Research Inst Nationwide Children'S Hosp

NIH Research Projects · FY 2026 · 2022-03

PROJECT SUMMARY/ABSTRACT Patent ductus arteriosus (PDA), the most common cardiovascular condition in preterm infants, is associated with mortality and harmful longer-term outcomes including chronic lung disease (CLD) and brain injury. Although treatment does not benefit all infants with PDA, likely due to spontaneous closure, treatment of some infants with symptomatic PDA is necessary. Medications are often used to close persistent preterm PDA in the initial four weeks postnatal, but fail to close the PDA in 1/3 of infants, in whom an intervention is the only remaining definitive closure option (failed pharmacological management). A treatment dilemma exists in the first postnatal month for the subset of infants with persistent, hemodynamically significant, and clinically symptomatic PDA (HSPDA) after postnatal week one following failed pharmacological management. Invasive, intrathoracic PDA surgery was tra- ditionally employed for infants with HSPDA, but associations between surgery and adverse neurodevelopment prompted widespread adoption of non-interventional, supportive treatment. This watchful-waiting approach avoids or delays procedure-related complications, but prolongs developing brain and lung exposure to PDA- related hemodynamics. Evidence is emerging that duration of HSPDA exposure is an important predictor of CLD and/or death. Percutaneous catheter-based closure (PPC) is a novel, minimally-invasive means of closing a HSPDA. A duct occluder (ADO-II AS) was recently approved (1/2019) by the US FDA for preterm infants weigh- ing ≥700 grams. However, the effectiveness of PPC in improving important neonatal outcomes relative to sup- portive (non-intervention) HSPDA management has never been evaluated via a randomized trial (RCT). The uncertainty is whether PPC should be performed early (days 7-30 postnatal) for all infants with HSDPA to prevent PDA-related complications or only rarely as a last resort following a prolonged trial of supportive management. The objective in this application is to determine if PPC improves cardiopulmonary and neurodevelopmental out- comes via a multicenter RCT comparing the two strategies. Aim 1 will determine the effect of PPC versus sup- portive treatment on ventilator-free days (VFDs) at 30 days post-randomization (non-survivors will be scored as having zero VFDs). Aim 2 will determine the effect of PPC versus supportive treatment on secondary cardiopul- monary, safety and neurodevelopmental outcomes. Aim 3 will evaluate whether neurodevelopment at 3-4 months corrected age is mediated by improved neurodevelopmental profiles at 34-36 weeks postmenstrual age. Aim 4 will evaluate potential effect modifiers of HDPSA (e.g., sex, race/ethnicity, gestational age, age at ran- domization) on VFDs and secondary outcomes. This trial will immediately advance the care of extremely preterm infants with HSPDA following failed medical management by identifying whether PPC or supportive treatment better improves cardiopulmonary and neurodevelopmental outcomes.

NIH Research Projects · FY 2026 · 2022-03

Abstract Worldwide, nearly 3 million children die each year from sepsis. Red blood cells (RBC) are transfused in ~50% of children with septic shock, with the intent to enhance oxygen delivery, help resolve shock, and prevent organ dysfunction. However, RBC transfusion has repeatedly been associated with adverse outcomes in critical illness, suggesting harm. For most children with septic shock we lack data to identify who should or should not be transfused. Interventional trials and RBC transfusion guidelines have used hemoglobin concentration alone to inform RBC transfusion decisions. However, this is likely not the best way to decide when to transfuse RBCs to a patient with shock. Our preliminary data in septic children suggest that hemodynamic measures better identify children who might benefit from RBC transfusion and that children with severe immune suppression may be at greater risks of transfusion-related harm. Lastly, our data show that RBC transfusion effects likely differ based on RBC unit collection, storage, and processing methods, and resultant quantities of soluble mediators. Together, these data support our hypothesis that physiologic and blood product factors will predict when children with septic shock will benefit from, or be harmed by, RBC transfusion. The overall goal of our research program is to develop a personalized-medicine approach to RBC transfusion in children with septic shock. Our objective for this proposal is to build decision support tools that can be used in future clinical trials to identify when children with septic shock should or should not be transfused with RBCs. Our proposal uses robust machine learning techniques that are designed to use a very large number of dynamic variables to define personalized treatment decisions that maximize clinical outcomes. With these methods, and an agnostic, data-driven approach, the resultant decision rules will be free of clinician bias and can consider a much wider array of clinical parameters than have traditionally been used in transfusion trials. We will conduct a multicenter prospective observational study of 660 children with septic shock to accomplish the following specific aims: Aim 1: Determine which clinical, hemodynamic, and blood product-specific factors should drive RBC transfusion decision-making in children with septic shock. Using data from the electronic medical record, we will use outcome-weighted learning to build dynamic transfusion algorithms to minimize predicted daily organ dysfunction (PELOD2 scores). Aim 2: Identify immune phenotypes that predict differential response to RBC transfusion in children with septic shock. We will collect serial blood samples from subjects to measure a validated panel of inflammatory and immune function biomarkers and test the hypothesis that outcomes related to RBC transfusion will differ based on pre-transfusion levels of biomarkers of inflammation and/or immune suppression. We expect our data to transform the design of interventional trials of data-driven RBC transfusion algorithms to shift the transfusion paradigm away from hemoglobin-based strategies and improve outcomes for critically ill septic children.

