at-home care by family caregivers.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT Infantile rhabdomyosarcoma (RMS) is a newly identified and poorly understood aggressive cancer with immature skeletal muscle properties that affects young children. Recent clinical sequencing efforts have identified a spectrum of likely biologically related gene fusions that genetically define infantile RMS: the most common being a fusion between two transcriptional co-activators with roles in normal muscle development, termed VGLL2- NCOA2. Although we know the defining oncogenic event, there are no therapies targeting the genetics of the disease. Thus, patients are treated with general chemotherapy, surgery, and radiation, often ineffectively or with harsh long-term side effects. There is a pressing need to understand the biology of infantile RMS, contextualize infantile RMS biology with other RMS sub-types, and leverage this information to delineate therapeutic targets. Progress is limited by a lack of animal models, cell lines, and PDXs to study the disease dynamics. My long-term goal is to integrate vertebrate zebrafish, mouse, cell culture models and patient samples to identify conserved genetic programs for RMS tumorigenesis and novel therapeutic strategies. Toward that end, this project’s main objective is to elucidate the underlying biology and therapeutic targets in fusion-oncogene driven infantile RMS. Our central hypothesis is that VGLL2-NCOA2 leverages normal developmental programs, including ARF6, to mediate infantile RMS tumorigenesis, and that targeting these pathways is a therapeutic opportunity. Our specific aims will address this hypothesis by: (Aim 1) Delineating VGLL2-NCOA2 structure-function requirements for tumorigenesis, (Aim 2) Establishing mechanisms of VGLL2-NCOA2 and ARF6 cooperation in rhabdomyosarcoma, and (Aim 3) Determining VGLL2-NCOA2 muscle lineage context and temporal prerequisites for tumorigenesis. Completing these studies at the interface of developmental and cancer biology will generate significant new knowledge regarding fusion-oncogene leveraging of developmental programs and will identify potential therapeutic targets. The proposed research is conceptually innovative because it leverages a cross-species comparative oncology approach to pinpoint the most important molecular drivers in a new disease, and it is experimentally innovative because it utilizes multiple new vertebrate (zebrafish and mouse) infantile RMS models developed by our group. Successful execution of this project will generate exciting data focused on delineating the basic biology of infantile rhabdomyosarcoma to directly impact and guide clinical care.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT As congenital heart disease (CHD) survivors enter adulthood, they have a greater risk for developing acquired cardiovascular complications (e.g., hypertension and coronary artery disease). These comorbidities are amenable to lifestyle changes, such as increasing physical activity, yet adolescence and young adulthood are when physical activity rates begin declining. The CHD Physical Activity Lifestyle intervention (CHD-PAL) targets transition-age CHD survivors, using an engaging face-to-face videoconferencing format that this theory- informed and tailored to the unique physiology and activity needs of each participant. The CHD-PAL videoconferencing sessions address elements of the Theory of Planned Behavior (TPB; i.e., attitudes, subjective norms, and perceived control for engaging in a behavior) and implements self-monitoring and goal- setting techniques. The CHD-PAL feasibility/preliminary efficacy trials indicated that CHD-PAL is feasible for AYAs and that CHD-PAL increases time spent in moderate-to-vigorous physical activity (MVPA) as compared to the control group for AYAs who engage in lower levels of physical activity. However, a larger trial is needed to determine the impact of CHD-PAL on MVPA, purported mechanisms (i.e., elements of TPB), and health outcomes among AYAs with CHD. The primary objective of the current study is to determine the impact of CHD-PAL on change in MVPA among 144 AYAs (ages 15-25) with moderate and complex forms of CHD who will be randomized to 1 of 2 arms: CHD-PAL or attention control (Control). CHD-PAL consists of a 20-week videoconferencing-administered physical activity intervention (9, 20- to 30-minute sessions; Fitbit® to self- monitor and set goals) with an interventionist (“coach”). Control participants will receive the same number and frequency of contacts with a coach using the same modality to discuss using the Fitbit without addressing the TPB hypothesized mechanisms or being directed to self-monitor or set goals. The primary study outcome is change in MVPA as measured by an accelerometer. Change in the TPB hypothesized mechanisms will be assessed as secondary outcomes and change in cardiorespiratory fitness (i.e., peak VO2 and METs) will be explored. Our specific aims are to (1) determine the impact of CHD-PAL on change in MVPA and examine effect durability, (2) explore change in the TPB mechanisms and their relevance to change MVPA, and (3) explore the impact of CHD-PAL on change in cardiorespiratory fitness. The current study is the next step in an iterative process to refine CHD-PAL before multisite assessment of longer-term health implications and cost effectiveness of the intervention for AYAs with CHD in a clinical setting. Ultimately, this research has the potential to improve cardiovascular outcomes for transition-aged CHD survivors, an understudied growing population in need, as well as other pediatric chronic conditions with cardiopulmonary risk.

