Ohio State University

NIH Research Projects · FY 2025 · 2014-08

Project Summary The proposed project is designed to advance our understanding of the development of category learning – a fundamental component of human intelligence. The proposed research is based on the hypothesis of multiple mechanisms sub-serving category learning: (a) an early developing mechanism (Mechanism1) is based on distributed attention and learning of within-category statistics and (b) later developing mechanism (Mechanism2) is based on selective attention to category-relevant information. Under Mechanism1, both relevant and less relevant dimensions are encoded, with learned representations being similar to the input stimulus structure (i.e., no learning-based representational change). Under Mechanism2, learned representations are different from input stimulus structure (we refer to this difference as learning-based representational change). Differences between Mechanism1 and Mechanism2 will transpire in many performance indicators, including attention allocation during learning, memory for features, shapes of learning curves, and accuracy and response times during training and testing. To test these hypotheses, we will conduct a series of experiments with 4-9-year-old children, and adults. The proposed project has the following Specific Aims. Specific Aim 1 is to conduct cross-sectional experiments and a longitudinal study examining mechanisms of category learning across development. Mechanism1 and Mechanism2 predict qualitatively different patterns of (1) attention allocation, categorization, and memory and (2) pre- and post-learning representations of categories. Specific Aim 2 is to apply computational models to data collected within Study 1 to identify the differences between the two hypothesized mechanisms of category learning. To achieve this goal, eye gaze and categorization and memory choice and response time data will be submitted to a suite of models capturing the hypothesized mechanisms. The proposed project will advance our understanding of links among critical aspects of typical cognitive development – selective attention, category learning, and memory.

NIH Research Projects · FY 2026 · 2014-03

PROJECT SUMMARY This project encompasses a multi-disciplinary team of basic scientists and clinical investigators dedicated to finding effective new therapies for patients with cancer. The Ohio State University Comprehensive Cancer Center (OSUCCC) is a comprehensive biomedical research campus with strong collaborations between experienced investigators from multiple oncologic disciplines and a vibrant pattern of discovery in the basic sciences. The OSUCCC has partnered with investigators at the University of Kentucky Markey Cancer Center (MCC), and the University of Utah Huntsman Cancer Institute (HCI), with whom they have had a strong relationships in the past. During the course of the award, the University of North Carolina (UNC), and Weill Cornell Medical (WCM) Center have been added to this consortium. These sites provide access to a large population of cancer patients that requires access to cancer clinical trials, many of whom reside in rural areas such as Appalachia or the American West. Under the leadership of Dr. William Carson, a surgeon with experience in immune therapy, and Translational Scientist Dr. Jennifer Woyach, a hematologic oncologist with skill in developing targeted therapies, this highly integrated team will explore novel therapeutic agents and treatment modalities, test new immune-based therapies, evaluate drug resistance mechanisms and explore the promise of genomic profiling of the cancer cell in order to develop more effective treatments for cancer. Notably, investigators in this experimental therapeutics program have been engaged in the conduct of phase I/II cancer studies for decades and are experienced in the design and conduct of correlative laboratory studies that can confirm the ability of a new drug to hit a specific molecular target and define a precise mechanism of action. Ohio State has collaborated extensively with other cancers centers dedicated to experimental therapeutics and will continue to do so within the context of the UM1 mechanism. The existence of strong laboratory bench research and pharmacology at each site will ensure that this group of translational investigators will continue to generate new concepts for submission within the NCI’s Experimental Therapeutics Clinical Trials Network (ETCTN) mechanism. A major goal of this consortium is to accrue over 100 patients per year to ETCTN studies and in this reporting period (10/01/2024-12/31/2025) 136 enrollments were recorded in a variety of cancer types. Since March 1st, 2020, this LAO has enrolled a total of 541 patients on ETCTN clinical studies. Of prime importance to this consortium is the education and training of early career investigators so that they are prepared to lead new translational studies. Indeed, many studies from this clinical research group have had an early career investigator as its leader. The experience, variety and cohesiveness of this research team combined with an unwavering commitment to ETCTN goals and principles will position it for continued success and innovation within this exciting clinical research mechanism.