NIH Research Projects · FY 2025 · 2021-09

Project Summary/Abstract: Diabetes mellitus is associated with many complications, including increased infection risk. With diabetes, one of the most common sites of infection is the urinary tract. In people with diabetes, urinary tract infection (UTI) is more common and has worse outcomes. The mechanisms that predispose people with diabetes to UTI are not defined. A greater appreciation for the host defense mechanisms that protect the urinary tract from microbial insult is needed to develop new UTI prevention and treatment strategies. This application’s objective is to identify how insulin signaling regulates innate immune defenses in the bladder. Our published and supporting data demonstrate that bladder urothelial defenses are regulated by insulin-mediated targets, including peroxisome proliferator-activated receptor-γ (PPARγ), insulin receptor signaling, and histone deacetylase proteins. Specifically, our data suggest PPARγ activation and histone deacetylase inhibition enhance insulin signaling, strengthen the urothelial barrier, and enhance innate immunity, including the production of antimicrobial peptides and the urothelial barrier. In contrast, silencing urothelial insulin receptor expression increases UTI susceptibility. These data support our central hypothesis that insulin and insulin receptor signaling have key roles in activating innate immune responses and regulating UTI host defense. Expanding upon these findings, we propose a comprehensive analysis of insulin’s ability to regulate bladder urothelial defense mechanisms. Aim 1 will determine the effects of progressive insulin resistance and diabetes on the bladder’s antibacterial defenses. We will also investigate if activating PPARγ triggers insulin signaling to enhance immune defenses and reduce UTI susceptibility. Aim 2 will interrogate the impact of insulin receptor signaling on the bladder’s immune defenses and urothelial responses and repair to UTI. Aim 3 will define the effect of histone deacetylase proteins on insulin signaling and the bladder’s immune defenses. Our long-term research goal is to identify why people with diabetes have increased UTI risk and improve their care. By evaluating the role of insulin signaling in host defense, our expected outcomes may have profound influence on human health as they may develop insulin-signaling targets as new UTI therapeutics.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY/ABSTRACT Nephrotic syndrome is a leading cause of end stage kidney disease, which is the eighth leading cause of death in the United States. Thrombin injures podocytes and its inhibition reduces nephrotic-range proteinuria and podocyte injury, two key drivers of nephrotic syndrome progression toward end stage kidney disease. Thus, there is a critical need to discern the molecular mechanisms underlying thrombin-mediated podocyte injury without which, the development of targeted, safe, and effective therapies that slow or halt nephrotic syndrome progression is likely to remain limited. The overall objective of this proposal is to define molecular mechanisms underlying thrombin-dependent, protease-activated receptor-mediated podocyte injury and determine if inhibition of this signaling pathway reduces progression toward end stage kidney disease. The central hypothesis is that thrombin-mediated protease-activated receptor signaling is a modifiable driver of RhoA-dependent podocyte injury during nephrotic syndrome progression. This project will integrate methods from the podocyte and coagulation biology fields including: mouse and rat nephrotic syndrome models, coagulation factor knockdown and conditional protease-activated receptor knockout mice, innovative nanoparticle-mRNA overexpression of coagulation factors, repurposing of Food and Drug Administration approved direct oral anticoagulants to mitigate podocyte injury, a novel flow cytometry approach to quantitate podocyte injury, and molecular biology methods including bimolecular fluorescence complementation and bioluminescence resonance energy transfer in genetically modified podocyte cultures. These complementary methods will be used to investigate the pathophysiologic role of thrombin in podocyte injury and nephrotic syndrome progression toward end stage kidney disease. Our Aims are designed to (1) Reveal the prothrombinase that produces intraglomerular, podocytopathic thrombin to drive podocyte injury and nephrotic syndrome progression, (2) Test the ability of direct oral anticoagulant therapy as a novel method to reduce nephrotic syndrome progression, and (3) Discover the molecular mechanisms by which thrombin-mediated protease-activated receptor signaling stimulates RhoA- dependent podocyte injury. This project is directly responsive to the mission of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) which is to “…support medical research…on kidney…and hematologic diseases, to improve people’s health and quality of life.” In addition, this project directly addresses important research priorities described in the Kidney Research National Dialogue and key aspects of the Healthy People 2030 Chronic Kidney Disease objectives. Completion of the proposed project is expected to establish the mechanisms underlying thrombin-mediated podocyte injury and enable exploitation of existing, Food and Drug Administration approved, direct oral anticoagulants as novel therapeutics to slow or halt NS progression.

NIH Research Projects · FY 2025 · 2021-09

Project Summary/Abstract Genomic medicine is the discipline of interpreting genomic information about an individual as part of their clinical care, for diagnosis, prognosis, or therapeutic decision-making. Integral to the practice of genome interpretation is the collection of multiple lines of evidence from knowledgebases to support or refute the clinical significance of evaluated variants. Modern clinical variant knowledgebases maintain literature and variant coverage that is mostly non-overlapping. This diversity of content causes a known problem in genome interpretation: analysts tasked with assembling a clinical variant report choose to spend considerable time navigating multiple resources and collating evidence, or risk missing critical information by selectively evaluating fewer resources. The resulting effort needed for an analyst to clinically interpret a variant list is known as the interpretation bottleneck, for its rate-limiting role in the clinical evaluation of patient genomes. Data integrators from public and private genomic medicine organizations work to alleviate this bottleneck by developing integrative clinical interpretation applications for use by genome analysts. As new knowledgebases are created, each of these public and private data integrators is left with the task of designing and maintaining another interface for each new resource, leading to combinatorial growth of data harmonization effort across the entire system. This approach is not scalable. This project will enable a transition to a scalable, interoperable, and federated genomic data ecosystem from the data integrators and knowledgebases already in existence today. To build an interoperable network of knowledgebases will require development and validation of a computable knowledge framework for genomic medicine. The framework will require the drafting of modern genomic knowledge standards, and development of the tools and services needed to support the implementation of those standards. These objectives will be carried out through coordination of several research activities with the Variant Interpretation for Cancer Consortium, ClinGen, and the Global Alliance for Genomics and Health. Research will involve conceptualization of genomic knowledge as precise computable concepts, designing schema for those concepts, developing framework support tools, and building intuitive user applications to leverage these advances. As a result of this research, new knowledgebases implementing this framework become immediately accessible to existing applications, while new applications and workflows implementing this framework are immediately able to leverage a wide breadth of data sources. In addition to these immediate benefits, the creation of a standardized, federated knowledge network reduces barriers for developing new products, spurring innovation towards novel applications for research, education, and clinical decision support tools.

NIH Research Projects · FY 2025 · 2021-09

Abstract No Change

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY/ABSTRACT Congenital urinary tract obstruction (UTO) is a leading cause of chronic kidney disease and end stage renal disease in children. Current management strategies cannot prevent chronic kidney disease progression. Recently published data from my F32-funded postdoctoral studies identify renal urothelial remodeling as a protective adaptation to UTO. Both congenital and acquired UTO trigger the formation of Uroplakin (Upk) expressing urothelial cells (UC) that synthesize a bladder-like urothelial plaque. Depletion of urothelial plaque in mice with congenital UTO accelerates renal parenchymal loss, functional impairment, and death – attesting to key roles for Upk-UCs in preventing obstructive nephropathy. A greater understanding of renal urothelial development and repair may lead to therapies aimed at attenuating obstructive kidney disease. Fundamental knowledge gaps exist, however, in our understanding of the formation of Upk-UCs during development and UTO. I have recently demonstrated that Keratin 5 (K5)-expressing UCs differentiate into Upk-UCs during development and following UTO. This application takes direct aim at the hypothesis that K5-UCs are progenitors whose fate is governed by an intrinsic molecular program that varies over time and in response to injury. The anticipated outcome of this research is to establish molecular mechanisms that govern K5-UC progenitor activity, and to determine the contributions of K5-UC progenitors during development and following UTO. In Aim 1, I will investigate whether temporally restricted K5-UC progenitor activity is cell-intrinsic using organoid assays; examine the role of Notch signaling in the regulation of K5-UC fate; and define molecular programs that regulate urothelial development and repair. In Aim 2, I will investigate the significance of the K5-UCs by evaluating the impact of depletion and expansion of K5-UCs on urothelial development and repair during UTO. The studies proposed in this application will reveal the cellular and molecular basis of Upk-UC formation – with the hypothesis that K5-UCs form Upk-UCs in a Notch dependent manner. Successful completion of these aims will provide the foundation for the development of therapies that target K5-UCs for differentiation to attenuate obstructive kidney disease in patients with UTO. In fulfilling these Aims, I will develop critical skills in rare cell isolation, organoid development, signaling pathway analysis, bioinformatics, renal physiology and pathophysiology of obstructive nephropathy. Mastery of these skills, in combination with structured career development activities under the guidance of my mentors and research advisory team, will prepare me to successfully compete for R01 funding and launch my career as an independent scientist focused on developing therapies aimed at attenuating chronic kidney disease progression in children with UTO.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY/ABSTRACT – Nationwide Children’s Hospital Nationwide Children’s Hospital (54 pediatric ICU beds and 20 cardiothoracic ICU beds with a combined annual census of >3,500 patients) and our Ancillary Site, Rainbow Babies and Children’s Hospital (24 pediatric ICU beds with an annual census of >1,600 patients), will be strong assets to the 4th cycle of the Collaborative Pediatric Critical Care Research Network (CPCCRN). The overall aim of this proposal is to advance the field of pediatric critical care medicine through the collaborative development and execution of transformative studies that benefit critically ill children. As one of the current CPCCRN sites, we (Hall – PI, Yates – Co-I, Steel – RC) have consistently been leaders in subject enrollment and project development. Dr. Hall’s Immune Surveillance Laboratory (ISL) at the Abigail Wexner Research Institute at Nationwide Children’s Hospital has served a central role in the two interventional drug trials performed by the network this cycle. These trials using the immunostimulant drug GM-CSF for the reversal of critical illness-induced immune suppression, established the safety and feasibility of multi-center, real-time immune function monitoring and modulation in our hands and, along with the current cycle’s PHENOMS sepsis phenotyping study, led us directly to the proposed study, “Personalized Immunomodulation in Sepsis-induced MODS”. This study includes two distinct, embedded, double-blind, placebo-controlled, randomized clinical trials of immunomodulation that are tailored to each subject’s prospectively-tested immune phenotype. The ISL will provide highly standardized immune function and inflammation testing kits with which the network already has extensive experience. Subjects who are found to have severe immune suppression without severe inflammation will be allocated to the “GM-CSF for Reversal of Immunoparalysis in Sepsis-induced MODS (GRACE)-2” study where they will receive GM-CSF or placebo. Subjects with moderate to severe systemic inflammation will be allocated to the “Targeted Reversal of Inflammation in Pediatric Sepsis-induced MODS (TRIPS)” study in which subjects will be adaptively randomized to receive the anti-inflammatory drugs anakinra, tocilizumab, or placebo. This highly innovative approach is designed to ensure that the right subject receives the right immune care that matches their immunologic derangement. Our primary outcome, the cumulative PELOD-2 score over 28 days, will assess both ICU morbidity and mortality, and our secondary outcomes will assess long term morbidity and health-related quality of life. This project is an ideal platform for ancillary studies and will represent a transformative approach to sepsis care in children. Nationwide Children’s Hospital and Rainbow Babies and Children’s Hospital (Shein – PI, Slain – Co-I) are certain to be strong contributors and collaborators in the next cycle of CPCCRN and will help move our field forward through the generation of new, generalizable knowledge that will inform the treatment of critically ill children.