NIH Research Projects · FY 2024 · 2022-09

Project Summary Cystic fibrosis (CF) is caused by mutations in a single gene called the cystic fibrosis transmembrane conductance regulator (CFTR), which codes for an ion channel that transports Cl- ions. CF affects many organs but lung failure caused by repeated respiratory infections is the leading cause of death. When CF was first described, most patients died as children. Therapeutic interventions that do not restore CFTR function still enabled patients to survive into adulthood. Recently developed small molecule modulators restore CFTR function modestly and have been shown to reduce pulmonary exacerbations. However, these therapies are expensive, have side- effects and cannot treat all CF patients. As a monogenic disease, CF has been the target of several in vivo gene therapy studies that aimed to restore CFTR function. However, these studies were unsuccessful due to challenges in delivery and immunity mediated against viral vectors. Ex-vivo gene therapy in which corrected airway stem cells are transplanted into patients have been proposed. However, these are limited by our failure to efficiently correct CFTR mutations in a readily accessible airway stem cell type. W e have identified the sinuses as a readily accessible source of sinus basal stem cells and optimized the use of Cas9 and adeno-associated virus (AAV) to gene edit these basal stem cells. We have corrected the most common CFTR mutation (F508del mutation) in >40% alleles. However, several other mutations which cannot be treated using current therapies remain. Moreover, the safety of gene editing using Cas9 and the long-term differentiation potential of edited sinus basal stem cells to regenerate the sinus and bronchial epithelia need to be characterized. Here, we propose to use Cas9/AAV to insert the CFTR cDNA with a truncated CD19 (tCD19) enrichment marker at exon 1 of the endogenous CFTR locus to achieve universal correction of CFTR mutations. We will characterize the safety of genome editing using next-generation sequencing and the differentiation potential of edited sinus basal stem cells using single-cell RNA seq and immunohistochemistry. Preliminary results show that we can obtain an enriched population of tCD19+ sinus basal stem cells after gene editing. These corrected sinus basal stem cells retain their differentiation potential to produce epithelial sheets that show >90% CFTR function (response to CFTR inhibitor or activator) relative to wild-type samples in an Ussing chamber electrophysiological assay. However, further work is needed to determine if the corrected sinus basal stem cells generate all the other airway cell types. Over the period of this grant, we will further validate the safety and efficacy of this platform and evaluate the long-term differentiation potential of these cells to generate all the cell types present in both the sinus and bronchial epithelia. These experiments are an important first step to optimize the autologous transplantation of edited airway stem cells to treat CF. The knowledge developed in this process can be applied to other airway diseases in the future.