NIH Research Projects · FY 2024 · 2013-08

Project Summary/ Abstract Dizziness in the emergency department (ED) is a common problem with many opportunities to implement efficient and evidenced-based practices. In DIZZTINCT-1, we developed and evaluated an implementation strategy that focused on increasing the performance of the Dix-Hallpike test (DHT) and canalith repositioning maneuver (CRM) in the ED by applying a benign paroxysmal positional vertigo (BPPV) -centric approach. We found that the strategy substantially increased DHT and CRM performance. In implementation fidelity interviews, providers who started using the DHT and CRM typically reported positive experiences, as reflect by the following quote: “He immediately felt better and walked out about 20 minutes later…it was awesome.” There was also a decrease in the use of head CTs, which are typically unnecessary with a BPPV-centric approach. Importantly, the decrease in head CTs did not lead to an increase in stroke misdiagnosis. DIZZTINCT-1, however, is limited in its potential to scale-up because it used investigator led education sessions, cash incentives, and did not have adequate engagement at nonacademic facilities. We learned about important revisions to the strategy that could increase generalizability and more routine provider use, particularly at nonacademic EDs. In DIZZTINCT-2, we will enhance and refine the strategy in four ways. First, the education sessions will be more generalizable because we will utilize local providers and an online CME program. Second, we will broaden the target providers to include nurses since we learned that nurses can play a major role in implementing the BPPV-centric approach. Third, we will respond to provider requests to expand the topic to include best practices for assessing stroke risk in dizziness visits and evidence-based diagnosis & management for vestibular neuritis. Expanding the topic could both increase exposures to the BPPV-centric resources and create more opportunities for best practices. Fourth, we will add patient-oriented resources, which also responds to providers’ requests and increases opportunities for best management. For DIZZTINCT- 2, we have partnered with Kaiser Permanente Southern California (KPSC) to test the strategy. KPSC has 12 EDs and ~40,000 annual dizziness visits. DIZZTINCT-2 will use a hybrid type 3 implementation-effectiveness trial of a stepped wedge randomized trial for the ED implementation strategy and an embedded randomized patient-level dissemination strategy. We have the following specific aims: Aim 1. To determine the impact of the revised and enhanced BPPV-centric implementation strategy on DHT/CRM performance in dizziness visits, at academic and nonacademic EDs, using a randomized stepped wedge design. Aim 2. To evaluate clinical outcomes associated with the implementation strategy using both a stepped wedge ED-level strategy and an embedded randomized clinical trial of a patient-level dissemination strategy. DIZZTINCT-2 is the first study to apply and evaluate a broad strategy to enhance optimal care in dizziness visits, to focus on nonacademic EDs, and to measure both implementation and patient outcomes.

NIH Research Projects · FY 2025 · 2013-07

Health development occurs across the lifespan and requires the use of the latest scientific knowledge to promote health and wellness. However, much of health science remains cross-sectional, narrowly focused, and lacking theoretical and methodological rigor. Over the past 9 years, the Ohio State University College of Nursing T32: Training in the Science of Health Development (TSHD), has provided predoctoral research training on health development for 19 predoctoral trainees and 1 postdoctoral fellow. We have demonstrated an ability to link trainees with research intensive mentors emphasizing health across the life course. In this renewal, we will continue to provide training in the science of health development expanded to strengthen training to promote healthier outcomes. The training program builds on the research strengths of the faculty at OSU in health development across the lifespan following an ecobiodevelopmental and life course health development model. Senior faculty mentors will guide predoctoral trainees and postdoctoral fellows in their studies, working closely with them to study influences on health development, and to use this knowledge to examine ways to optimize wellness outcomes within a health development framework. Training faculty are from multiple disciplines including nursing, human science, sociology, and medicine. Faculty have active research programs related to health development, causal mechanisms, and/or health and wellness outcomes. The specific aims of the training program are to: 1) recruit and retain qualified trainees pre- and postdoctoral trainees to conduct rigorous research in the science of health development with a focus on health promotion; 2) prepare trainees to develop and implement ethical health research in the science of health development across the lifespan; 3) provide scientific grounding and research experiences with highly qualified faculty and using extensively available resources to prepare trainees for research careers; and 4) increase the number and strengthen the scientific foundation of early career nurse scientists. We propose 9 predoctoral trainees (3 post-baccalaureate trainees and 6 post-master’s trainees with 3 and 2 years of support, respectively) and 4 postdoctoral fellows (each with 2 years of support). Achievement of specific aims will occur through a combination of didactic coursework, participation in ongoing faculty research, directed research residencies, mentorship, research seminars, independent research projects, grantsmanship training, publication and presentation, and research dissemination experiences. The TSHD program will further the National Institute of Nursing Research’s (NINR) goal to support research on the science of health and wellness, which is integral to NINR’s mission as well as across the NIH and numerous governmental and public agencies, all of whom have recognized that improving health and well-being is critical to reducing the burden of illness now and in the future.