NIH Research Projects · FY 2025 · 2021-08

Project Summary/Abstract Autosomal dominant Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent muscular dystrophies, affecting 1 in 7,500 to 1 in 20,000 individuals. FSHD was formally classified as a major form of muscular dystrophy in 1954, but the pathogenic events leading to the disease have only recently started coming into focus. Today, it is now recognized that FSHD pathogenesis involves aberrant expression of the DUX4 gene, which encodes a myotoxic transcription factor. The emergence of DUX4 as a primary insult underlying FSHD represented a momentum shift in the field as it provided an important target for model development and therapy design. Indeed, as FSHD is currently untreatable, developing effective FSHD therapies is a critical need in the field. We hypothesized that an FSHD treatment should center on inhibiting toxic DUX4 expression in skeletal muscles. The objective of this proposal is to develop effective prospective FSHD therapies aimed at reducing or eliminating toxic DUX4 expression. To do this, we will use new cutting edge RNA silencing and RNA editing approaches for which technology emerged only within the last 2-3 years. These approaches only cut RNA and not DNA, and therefore pose no risk of permanent genome modification in host cells. Because these strategies are only newly emerged, they have never been tested in vivo using gene therapy approaches in an animal model of disease. We will do that here, and thus our proposal will provide first proof-of-principle for in vivo efficacy use of CRISPR-Cas13 and RNA editing technology. Specifically, in Aim 1 we will develop a new CRISPR/Cas13 gene therapy approach to cleave DUX4 mRNA before it can be made into protein. In Aim 2, we will develop RNA editing strategies that are designed to change the DUX4 transcript and render it incapable of producing toxic full- length forms of DUX4 protein. Finally, since these strategies are new and abundant off-target data are currently lacking, in Aim 3, we will assess the precision of RNA cleavage and editing approaches in human FSHD and control muscle cells. Upon completion of these Aims, we expect to produce pre-clinical data supporting the translation of new AAV-based RNA-targeted therapies for FSHD that can be ultimately used for translation toward our goal of clinical application. These data may also support the broader use of this technology for other genetic disorders.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY/ABSTRACT Orofacial clefts are among the most common congenital conditions in the U.S., occurring in approximately one in every 800 births. Children with cleft palate with or without cleft lip (CP±L) require interdisciplinary care from infancy through adulthood to improve speech, facial appearance, and physical and psychosocial health. Cleft- related treatments are burdensome for affected children and their families, and lifetime healthcare costs are estimated at nearly $700 million U.S. dollars annually. Treatment guidelines for children CP± L are primarily based on clinical expertise and provide wide latitude in the types and timing of assessments and interventions. Although the American Cleft Palate-Craniofacial Association recommends that all cleft teams include a psychosocial professional to address the mental health, quality of life, emotional, behavioral, and social needs of children with CP±L, the types of services vary greatly across centers. In addition, it remains unknown which children with CP±L are at greatest risk for poor health and psychosocial outcomes and which demographic (e.g., race), medical (e.g., cleft type, timing of diagnosis) and contextual factors (e.g., caregiver stress) contribute to these risks. Consequently, there is limited evidence to inform the provision of timely and effective interventions to support the long-term mental and physical health of children with CP±L and their families. This project will address this gap by partnering with The Cleft Palate Registry/Research Outcomes Network (CORNET; NIDCR R01DE02749). CORNET is the largest U.S. prospective study in cleft care to date and focuses on surgical and speech outcomes (pre-palate repair through 3 years of age) in a cohort of infants (N = 1514) with CP±L across 16 geographically diverse cleft centers. Leveraging CORNET and an interdisciplinary team of investigators with expertise in cleft care outcomes, we propose to evaluate psychosocial and health outcomes in young children with CP±L and their caregivers through two new studies: 1) a cross-sectional study [N = 500] of medical and demographic factors predictive of health and psychosocial outcomes; and 2) a longitudinal, mixed methods study [N = 200] to evaluate contextual predictors of psychosocial and health outcomes over time. Specific aims include: 1) examine associations between medical and demographic factors and health (growth/BMI) and psychosocial outcomes (child health-related quality of life, adjustment) in children ages 2-5 years enrolled in CORNET; 2) prospectively assess the impact of contextual risk and protective factors on health and psychosocial outcomes over time (at baseline/pre-palate surgery, 24 months, and 36 months of age); and 3) qualitatively evaluate caregiver perceptions of health and psychosocial outcomes and treatment experiences over time through narrative interviews with 40 caregivers. Data from this study will elucidate early predictors of poor and optimal outcome trajectories and inform both the type and timing of interventions to ensure that all children born with CP±L achieve optimal health and well-being.