NIH Research Projects · FY 2024 · 2022-08

PROJECT SUMMARY / ABSTRACT Bleeding disorders in women remain under-recognized and under-treated. Although expert guidelines recommend screening adolescents with heavy menstrual bleeding (HMB) for von Willebrand Disease (VWD), our team has identified that under-screening remains widespread. Recent advances in VWD screening include the validation of bleeding assessment tools (BATs), with the International Society of Thrombosis and Haemostasis BAT (ISTH-BAT) serving as the current standard. However, the reference range of the ISTH-BAT score for young women is unknown, and there is a lack of research examining the accuracy of BATs in primary care settings. Our team has also shown that iron deficiency is common in young women with HMB, and while point-of-care (POC) ferritin technology is newly available, its utility as a screening tool for VWD in women with HMB has not been evaluated. The primary objective of this R01 application is to compare the validity of three screening strategies to identify young women with HMB who have an underlying diagnosis of VWD: 1) BAT, 2) POC ferritin, and 3) combined BAT + POC ferritin. Our rationale for this research is that early diagnosis of VWD in women with HMB can alleviate morbidity and mortality by enabling health care providers to optimally manage HMB and develop care plans for future surgical events and childbirth, thus decreasing the incidence and severity of bleeding events. Building upon our expertise in BATs, VWD, and past success in the recruitment of young women for HMB studies, we will achieve our objectives through the following specific aims: 1) establish the reference range of the ISTH-BAT in a general population of post-menarchal females 10-20 years of age, 2) compare the validity of the following screening tools (BAT, ferritin, BAT+ferritin) in identifying young women with HMB and underlying VWD, and 3) assess the feasibility of a primary care VWD screening algorithm, as well as patient, caregiver, and clinician experience. Our study population will include ~1,800 post-menarchal females presenting for care at five primary care clinics. Participants will complete the BAT and POC ferritin during their clinical visit. Those meeting the study definition of HMB will undergo laboratory testing for VWD. We will collect feasibility measurements (i.e., participation rate, time to complete screening algorithm). We will perform semi- structured interviews with a subset of participants, parents, and health care providers to explore domains such as the acceptability, appropriateness, and impact of VWD screening on clinic workflows. Our central hypothesis is that BAT + ferritin will have higher specificity for VWD than BAT or POC ferritin alone. Our project is innovative because it shifts the study of young women with bleeding disorders from the status quo of specialized hematology centers to the primary care settings in which young women with HMB initially present. The studies proposed here will serve as a foundation for comparing a VWD primary care screening algorithm against standard of care in a prospective clinical trial to measure its effect on health outcomes such as initiation of HMB and iron deficiency treatment, specialty referral, laboratory screening for underlying bleeding disorders, and patient quality of life.

NIH Research Projects · FY 2025 · 2022-08

Suicide is a major and growing public health problem among youth in the United States. Integrating suicide prevention strategies as a core component of health care delivery and providing access to health services for individuals at risk for suicide is a primary goal of the National Action Alliance for Suicide Prevention (NAASP). Lack of prevention strategies universally assimilated into routine health care is an obstacle to achieving meaningful reductions in youth suicide. To address this problem, we propose to develop the Center for Accelerating Suicide Prevention in Real-world Settings (ASPIRES) to hasten the implementation of effective and scalable evidence-based interventions to reduce youth suicide. ASPIRES will focus on integrated programs of research that span the continuum of care from early identification in primary and specialty health care settings, to acute and transitional care, and back into the community as part of routine health care practice. The target population is youth at elevated risk for suicide, the majority of which are from lower socioeconomic households experiencing significant health disparities. The specific aims of ASPIRES include: (1) Create an infrastructure to foster innovative, transdisciplinary approaches to accelerate the implementation and utility of youth suicide prevention interventions in real-world settings; (2) Conduct integrated programs of high-impact research to improve risk detection and deploy innovative interventions that have strong potential for scalability and sustainability in real-world settings; (3) Characterize the implementation context to generate recommendations for contextually sensitive implementation strategies for varied healthcare settings; (4) Cultivate the next generation of emerging and advanced scholars from different academic backgrounds to conduct state-of-the-art suicide prevention research; (5) Coordinate a program of pilot studies that test the most promising ideas to accelerate innovations in practice-based youth suicide prevention; and (6) Communicate and disseminate center-related findings to key stakeholders and promote data sharing. The center’s planned portfolio of science includes integrated efforts promoting accelerated research across a continuum of health care settings that could not be accomplished using individual project mechanisms. The signature (R01-level) hybrid effectiveness-implementation project focuses on universal suicide risk screening and enhancing quality improvement in pediatric primary care settings. Three exploratory projects include: 1) testing an established intervention in a specialty care setting to address young children at high familial risk for suicidal behavior; 2) testing an evidence-based treatment alternative to inpatient hospitalization that targets family functioning to reduce youth suicidal behavior in an acute care setting; and 3) developing a technology-based intervention to promote lethal means restriction during the “high-risk” transitional care period following discharge from a psychiatric hospital. The project team is well-suited to run the proposed center with expertise from multiple disciplines and an extensive community-based stakeholder and patient network.