NIH Research Projects · FY 2025 · 2013-04

PROJECT SUMMARY Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the United States and until recently was treated with chemoimmunotherapy at the time of disease related symptoms. Our team has been a major contributor to the introduction of the Bruton’s tyrosine kinase inhibitor ibrutinib and humbled by the results with this agent. Along with this work our recently completed R01 grant for which we seek renewal generated over 30 publications related to mechanism of action, resistance, and toxicities observed with ibrutinib. Additionally, we identified at least 5 new medications that either are in phase 1 clinical trials for resistant diease or will begin within the next year. The initial results of ibrutinib therapy in frontline CLL are promising with 92% of patients being progression free at 5 years and also having immune recovery that diminishes the frequency of infectious morbidity. However, the great majority of patients still have a small component of minimal residual disease (MRD) that requires continuous treatment resulting in long-term morbidity that impacts survivorship. When ibrutinib is discontinuation after extended treatment, it has been observed that some patients rapidly progress whereas other patients can have durable remissions off therapy. This suggests heterogeneity in the residual MRD tumor populations among CLL patients on extended BTKi. Aim 1 therefore focuses on utilizing novel techniques developed by the team to assess the clonal genomic, epigenetic, and biochemical changes in tumor cells from baseline to an extended time on treatment in responding patients treated with ibrutinib for 3 years. Additionally, we seek to understand differential immune statuses of patients with detectable compared to undetectable residual leukemia. Such studies will better guide combination studies in ibrutinib responsive patients to eliminate these residual cells and allow treatment discontinuation. Aim 2 will support a recently initiated phase 1b clinical trial with VAY-736 administered to patients who have been on ibrutinib for 1 year or more. VAY-736 is a BAFF- receptor directed antibody that blocks both BAFF signaling and also has enhanced antibody dependent cytotoxicity. We have demonstrated a novel BAFF-BCL3 signaling pathway that is active in CLL patients on ibrutinib and which may contribute later to resistance. Our pre-clinical and translational data support that VAY- 736 is synergistic with ibrutinib in the TCL1 mouse model of CLL, that it blocks BAFF signaling in CLL cells, and that NK cell function improves with ibrutinib therapy. This trial with ibrutinib followed by VAY-736 will be the first to give delayed antibody therapy when ibrutinib mediated immune recovery has occurred. If successful, this trial will provide justification to pursue future strategies allowing discontinuation of ibrutinib. Ultimately, our goal is to develop combination therapies, such as the one herein with ibrutinib and VAY-736 which produces durable complete remissions in a defined period of treatment leading to the ability to discontinue therapy and avoid the need for continuous long-term therapy.

NIH Research Projects · FY 2025 · 2011-08

PROJECT SUMMARY Chimeric antigen receptor T cells, or CAR T, are engineered white blood cells from patients that can destroy cancer. CAR T has the potential to cure several blood cancers, including leukemia and lymphoma. However, side effects of CAR T, called cytokine release syndrome (CRS) and neurotoxicity, can cause life-threatening problems with patients’ blood pressure, breathing, and brain. We developed a system to identify patients at risk of severe CRS and neurotoxicity by measuring two simple blood tests, CRP and ferritin, well before the CAR T are even given. We now propose a new approach to prevent CRS and neurotoxicity among those patients at greatest risk of CRS and neurotoxicity. This entails treating these high-risk patients with two prophylactic medications, dexamethasone and anakinra, before they show any signs of CAR T toxicity. In smaller studies, prophylactic dexamethasone or anakinra have been shown to be safe and offer strong signals of success in preventing CRS or neurotoxicity after CAR T. They have not yet been studied as a combination in this setting. Our proposed trial will be a large study of 182 patients who receive either dexamethasone plus anakinra or a placebo within the first few days of receiving CAR T. We will closely monitor patients for signs of CRS and/or neurotoxicity within the first 30 days of CAR T therapy, when this risk is the greatest. We will specifically investigate whether preventative dexamethasone and anakinra reduces the risk of such severe toxicity among high-risk patients and improve CAR T health outcomes. Work in the lab also suggests that preventing CRS and neurotoxicity will not only help to make CAR T therapy safer, but possibly more effective against cancer too. Research from our group shows that preventing CRS and neurotoxicity prevents the patient’s immune system from impairing CAR T function via a metabolite called arginine. We expect that successful completion of this project will facilitate safe CAR T therapy and possibly improve curative outcomes for treated cancer patients.