NIH Research Projects · FY 2025 · 2021-07

PROJECT SUMMARY / ABSTRACT Pediatric long-segment airway defects are caused by congenital malformations or result from trauma, infection, or malignancy. Although rare, these defects are often fatal. There is currently no established surgical technique to repair long-segment tracheal defects and the reconstructive options remain heroic. Tissue engineering has the potential to replace failed tissue with a normal, living organ. Despite its potential, clinical outcomes of tissue engineered tracheal grafts (TETG) have been poor. The main barriers to translation of tracheal replacement are graft collapse and delayed epithelialization. We assessed the performance of decellularized TETG (dcTETG) in our mouse model of orthotopic tracheal replacement. We identified that decellularized TETG can regenerate, restoring a functional surface airway epithelium (SAE), however outcomes are limited due to graft collapse. Using resorbable biomaterials to stabilize dcTETG, we created a Composite TETG (CTETG). We hypothesize the CTETG can improve overall survival in long-segment tracheal replacement, attenuate graft collapse, promote extracellular matrix (ECM production) and SAE differentiation. To test this hypothesis, we will first assess how CTETG promotes ECM regeneration in the tracheal cartilage. In our first aim, we will implant dcTETG and CTETG in a mouse model of tracheal replacement and quantify ECM production and mechanical properties. Using a conditional knock-out of chondrocyte-mediated ECM production, we will then assess the impact on graft chondrocytes on ECM production. In our second aim, we will define how SAE differentiation is promoted by CTETG. We hypothesize that modification of graft dimensions with splinting reduces wall shear stress (WSS) resulting in improved epithelial differentiation. To test the effect of WSS on SAE differentiation, we will implant dcTETG and CTETG of normal and small diameter, thus increasing WSS by reducing graft radius. To quantify WSS, we will use computational fluid dynamics (CFD) to topographically map WSS through the TETG and correlate these values with quantitative immunofluorescence of neo-epithelium. Finally, we will validate CTETG performance in an ovine model of tracheal replacement in our third aim. Using routine radiographic and endoscopic surveillance, we will quantify animal survival, clinical manifestations, graft dimensions, and graft regeneration. This proposal advances the field of airway tissue engineering through the development of a composite tissue engineered tracheal graft and defining the mechanical factors contributing to graft regeneration.

NIH Research Projects · FY 2025 · 2021-07

Project Summary/Abstract Urinary tract infections (UTIs) are among the most frequent and severe infections worldwide. Uropathogenic Escherichia coli (UPEC) is the primary causative agent of UTI. UPEC ascension from the bladder (cystitis) to the kidneys results in pyelonephritis (PN). Despite prompt antibiotic treatment, patients with PN can develop acute kidney injury (AKI) and renal scarring, which can ultimately lead to end-stage renal disease. Currently, no therapy is available to prevent the long-term sequelae following PN. The innate immune system serves instrumental roles in controlling UTI and represents a potential therapeutic target for UTI prevention and treatment. However, mounting evidence argues that dysregulated innate immune responses can lead to persistent inflammation and renal scarring during PN. A greater understanding of the cellular immune mechanisms underlying the development of renal inflammation and kidney fibrosis during PN will lead to novel therapeutic strategies to treat UTI and prevent the development of detrimental sequelae. I have recently demonstrated that neutrophils and macrophages have distinct roles during PN pathogenesis. While neutrophils prevent widespread UPEC dissemination, macrophages promote pro-inflammatory and pro- fibrotic immune responses during PN. The overall objective of this proposal is to investigate the functional roles of neutrophils and macrophages in the development of kidney fibrosis and dysfunction after a PN episode. My central hypothesis is that neutrophils eradicate UPEC and prevent permanent kidney damage, while macro- phage-mediated inflammation drives kidney injury and renal scarring during PN. The specific aims during this K award will test the following hypotheses: 1) Neutrophils have a protective antimi- crobial function, while macrophages induce interstitial fibrosis and renal dysfunction during PN (Aim 1). 2) Mac- rophages exert pro-inflammatory and pro-fibrotic functions during PN, which contribute to renal inflammation, scarring, and reduced kidney function (Aim 2). 3) Neutrophil NOX2 limits bacterial dissemination during PN, whereas macrophage NOX2 promotes oxidative stress and kidney injury (Aim 3). The proposed research will use an innovative preclinical mouse model of APN that replicates the development of kidney fibrosis following UTI and bridges methodologies in the areas of immunology, microbiology, molecular biology, and nephrology. The expected outcomes from this proposal will reveal novel biological functions for macrophages and neutrophils during PN, and will identify new targets that may alleviate PN-mediated sequelae. This approach in combination with structured career development activities under the guidance of my mentors and research advisory team, will prepare me to successfully compete for R01 funding and launch my career as an independent scientist focused on resolving some of the most challenging obstacles in the treatment of UTI.

NIH Research Projects · FY 2025 · 2021-07

Project Summary The increasing pervasiveness of highly lethal fentanyl and fentanyl analogs in the illicit drug supply in the United States, including Ohio, has posed a substantial challenge for public health officials seeking interventions to reduce unintentional overdoses. Rapid fentanyl test strips, designed to test for the presence of fentanyl and some fentanyl analogs in urine samples, are increasingly being used off-label by people who use drugs to test illicit drugs for fentanyl before consumption. Recent research indicates that when people who use drugs receive a positive fentanyl test result, they are more likely to perform overdose risk reduction behaviors (e.g., using less of the drug). However, due to the emergent nature of this harm reduction strategy, peer- reviewed published research on this topic is very limited. We propose to test an intervention to provide fentanyl test strip education and distribution to people who use drugs in a subset of opioid overdose education and naloxone distribution sites in rural and urban counties in Ohio. The long-term goal of this research is the reduction of overdose-related morbidity and mortality in Ohio and nationally. The research objectives of this study are: 1) Determine the feasibility and acceptability of providing fentanyl test strip education and testing materials distribution in existing opioid overdose education and naloxone distribution programs; and 2) Determine if adding fentanyl test strip education and distribution to opioid overdose education and naloxone distribution programs decreases opioid overdose rates among people who use drugs. Using a two-arm cluster- randomized trial design, we will answer the research objectives by testing the following 3 specific aims: 1) Determine the perceived barriers and facilitating factors associated with incorporating fentanyl test strip education and distribution in existing opioid overdose education and naloxone distribution programs in rural and urban counties; 2) Test the hypothesis that people who use drugs who receive fentanyl test strip education and testing materials as part of an opioid overdose education and naloxone distribution program will have improved knowledge and self-efficacy regarding how to test drugs for fentanyl and strategies for lowering their risk of an opioid overdose; and 3) Test the hypothesis that individuals who receive fentanyl test strip education and testing materials as part of an opioid overdose education and naloxone distribution program will have a lower opioid overdose rate than individuals who receive opioid overdose education and naloxone distribution only (“usual practice”). Fentanyl test strip use is becoming more common, but research supporting the practice is limited. We will investigate the feasibility, acceptability, and associated benefits and harms of integrating fentanyl test strip education and distribution into existing opioid overdose education and naloxone distribution programs in rural and urban communities.