NIH Research Projects · FY 2025 · 2022-07

While studying mechanisms of metastasis in osteosarcoma, we discovered that individual tumor cells respond differently when exposed to the foreign lung environment. Our early data suggest a hypothesis: that a small group of tumor cells survives the initial encounter with the lungs by stopping cell division and liberally producing inflammatory cytokines. The reaction of these rare “anchor” cells changes the surrounding lung tissue in ways that prepare it for colonization by rapidly proliferating tumor cells (“growth” cells). The cytokines released by anchor cells appear to alter the behavior of the surrounding lung cells, prompting a wound healing response. Unlike the normal wound healing response, however, this wound never heals. The environment created by this wound response is markedly different from that of the normal, healthy lung. Most importantly, cells and cytokines that make up the wound create an environment where growth cells not only survive, but proliferate rapidly, outcompeting the anchor cells to become the dominant subtype within the metastatic tumor. Here, we outline a research plan to test this hypothesis, rigorously evaluating our proposed mechanisms that establish the early metastatic niche and asking whether chemotherapy selectively kills growth cells, inadvertently leaving anchor cells intact to re-establish metastases once therapy ceases. The project is divided into three Aims. Aim 1 tests hypotheses relating to the mechanisms by which anchor cells create a fertile metastatic niche by activating the wound-healing machinery of the lung and facilitates identification of the lung-to-tumor signals that make this a fertile environment for growth cells. In the second Aim, we will determine how anchor and growth cells come about—whether distinct clones come pre-programmed for anchor or growth cell activity or whether dynamic developmental processes regulate maintenance of subpopulations within each tumor. Understanding this will be important for designing treatment regimens that maintain efficacy while minimizing toxicity. Finally, we will evaluate the use of pharmacologic inhibitors that target anchor cells directly or indirectly to see if these can augment the effects of conventional therapies and overcome resistance and relapse. By identifying agents that selectively target anchor cells, we can develop combination regimens that target both groups of tumor cells, rendering resistant disease treatable. The cooperation between cancer cells with discrete behaviors has immediate implications for treatment and suggests a need to develop strategies that target both growth cells and anchor cells. This work could drive a paradigm shift that would revolutionize the care of patients with osteosarcoma.

NIH Research Projects · FY 2025 · 2022-06

PROJECT TITLE Epidemiologic and Machine Learning Approaches to Frame Suicide Prevention Strategies Among Juvenile Justice Youth PROJECT SUMMARY / ABSTRACT Suicide is the second leading cause of death among youth aged 10-24 years in the U.S. One population found to have higher rates of suicidal behavior is youth incarcerated in the juvenile justice system. While progress has been made to reduce suicide for youth within juvenile correctional facilities, minimal consideration has been given to the risk for suicide in youth after incarceration. Previously incarcerated youth face numerous challenges reintegrating back into the community which can increase their risk for suicidal behavior. Estimates further suggest that 60% to 80% of youth involved in the justice system have significant mental health issues, and time spent in the system can exacerbate these conditions. The unmet need for mental health services by youth involved with the justice system is also a serious problem. Despite the recognized risk in this vulnerable population, evidence-based suicide prevention strategies are not integrated as part of routine reentry services for youth released from confinement. Even less is known about successful approaches to implement these strategies in juvenile justice systems. To address this gap, the proposed study uses innovative machine learning techniques to develop a risk prediction model incorporating youth characteristics and contextual factors associated with confinement (violence, victimization, segregation /isolation practices, health care services) to more accurately assess suicide risk in youth following incarcerated. Guided by these findings and a structured implementation science framework, this proposal will also conduct a pre-intervention assessment with key stakeholders to validate the utility of the machine learning model to inform intervention selection. Consideration will be given to potential facilitators and barriers to integrating the model into practice, and when, how, and where to intervene in the juvenile justice process. Achieving the aims of this proposed study will provide targeted intervention recommendations for suicide prevention among at-risk youth in the juvenile justice system. This proposal will also support the training of Dr. Ruch, who is devoted to a research career to reduce suicide in youth involved with justice system. Dr. Ruch’s training plan includes: (1) acquiring skills in machine learning and forecast modeling techniques to more accurately identify suicide risk and inform targeted preventions for youth in the justice system (2) enhancing knowledge of suicide prevention interventions, including health service systems to understand how health care practices and policies may facilitate or impede intervention for youth involved with the justice system and (3) strengthening skills in implementation science and advanced qualitative research methods to bridge the gap between research and practice. This line of inquiry will further the field of youth suicide research by introducing innovative technological approaches for suicide prevention in a significantly high-risk and underserved population, while also generating new insights about the distinct implementation challenges in the potentially resource constrained juvenile justice system.