NIH Research Projects · FY 2026 · 2021-07

Project Summary The proposed project examines the effects of pubertal suppression treatment on the mental health of transgender adolescents over time. The physical changes brought on by puberty often amplify gender dysphoria in transgender youth. Administering gonadotropin releasing hormone agonists (GnRHa) is an effective means of suppressing puberty to provide transgender youth, their families, and health care teams more time to consider whether partially and/or fully irreversible treatments are indicated. Pubertal suppression is endorsed by the World Professional Association for Transgender Health and the Endocrine Society as standard of care. Preliminary reports suggest that treatment with GnRHa may confer mental health benefits for transgender youth. However, GnRHa may also disrupt puberty-signaled neural maturation in ways that can undermine mental health gains over time and impact quality of life in other ways. The overall impacts of GnRHa treatment have not been systematically studied. In order to probe these effects, this project focuses on the assessment of dimensional mental health and three neural systems that map onto the NIMH RDoC matrix: cognitive/emotional control, social cognition, and reward responsiveness. Existing literature documents marked maturation in these systems during normative adolescent development, and gonadal hormones are thought to contribute to this maturation. We will take a multimodal approach, in which self- and parent-report, standardized neuropsychological assessments, and neuroimaging methods are used to assess the effects of GnRHa treatment over a two-year study period. We will enroll 132 transgender adolescents across three sites: Nationwide Children’s Hospital; Children’s National Hospital; and Lurie Children’s Hospital. Half will be undergoing pubertal suppression with GnRHa and the other half will be transgender youth not undergoing treatment. Evaluating the impact of GnRHa treatment on mental health functioning as well as puberty-linked RDoC system maturation will clarify its potential protective and risk effects to support optimization and personalization of treatment protocols.

NIH Research Projects · FY 2025 · 2021-06

PROJECT SUMMARY While motor vehicle crash risk is 2-6 times higher for all drivers engaging in cellphone use, cellphone use while driving is most prevalent among young drivers (18-24 years). Young drivers have both the highest phone use while driving and the highest crash rate per capita among all ages, but they are understudied. Technological solutions, including cellphone-blocking apps and driving mode (e.g., Apple’s “Do Not Disturb While Driving”), may be promising, but research on effectiveness remains sparse. Our pilot R21 found that a commercial app is effective in reducing cellphone use while driving, but had insufficient power to examine high-risk driving events. Few studies have examined driving mode or compared driving mode with a commercial app in reducing phone use and high-risk driving events. Therefore, we propose an R01 with objective to conduct a randomized controlled trial to determine the effects of a cellphone app and a driving mode intervention in reducing cellphone use and high-risk driving events in drivers aged 18-24 years. We hypothesize that cellphone use and high-risk driving events can be substantially reduced if a cellphone app or driving mode is active. We also hypothesize that the driving mode is as effective as the app. The aims of this project are to estimate the effects of the phone app and driving mode interventions in reducing calling, texting, and handheld phone use (Primary Aim 1), determine the effects of the phone app and driving mode interventions in reducing high-risk driving events (Primary Aim 2), and pilot test the feasibility of tracking traffic violations and crashes using existing databases (Exploratory Aim 3). A prospective, randomized, parallel-group, three-arm trial will be conducted. A total of 1,200 young drivers will be randomized to receive: (1) a commercial app (active FleetSafer) that blocks handheld phone use while driving, but allows emergency calls and phone use after pressing the passenger button; (2) a driving mode (provided by the cellphone manufacturer or service provider) that blocks handheld phone use while driving, but allows emergency calls and manual override or (3) an inactive FleetSafer app that permits and tracks calls and texts (controls). Participants will be studied for six months (month 1: baseline, month 2-6: intervention). The outcomes will include: (1) calling and texting while driving tracked by FleetSafer, and (2) handheld phone use while driving and high-risk driving events captured by a video camera. We will estimate the effectiveness of the app and driving mode interventions in reducing calling, texting, and high-risk driving events. Guided by our preliminary R21, this study is innovative as we focus on novel technological approaches to address the epidemic of cellphone-related distracted driving. We will employ proven video capture methods to identify high-risk driving events and assess the contribution of cellphone use. This study is significant, because the findings will provide information regarding the effectiveness of cellphone-blocking apps and driving modes in reducing cellphone use and high-risk driving behaviors in teens and young adults.

NIH Research Projects · FY 2025 · 2021-02

Hypoplastic left heart syndrome (HLHS) is a severe type of congenital heart defects, which is characterized by the underdevelopment of left side of the heart. The clinical presentation of HLHS includes hypoplasia of the left ventricle and structural defects in mitral valves, aortic valve, and ascending aorta. HLHS newborns usually die within a week without surgical treatment. We and others have linked the pathogenic NOTCH1 mutations to HLHS and calcific aortic valve disease. It appears that abnormal NOTCH signaling interrupts the communication between myocardium and endocardium thus leads to incomplete growth of ventricular chamber. However, the mechanisms by which NOTCH1 mutations results in hypoplasia of the left ventricle are largely unknown due to limited models for studying HLHS. Genetically engineered animals are not capable of reproducing the clinical phenotypes in HLHS patients. Previous studies have focused on the structural and electrophysiological defects in cardiomyocytes from HLHS patient-derived induced pluripotent stem cells (iPSCs), which may not recapitulate the underlying non-cell autonomous scenarios in the hypoplastic ventricles. In this proposal, we hypothesize that NOTCH1-mediated myocardial-endocardial crosstalk is required for normal human ventricular cardiomyocyte differentiation, and NOTCH1 mutations leads to abnormal myocardial-endocardial interactions which cause the hypoplasia of ventricular cardiomyocytes in HLHS. We will employ an integrated stem cell model using HLHS and CRISPR genome-edited iPSCs to investigate how NOTCH1 mutations lead to abnormal myocardial- endocardial interactions in HLHS. We will design a novel co-culture platform using human iPSC-derived cardiomyocytes (iPSC-CMs) and endothelial cells (iPSC-ECs) with distinct NOTCH1 genetic composition to study the intercellular communication between endocardium and myocardium in both healthy and diseased conditions. In Specific Aim 1, we will investigate the cellular and molecular mechanisms by which endothelial NOTCH1 deficiency suppresses human ventricular cardiomyocyte differentiation and proliferation. In Specific Aim 2, we will determine how the crosstalk between myocardium and endocardium affects ventricular cardiomyocyte differentiation and proliferation by co-culture of human iPSC-CMs and iPSC-ECs. In Specific Aim 3, we will decipher the mechanisms by which NOTCH1 mutations results in the dysfunctional myocardial- endocardial interactions and contribute to hypoplasis of the left ventricle using genome-edited HLHS-iPSCs. The completion of this R01 project will have a major impact on the understanding of HLHS through interactions between endocardium and myocardium using clinically relevant and patient-derived cardiomyocytes and endothelial cells.

NIH Research Projects · FY 2025 · 2021-02

Summary: The exquisite specificity, amplitude, and quality of T cells govern tumor initiation, progression, and responses to therapy. Two of the most revolutionary and promising immunotherapies are the immune checkpoint blockade and the adoptive cell transfer, which are both dependent on the robust engagement of cytotoxic T effector (Teff) cells to control or eradicate cancer. A robust T cell-mediated anti-tumor response requires the coordination of nutrient and energy supplies with Teff cell expansion and function. However, the high metabolic demands of tumor cells compromise the function of Teff cells by competing for nutrients within the tumor micro-environment (TME). We propose that the critical barrier, which limits the patient’s response to immunotherapy, is the hostile metabolic microenvironment within tumors. We have previously shown that the transcription factors c-Myc and HIF1alpha are differentially required for driving the central carbon metabolic programs during T cell acti-vation and differentiation. We recently revealed that asparagine (Asn) is the most upregulated amino acid upon T cell activation, and its bioavailability represents a key metabolic node that governs the central carbon metab-olism and effector function in Teff cells. Some cancer cells solely rely on extracellular Asn to support growth and proliferation, representing a metabolic vulnerability of cancer. However, Teff cells can maintain an intracellular Asn pool for cell growth and function either through the uptake of extracellular Asn or through de novo biosyn-thesis of Asn, indicating a layer of metabolic plasticity of T cells. Enforced restriction of extracellular Asn rewires central carbon catabolic programs, leading to enhanced anti-tumor effector function in Teff cells. Moreover, these Teff cells are characterized by an enhanced ATF4 and Nrf2 signaling response. Hence, we hypothesize that modulation of Asn bioavailability can optimize carbon assimilation and integrate stress-response sig-naling pathways, enabling a robust anti-tumor response in metabolically restricted tumor microenviron-ments. To test our hypothesis, we propose to 1) decipher the reprogramming of central carbon metabolic path-ways and assess the impact of key metabolic steps on Teff cells in the context of Asn restriction; 2) determine the role of ATF4/Nrf2 axis in regulating the effector function of Teff cells; 3) target critical signaling and metabolic nodes to engineer central carbon catabolic programs, thus enhancing function and persistence of Teff cells, and 4) develop and test strategies to simultaneously exploit Asn dependence as a cancer cell metabolic vulnerability and maximize systemic anti-tumor immunity. Collectively, the completion of this project will reveal fundamental principles of the emerging connections between the tumor’s microenvironment, cell metabolism, and anti-tumor immunity. These studies are critical to developing novel approaches that improve clinical outcomes of cancer immunotherapy substantially.

NIH Research Projects · FY 2026 · 2021-02

Despite increased survival,1 over two-thirds of children with cancer experience late effects, such as secondary cancers, sensorimotor deficits, and neurocognitive impairment.2,3 Psychosocial late effects, particularly social isolation and victimization, difficulties forming and maintaining friendships, and emotional distress, are common for survivors of central nervous system (CNS) disease or those who receive CNS- directed therapy (e.g., cranial radiation, intrathecal chemotherapy).4-6 Unfortunately, interventions to improve outcomes have had limited success.7,8 So why don’t childhood cancer survivors have friends and feel happy? Our model posits that residual deficits in social cognition contribute to negative peer interactions and poor psychosocial outcomes in children with brain injury.10,11 However, most work has focused on adult survivors of pediatric cancer and not children diagnosed early in life (preschool). These young survivors may be at greatest risk for difficulties for several reasons. First, the peak onset of the most common pediatric cancers occurs before age 6.1 Second, their treatments have an especially harmful impact on brain development and a high rate of sensorimotor deficits.2,3 Third, children are treated up to 3 years and isolated at a critical time for social development. Fourth, parents are at risk for distress, which may impair their ability to buffer negative effects on their children.17,18 Thus, there is an urgent need to characterize psychosocial risk in children treated for early onset cancer and to evaluate the utility of our model to inform more effective, targeted interventions. Our long- term goal is to reduce morbidity and improve the well-being of children with cancer. The objective of this controlled, multi-site study is to identify predictors of friendships and emotional distress in young cancer survivors (i.e., diagnosed < age 6, >1 year off treatment). Using a rigorous matched control design, we will assess peer interactions and friendships in the elementary classrooms (i.e., grades 3-5) of 200 survivors. Individual and family functioning will be assessed during home visits with families of survivors and 200 matched classmates. We will identify deficits in social cognition and peer interactions, as well as environmental resources (e.g., parenting, school climate), that predict long-term psychosocial adjustment (i.e., friendships, distress). The rationale is that deficits in social cognition and peer interactions contribute to psychosocial risk, which could be mitigated by resources in the school and family environments. Aim 1. Compare the long-term psychosocial adjustment of young survivors to matched peers and identify group differences in social cognition and peer interactions that may predict poor adjustment. Aim 2. Identify specific social cognitive and peer interaction factors that account for psychosocial adjustment in young survivors. Aim 3. Identify environmental resources that protect psychosocial adjustment in young survivors. This research is significant as it will delineate early risk and protective factors that predict long-term adaptation for young survivors and leave us in a prime position to develop interventions that will improve survivorship care and prevent long-term morbidity.

NIH Research Projects · FY 2025 · 2020-12

PROJECT SUMMARY Asthma remains a significant healthcare burden for children and has a long-term impact on their development and health. Inhaled corticosteroids are key for managing asthmatic symptoms and disease progression. However, children with severe asthma are insensitive or resistant corticosteroid therapies, leading to the need for systemic use at high doses. Airway smooth muscle (ASM) is a key structural cell that regulates airway function and tone. In severe pediatric asthma, airway inflammation, hyperresponsiveness (AHR), and remodeling continues despite aggressive corticosteroid treatments. Yet the underlying biological mechanisms of corticosteroid insensitivity or resistance, particularly in ASM, remain undefined. Studies have reported associations between Th1 inflammation, as indicated by increased Th1 lymphocyte airway infiltration and IFNγ levels, and severe asthma. Additionally, we recently showed that combined exposure to IFNγ and TNFα uniquely induces corticosteroid resistance in ASM. These data have led us to hypothesize that IFNγ and TNFα interactions enable pro-inflammatory signaling pathways, notably NFκB and JAK/Stat1, to remain activated in the presence of corticosteroids. Via 2 Specific Aims, we will use novel mouse and human models of corticosteroid resistance to examine airway inflammation, hyperresponsiveness (AHR), and remodeling in ASM. Specific Aim 1 will test the hypothesis that IFNγ enhances airway hyperresponsiveness and remodeling in ASM during steroid resistant allergic airway inflammation. While Specific Aim 2 will test the hypothesis that combined exposure to IFNγ and TNFα opens chromatin structure, leading to corticosteroid resistance in human pediatric ASM. This proposal will involve using cellular, molecular, and bioinformatic approaches to understand how interactions between IFNγ and TNFα enhance Ca2+ regulatory mechanisms and transcriptional regulation in ASM. Furthermore, we will examine whether targeting the JAK/Stat pathway can improve corticosteroid sensitivity in ASM and improve airway function. These novel studies will expand the current understanding of how airway structural cells, such as ASM, develop corticosteroid resistance while also beginning to define mechanisms that mediate corticosteroid resistance in severe pediatric asthma.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY/ABSTRACT High Mobility Group Box 1 (HMGB1) is a 215-amino acid protein that plays multiple roles in humans. Intracellularly, HMGB1 is chromatin-associated and involved in virtually all types of DNA metabolism (e.g. replication, repair, recombination), primarily through its ability to bind with high affinity and specificity to various DNA structures. Extracellularly, HMGB1 is the prototypical damage-associated molecular pattern molecule (DAMP) with strong pro-inflammatory functions. Here, we have discovered, and will show, that endogenous HMGB1 has a heretofore unknown function in its ability to control bacteria that cause chronic and recurrent infections, which thereby contributes to the delicate balance of host-pathogen interactions. For bacteria to enter a chronic infection state, they must assume a community architecture called a biofilm, replete with a self-made extracellular matrix commonly composed of scaffolded extracellular DNA (eDNA) that is highly resistant to clearance by both the host immune system and antimicrobials. We have previously shown that this eDNA-dependent structure is stabilized by the DNABII family of bacterial proteins, that when added exogenously can drive free-living (planktonic) bacteria into a biofilm. Unlike these proteins, we show that HMGB1 destabilizes the eDNA structure and drives biofilm-resident bacteria into the planktonic, vulnerable state. The DNABII family and HMGB1 have similar DNA structure binding preferences in vitro despite a lack of primary amino acid sequence identity and secondary structure. We therefore hypothesize that despite their similar DNA structure binding preferences, these proteins facilitate converse reactions. Further, the fact that endogenous native HMGB1 steady state levels restrict, but fail to clear, chronic infections suggests a balance with HMGB1’s needed pro-inflammatory functions, i.e. release of bacteria from biofilms under strong inflammatory conditions could lead to sepsis. Herein, we will work under the scientific premise that eDNA-binding is essential for HMGB1 to disrupt bacterial biofilms and further, that it will be possible to separate its anti-biofilm activity from pro-inflammatory functions. Indeed, we have truncated HMGB1 to 97 amino acids, a form which still retains full anti-biofilm activity but without pro- inflammatory functions, thereby likely able to tip the host-pathogen interaction in favor of the host. Through the completion of 3 highly integrated specific aims, we will determine the capacity of this HMGB1 derived 97-mer to act as an anti-biofilm agent on biofilms formed by diverse human pathogens in vitro as well as biofilms within polymicrobial clinical samples, assayed ex-vivo (to determine the breadth of activity and support our overarching hypothesis; AIM 1), the anti-biofilm mechanism of action, through a process of DNA binding (AIM 2), and the therapeutic efficacy in two distinct animal models of biofilm infections (AIM 3).