NIH Research Projects · FY 2025 · 2022-06

PROJECT SUMMARY Tissue engineering provides a strategy for developing improved prosthetic biomaterials for use in congenital heart surgery. The overriding premise of our work is that tissue engineering can be used to regenerate autologous neotissue to repair or replace cardiovascular tissues that are congenitally malformed and that the tissue engineered constructs will perform better than prosthetic biomaterials. We developed a tissue engineered vascular graft (TEVG) specifically for use in congenital heart surgery and are currently performing a clinical trial evaluating its safety as an extracardiac conduit in the Fontan operation in which a vascular graft is used to connect the inferior vena cava (IVC) to the pulmonary artery. The broad, long term objective of this study is to translate this technology to the clinic for use in children with congenital heart disease. In order to obtain FDA approval, we must demonstrate the efficacy of the TEVG in a relevant preclinical animal model. The goal of this proposal is to evaluate the late term efficacy of TEVGs compared to PTFE grafts (the current clinical standard of care) using the ovine IVC vascular interposition graft model which we previously developed and validated for this purpose. To this end we propose three specific aims: In the first aim we will evaluate the physiological properties of the TEVG implanted in the ovine model between 9-10 years including compliance and vasoreactivity in addition to growth capacity. We will use intravascular ultrasound (IVUS) and invasive pressure monitoring to measure and compare the compliance of the TEVG and native IVC in age- and sex-matched sheep at various loading conditions. Next we will also use the IVUS and invasive pressure monitoring coupled with pharmacological testing to evaluate and compare the response of the TEVG and the native IVC to various pharmacological reagents at physiologically relevant doses. Finally, we will measure the change in size and geometry of the TEVG using serial 3D angiography to rule out aneurismal dilation and determine the functional growth capacity of the TEVG over the natural life span of the animals in our study. In our second aim we will use computed tomography to evaluate and compare the degree of ectopic calcification between TEVGs and PTFE grafts implanted in the ovine model. In the third aim we will evaluate and compare the hemodynamic performance of TEVGs to PTFE grafts implanted in the ovine model using 4D MRI and invasive hemodynamic monitoring. We will evaluate graft performance both at rest and during simulated stress using dobutamine stress testing then use the 4D flow and invasive hemodynamic pressure data to analyze the degree of disordered flow and associated energy loss within the grafts over cardiac and respiratory cycles at different hemodynamic states using computational fluid dynamics. The development of an improved TEVG with growth capacity has the potential to improve outcomes for children born with congenital heart disease.

NIH Research Projects · FY 2025 · 2022-06

PROJECT SUMMARY: Despite decades of research and growing public awareness, obesity affects Black children from low-income households disproportionately. This leads to disparities in obesity, cardiovascular disease, and several other co-morbidities in adulthood. Parents play an important role in obesity and cardiovascular disease prevention by shaping their child’s dietary and lifestyle behaviors early in life. However, Black parents from low-income households face numerous socioeconomic barriers. Parents from these communities seek tangible and practical lifestyle advice that can be implemented despite these barriers. While health care providers in the primary care setting are often tasked with providing this advice and empowering parents to implement lifestyle behavior change, they lack efficient, effective, culturally relevant, and engaging tools that can convey the intergenerational risk of obesity and cardiovascular disease and facilitate changes in lifestyle behaviors for all members of the family. My long term goal as an independent researcher is to improve child health outcomes through a career focused on reducing disparities in obesity and its comorbidities by designing family-centered, bio-behavioral interventions that evoke motivation to change, facilitate progression to actionable steps, and augment the maintenance of behavior change in families from low-income households and minority racial groups. The objective of this study is to develop, assess, and evaluate the acceptability, feasibility, and preliminary efficacy of two visual communication tools, that make use of a visual image (graphical versus illustrative) coupled with structured, culturally relevant, brief behavior change counseling, to convey CVD risk in Black parents with obesity who have a school-age child (6-11 years) and are from a low-income household. Specifically, this study aims to: (1) develop two visual communication tools via iterative focus groups with a) Black parents affected by obesity and b) primary care health care providers (HCPs); (2) determine the acceptability and feasibility of each visual communication tool during a simulated clinical encounter with Black parents and HCPs; and (3) determine the preliminary efficacy of the two visual communication tools on intention to change, perceived risk, knowledge of CVD risk, and short-term lifestyle behavior change in parents affected obesity compared to a standardized CVD risk score. My career development plan includes mentorship, formal coursework, and seminars in three focus areas: acquire skills in the development of visual communication tools to convey disease risk in a culturally relevant way; gain expertise in the clinical application of Motivational Interviewing through culturally relevant brief behavior change counseling; obtain competence in designing randomized controlled trials in family-based behavior change interventions. Results from this study will determine the most salient tool for this population which will be tested in a randomized controlled trial (R01) to determine the effect on lifestyle change in parents and their children.