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY Returning to drive after an mild traumatic brain injury (mTBI) is an immediate goal for many individuals as they return to their daily activities. However, evidence-based guidance about when those with mTBI can safely return to drive is lacking. While an mTBI can lead to significant cognitive and functional impairments, little is known about how mTBI affects driving, especially among teen drivers who are at an increased risk of both mTBI and motor vehicle collisions compared to other age groups. The long-term goal of this research is to evaluate the effects of mTBI on teen's driving performance and inform clinical practice guidelines on when teens can safely return to drive post-mTBI and under what conditions. We will test the following specific aims: Aim1: Characterize the trajectory of driving from acutely post-injury to symptom resolution among teen drivers with mTBI compared to healthy controls. Aim 2: Examine the effect of cognitive load on driving performance from acutely post-injury to symptom resolution in teen drivers with mTBI compared to healthy controls. Aim 3: Examine the extent to which differences in driving performance between teen drivers with and without mTBI, especially under increased cognitive load, are mediated by acute post-injury neurocognitive function. We will enroll 200 teen drivers ages 16-19 years from two study sites to increase racial, geographic, and socioeconomic diversity. Participants will include 100 teen drivers (50 per site) with a physician-confirmed isolated mTBI and 100 (50 per site) healthy controls with no history of TBI matched for age, sex, driving experience, and athlete status. Primary driving outcomes will be assessed using two innovative, complementary approaches: 1) high-fidelity driving simulators will be used to assess driving performance under 4 experimental study conditions at up to 9 time points: acutely post-injury (≤ 96 hours of injury) and then weekly until symptom resolution or 8 weeks post-injury, whichever occurs first; 2) self-report surveys of real- world driving behaviors will be completed by all participants daily. This is the first study to longitudinally evaluate teen driving after mTBI from acutely post-injury to symptom resolution. The study will fill critical gaps by providing evidence on how increased cognitive load and underlying neurocognitive function post-injury may impact driving performance. Our results will have a significant impact on clinical practice and guidelines by providing evidence to inform the development of clinical return to drive guidelines, and to help healthcare providers make informed clinical recommendations regarding when a teen can safely return to drive after mTBI.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY Motor vehicle collisions (MVCs) are the leading cause of death among teens in the United States. Teen drivers who have committed a traffic violation are at an even higher risk of MVC-related injuries and deaths compared to their counterparts without a traffic violation. While parent engagement interventions are an effective strategy to improve driving safety among teens of all risk profiles, these interventions have not been translated and tested among high- risk teen drivers such as those with a traffic violation. Furthermore, to date, no studies have examined the cost- effectiveness of interventions that promote safe teen driving practices. This proposed study addresses princi- pal gaps in teen driving research by translating an evidence-based universal intervention to a high-risk, yet un- derstudied, population of teen drivers with a traffic violation. This study will test, in a hybrid randomized controlled trial (RCT), the implementation, effectiveness and cost-effectiveness of the new intervention, Steering Teens Safe+ (STS+) that integrates in-vehicle driving feedback technology with parent communication training. Our long- term goal is to inform juvenile traffic courts’ adoption and implementation of evidence-based, cost-effective in- terventions into high-risk driving populations, and reduce MVCs and MVC-related injuries and deaths. Our three specific aims are: Aim 1: Determine if both intervention groups are superior to and more cost-effective than the control group on the outcomes of parent-teen communication, teens’ risky driving behaviors, traffic violation re- cidivism, and MVCs. Aim 2: Examine differences in intervention outcomes and cost-effectiveness by mode of deliv- ery (expert- vs. peer-delivered intervention). Aim 3: Identify the contextual factors associated with adoption and im- plementation of the intervention. We will recruit 290 parent-teen dyads from rural and urban juvenile traffic courts in Ohio following their mandatory court hearing. Each dyad will be comprised of a teen driver (ages 16 to 17) who has committed a moving violation and a parent/legal guardian. Enrolled dyads will be randomly assigned to 1 of 3 study groups: 1) Expert-delivered intervention, 2) Peer-delivered intervention, and 3) Control. Our central hypothesis is that the peer-delivered intervention is non-inferior (i.e., not much worse) to and more cost-effective than the ex- pert-delivered intervention and that both intervention groups are superior to the control. This project is significant because it represents a substantial step forward in national research focused on teen drivers, an area in which implementation research has been underrepresented. This study is innovative because it will recruit high-risk teen drivers through a unique partnership with rural and urban traffic courts, utilize cutting-edge in-vehicle driving feed- back technology, and test the mode of intervention delivery. The findings will facilitate the widespread adoption, implementation, and dissemination of STS+ in rural and urban settings and will have an impact on juvenile traf- fic courts’ practices and policies aimed to improve teen driving safety by reducing MVCs and MVC-related injuries and deaths.

NIH Research Projects · FY 2025 · 2020-09

Project Summary The Biopathology Center (BPC), part of the Abigail Wexner Research Institute of Nationwide Children’s Hospital, houses the Experimental Therapeutics Clinical Trials Network (ETCTN) Biospecimen Bank (Biobank). In this project, the ETCTN Biobank will expand to include other National Cancer Institute (NCI)-supported early-phase and experimental trial networks and investigators and be known as the Early-Phase and Experimental Clinical Trials (EET) Biobank. The NCI supports a clinical trials infrastructure to facilitate the early stages of development and evaluation of anti-cancer therapeutic agents. The EET Biobank will promote a collection of standardized biospecimens by procuring, processing, banking, and distributing high-quality human biospecimens from cancer patients who participate in NCI Phases 0, I, and II trials and other experimental therapeutic cancer trials. EET clinical trials will include a range of cancer types (i.e., breast, lung, colon, prostate, leukemia, melanoma, lymphoma, and multiple myeloma). These biospecimens will be linked to detailed biospecimen-related data (including information on surgical, pathological, and radiological reports), as well as comprehensive clinical data, including detailed drug information, treatment histories/outcomes, and cancer recurrence data. The EET Biobank will work closely with study teams and investigators to ensure that biospecimens are handled appropriately for planned and future research. In these efforts, the EET Biobank will continue to support the processing, banking, and distribution of biospecimens to the Cancer Immune Monitoring and Analysis Centers (CIMACs). Biospecimens will first be distributed to investigators for planned research designed to meet the objectives included in the clinical trial. After the objectives in the clinical trial are met, the EET Biobank will then distribute biospecimens to qualified investigators for projects approved by the Cancer Therapy Evaluation Program (CTEP). The EET Biobank seeks to promote outstanding research through the banking of high-quality, clinically annotated, cancer-related human biospecimens. To support this effort, the EET Biobank will manage these biospecimens under strict guidelines and standard operating procedures based on current best practices for biorepositories, current regulatory guidelines, and the latest laboratory technologies. The EET Biobank will benefit from the BPC’s experience in supporting biobanking efforts for several NCI-funded groups, including the NCTN (Children’s Oncology Group [COG], SWOG [formerly the Southwest Oncology Group], NRG Oncology) and the ETCTN. Coupled with a firm commitment to quality and to the integrity of its operations, the EET Biobank will be uniquely able to provide an accurate and effective resource of high-quality tumor and normal samples with associated clinical and epidemiologic information.

NIH Research Projects · FY 2024 · 2020-08

PROJECT SUMMARY/ABSTRACT One in 10 children in the U.S. is born preterm and consequently at high risk for long-term cognitive deficits and poor academic performance. While omega-3 docosahexaenoic fatty acid (DHA) dietary supplements have been touted to promote cognitive development in children born preterm, several recent studies have produced suggestive evidence of long-term adverse effects. The long-term goal is to ensure that interventions to help children born preterm succeed in school are safe and effective. The objective of this application is to determine the long-term effects of DHA supplementation on general cognitive ability, language, and executive function, and to examine genetic explanations for treatment effects, by continuing to follow the children from the fully blind, randomized, placebo-controlled trial called Omega Tots. The central hypothesis is that children born preterm who were randomized to 180 days of DHA at age 1 will exhibit poorer general cognitive ability, greater language deficits, and more impaired executive function at age 9-10 versus children randomized to placebo. The rationale for this project is that a careful examination of the long-term effects of DHA supplementation will offer valuable clarification about the appropriateness of DHA as an intervention to promote neurodevelopment among children born preterm. The central hypothesis will be tested by pursuing 2 specific aims: 1) Determine the long-term effect of DHA supplementation at age 1 year by comparing general cognitive ability, language, and multiple facets of executive function between the DHA and placebo arms at age 9-10. 2) Determine the role of variability in fatty acid metabolism genetics en masse on the effect of DHA supplementation on short and long-term outcomes, and further focus on 2 previously published FADS2 genetic variants. Under Aim 1, the approach will be an innovative prospective cohort of children from Omega Tots who will participate in detailed, in-person assessments at age 9-10 including evaluation by blind assessors and parent and teacher reports of outcomes. For Aim 2, SNP-based heritability methods will examine the role of fatty acid metabolism genes as measured in stored blood or saliva to explain observed treatment effects. The proposed research is innovative, in the applicant's opinion, because it represents a substantive departure from the status quo by conducting robust, multi-informant follow-up assessment of general cognitive development, language and executive function of a large child cohort who participated in a DHA supplementation trial, as well as integrating, for the first time ever, consideration of fatty acid metabolism genetics as possible explanatory factors for short and long-term adverse effects. The expected outcome is the determination of the effects of DHA supplementation at age 1 on cognitive ability, language, and multiple facets of executive function at age 9-10, and new insight into the role of specific genetic contributors as explanatory mechanisms for short and long-term effects. This contribution is expected to be significant because, if DHA supplementation has persistent, adverse effects on the neurodevelopment of US children born preterm, such findings would directly inform clinical recommendations about supplementation.

NIH Research Projects · FY 2024 · 2020-07

PROJECT SUMMARY: The lack of a clear understanding of Disorders of Deglutition (DD) in infants, i.e., impair- ments in eating, dysfunctional swallowing, and aerodigestive symptoms contributes to the rising prevalence and consequences of dehydration, malnutrition, high tube-feeding rates, neurodevelopmental deficits, and chronic hospital visits. These problems are common in the neonatal intensive care units (NICUs) graduates, particularly among those born prematurely or surviving after perinatal neuropathology. The estimated cost per neuropathol- ogy survivor varies from 350K to 500K US$, and prematurity contributes to a staggering, underestimated health care burden of over ~26 billion US$. This proposal addresses this knowledge deficit and sets the stage for early and safe-feeding intervention protocols in infants with DD by addressing both diagnostic- and rehabilitative-chal- lenges to alleviate infant eating concerns that are vital to improving aerodigestive health and neurodevelopment, which is our long-term goal. The central hypothesis is that characteristics of pharyngeal-, upper esophageal sphincter-, and esophageal-motility reflexes, and their contiguous and cross-systems relationships will differ in control and study infants. Our rationale is that identifying these sensory-motor biomarkers will clarify the specific pathophysiological changes contributing to DD in infants with neuropathology, so that inducible self-regulatory functions and recovery strategies can be developed. To accomplish this, novel, high-fidelity, video-integrated, high-resolution impedance manometry methods will be employed at the crib-side while monitoring physiological safety parameters in infants with DD but without neuropathology (control infants) and infants with DD and neu- ropathology (study infants). Our two specific aims are 1) to identify diagnostic biomarkers related to pharyngo- esophageal motility and airway safety which distinguish baseline and active swallowing mechanisms in control vs. study infants, and 2) to test the safety and effectiveness of targeted lingual nutritive stimulation in restoring pharyngo-esophageal motility and airway safety functions in tube-fed control and study infants during maturation. Applying robust state-of-the-art technological advances using video-integrated, high-resolution impedance ma- nometry at the crib-side, new mechanistic insights will be gained by examining the effects of targeted provocation on full column esophageal motility, and airway-digestive interactions. Completion of the proposed aims will 1) ad- vance data analysis algorithms and feeding protocols to facilitate transdisciplinary training, bio-feedback, and parent education; and 2) design a decision-making process to improve personalized nutritive therapies. This proposal addresses a critical need in neonatal gastroenterology by examining unique mechanisms and defining the basis for preventative and corrective therapies critical to addressing this challenging public health burden, which contributes to significant socio-economic burden, prolonged hospital stays, neurodevelopmental delays, or death. This will be accomplished by improving infant feeding, swallowing, airway, and digestive difficulties and advancing nutrition, growth, and long-term neurodevelopment, all within NIDDK's mission.