NIH Research Projects · FY 2025 · 2022-05

Project Summary In Columbus Ohio’s Linden neighborhood, a historically segregated and disinvested community that has been devastated by decades of discriminatory race-based policies, infant mortality rates (IMR) are over 20 deaths per 1,000 live births (2%) with racial disparity ratios nearing three. Researchers have linked infant mortality and poor birth outcomes to maternal education, maternal experiences of stress and discrimination, pove rty, lack of access to healthy foods, lack of stable housing, and lack of access to prenatal/medical care. These risk factors are concentrated in majority minority neighborhoodsdue to historical and contemporary policies and practices rooted in structural racism (e.g., redlining, restrictive covenants, unfavorable zoning) that segregated both people and resources within communities. Linden is apredominately Black (63%) neighborhood with apopulation of 180,000 residents, of which approximately 45% live below the federal poverty level. Building on Nationwide Children’s Hospital’s (NCH) history of housing and community development through its Health Neighborhoods/Healthy Families community partnership on the city’s south side, NCH targeted re-investments in Linden are intended to improve housing quality and affordability, educational outcomes, access to healthcare, economic development, and social connections of residents. Informed by Life Course Theory (LCT), the objective of this proposal is to describe discriminatory policies influencing IMR and other maternal and child health experiences and outcomes across generations of Black women and importantly, demonstrate how community re-investment can be designed to target and rectify historic and contemporary structural racism and discrimination. Specifically, we aim to: (1) examine the experiences of multiple generations of Black women on the intersection of structural racism and reproductive health through the lens of historical and contemporary policies that effect communities; (2) conduct real-time formative evaluation of a targeted community investment initiative explicitly informed by the community’s history of structural racism; and (3) measure relative changes in short term infant and maternal health disparities in the target community and a statistically matched comparison geography.

NIH Research Projects · FY 2025 · 2022-05

Project Summary/Abstract Tonsillectomy, with or without adenoidectomy, is one of the most common surgical procedures in the United States, performed in more than 500,000 children annually. Tonsillectomies in children are most commonly performed for obstructive sleep disordered breathing (oSDB) or recurrent throat infection. The procedure improves oSDB symptoms, behavior, and quality of life in children with oSDB. It is also an effective treatment for children with severe recurrent tonsillitis. Nevertheless, many children experience a resolution of oSDB or mild tonsillar infections over time without having surgery. As such, tonsillectomy is subject to considerable variation in use and likely overuse in some groups. Evidence of potential overuse comes from the fact that the rate of tonsillectomy for recurrent throat infection is 2-3 times higher in rural white children than non-rural white children or either black or Hispanic children. In contrast, black and Hispanic children are far more likely than white children to have oSDB, but they are less likely to undergo tonsillectomy for this condition. It is likely that factors acting across multiple levels and domains drive these differences in tonsillectomy use, including factors acting at the patient/family, primary care provider (PCP), primary care practice, surgeon, and community levels. Although it is often supposed that the large sociodemographic and geographic variation seen in tonsillectomy use is largely explained by the varying opinions and preferences of providers, a large body of research suggests that patient knowledge, preferences, and expectations have as great or greater an impact than provider opinion on sociodemographic differences in rates of adult elective surgery. An understanding of the relative importance of patient/family, clinician, and community-level factors on racial/ethnic and geographic differences in pediatric tonsillectomy use is critically needed to maximize the benefits of this common surgical procedure in the pediatric population, while minimizing the unnecessary costs and complications with which it is associated. This mixed-methods project will identify and quantify the impact of factors acting across multiple levels and domains on racial/ethnic and geographic differences in pediatric tonsillectomy use. We will analyze healthcare utilization data from 2016-2019 on all publicly insured U.S. children. We will also conduct interviews with diverse samples of caregivers whose children have undergone tonsillectomy and with PCPs who refer for and otolaryngologists who perform tonsillectomy. Our findings will facilitate future improvements in the appropriateness of care of children being considered for tonsillectomy by informing the development and targeted dissemination of educational materials and shared decision-making tools that can be used by families and clinicians.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY/ABSTRACT Critical injury, including traumatic brain injury (TBI), remains one of the most common causes of morbidity and mortality in children. Despite efforts to develop pharmacotherapy for TBI, clinical trials have proven ineffective. Improvements in outcome have largely been due to improvements in medical care. One known complication of severe TBI is nosocomial infection; the incidence may be as high as 50% with mortality as high as 37%. Even in the absence of mortality, infection can lead to secondary brain injury and poor outcomes. One cause for post- injury nosocomial infections is a profound anti-inflammatory response known as immunoparalysis. TBI is strongly associated with immunoparalysis, and more recent data suggest that patients with TBI plus systemic injury (polytrauma) are even more prone to nosocomial infection than patients with either injury alone. One pathway by which this may occur is through a neurally-mediated mechanism known as the cholinergic anti-inflammatory pathway (CAIP), which involves signaling from the brain to splenic leukocytes via the splenic nerve. Attenuation of the CAIP is a potential method for reversing immunoparalysis, but other therapeutic targets include mechanism-independent immunomodulation. Unfortunately, there is little preclinical data examining the timeline for immune suppression following injury or how reversing post-injury immune suppression may affect the injured, recovering brain. The overall goal of this proposal is to develop immunomodulatory approaches to improve outcomes through safe restoration of immune function following critical injury in children. Our central hypothesis is that post-injury immune suppression is an important acute and chronic sequela of critical injury that can be attenuated without negatively impacting neurological outcomes. Experiments will involve using a clinically relevant combined injury model in juvenile rats: an experimentally induced TBI (controlled cortical impact) followed by hemorrhage induced by aspiration of blood from the femoral artery. To perform mechanism-specific attenuation of post-traumatic immunosuppression, we propose using splenic denervation to inhibit the CAIP. As splenic denervation is clinically not practical, we will also use pharmacotherapeutic agents to target the CAIP, including treatment with an α7 nicotinic receptor antagonist (memantine) or a beta-adrenergic antagonist (propranolol). We will also examine mechanism-independent pharmacotherapy of post-traumatic immune suppression using several immunostimulants (GM-CSF, rIL-7, INF ɣ, and anti-PD-1). Finally, as the long-term immunologic effects of severe traumatic injury are poorly understood, we will quantify the persistence of immunosuppressive effects of severe trauma in both our TBI/H model and in critically injured children. This career development award will generate further preliminary data and provide me with the necessary tools to obtain research independence and further funding in the area of pediatric neurotrauma.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY Pediatric cancers are generally quite different than adult cancers. For example, pediatric cancers exhibit unique oncogenic mechanisms, often reflective of aberrant developmental pathways. Thankfully, pediatric cancers are rare, and so the field must rely more strongly on cooperation, collaboration, and team-science to enable scientific progress and translation to the clinic. These realities, when combined with an insufficient research workforce, necessitate the development of a specifically-designed training program for pediatric oncology research. The overarching goal of the “Training Program in Basic and Translational Pediatric Oncology Research” is to provide postdoctoral and graduate student trainees with the requisite skills and expertise to develop into successful researchers focused on pediatric oncology. The Training Program is centered at the Abigail Wexner Research Institute at Nationwide Children’s Hospital, a world-renowned pediatric research hospital environment, and also leverages the strengths of The Ohio State University as an academic partner. Training includes strong mentorship in laboratory-based basic and translational research with newly-developed program-specific classwork, a broad palette of elective classwork, thoughtful training in career-development, team science, and relationship-building, and a clinical exposure plan to enable trainees to better appreciate the impact of their work on patients, families, and clinical teams. This new application seeks 6 training slots per year: 3 postdoctoral fellows and 3 graduate students. Trainees will generally spend 2 years in the Training Program. Postdoctoral trainees include Pediatric Heme/Onc/BMT MD (or MD/PhD) fellows and PhD (or MD/PhD) postdoctoral trainees. Graduate students are drawn from one of three graduate programs at The Ohio State University. A well-constructed trainee selection plan with a focus on diversity will ensure that the trainees who enter the Training Program have a high-likelihood for success in their ultimate entry into the field of pediatric cancer research. Finally, the Training Program includes a thoughtful logic model as a framework for program evaluation and continuous improvement cycles. The trainees, the mentors, and the Training Program itself will all be subjected to rigorous evaluation by our External and Internal Advisory Boards, consisting of individuals with key areas of expertise and focus, to ensure that the Training Program continues to evolve as training needs evolve. Overall, the Training Program in Basic and Translational Pediatric Oncology Research will expand highly- skilled pediatric oncology research and improve its collaborative potential to transform the care of children with cancer.