NIH Research Projects · FY 2025 · 2010-05

PROJECT SUMMARY Impulsive choices involve trade-offs between amount and delay by delivering smaller-sooner (SS) versus larger-later (LL) rewards. Impulsive choices occur when individuals frequently choose the SS when it is suboptimal to do so. Impulsive choices have been identified as a trans-disease process due to their association with a wide range of diseases and disorders including substance abuse, gambling, obesity, and attention-deficit/hyperactivity disorder. Impulsive choice can be both a pre-cursor to and product of maladaptive behaviors. The overarching goal of our research program is to identify the underlying mechanisms of impulsive choices and target those mechanisms using interventions to promote self-control. Time discrimination deficits and delay intolerance predicted stable individual differences in impulsive choice in the rat pre-clinical model. Poor timing and delay intolerance are purported endophenotypes in attention-deficit/hyperactivity disorder, providing important links with the rodent pre-clinical model. Time-based interventions have successfully moderated impulsive choices and improved time discrimination in rodents. Time-based interventions were most successful in promoting self-control in the most impulsive individuals. Most importantly, interventions that involved active waiting and that required time discrimination were most effective, suggesting a causal role for timing processes in the time-based interventions. Based on the previous results, the timing dysfunction model (TDM) proposes that impulsive choices arise from distorted timing processes, which may result in imprecise or inaccurate timing. Dysfunctional timing processes can lead to impulsive choices. Thus, the TDM proposes that timing processes are a primary candidate for therapeutic interventions. In addition, different neurobiological mechanisms may be responsible for the different contributions of specific timing processes to impulsive choices. Aim 1 will demonstrate distinct roles for specific timing processes in promoting self-control. This aim will confirm the TDM and pinpoint the mechanisms of time-based intervention effects on impulsive choices for future neuroscientific and translational research. Aim 2 will assess effects of the interventions on structural connectivity in cortico-striatal pathways, which are prime candidates for the time-based intervention effects on timing and impulsive choices. This aim will use diffusion tensor imaging (DTI) to measure structural connectivity. Aim 3 will use Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to depress activity in neurobiological pathways that are likely candidates for the time-based intervention effects. The three aims will identify specific cognitive and neural mechanisms of time-based interventions. This research is significant due the critical need for effective interventions to moderate impulsive choices. As a trans-disease process, impulsive choice has broad relevance for human health and is of significant relevance to the NIMH mission.

NIH Research Projects · FY 2024 · 2010-04

Project Summary/Abstract Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disorder characterized by profound fatigue, as well as immune and neurocognitive dysfunction. The etiologies and the drivers of ME/CFS remain unknown and there are no useful biomarkers for distinguishing the various subgroups. Our innovative studies over the ten previous years of this award have demonstrated that the deoxyuridine triphosphate nucleotidohydrolases (dUTPase) encoded by the Epstein-Barr virus (EBV) and more recently by the human herpesvirus 6 (HHV-6) have novel immunoregulatory and neuroregulatory functions that contribute to the pathophysiology observed in a subgroup of patients with ME/CFS. In this renewal application, we will continue our mechanistic studies to define the role that the EBV and HHV-6 dUTPases have in ME/CFS. Our overall hypothesis is that the increased abortive replication of EBV in plasmablasts/plasma cells in a subgroup of patients genetically susceptible to developing ME/CFS induces the increased synthesis and release of EBV dUTPase in exosomes. Ligation of EBV dUTPase-containing exosomes with TLR2 present on antigen- presenting cells (APCs) in the local microenvironment triggers the production of pro-inflammatory TH1 cytokines as well as activin A, which in turn stimulates the differentiation and proliferation of follicular helper T (TFH) cells, resulting in IL-21 production, which contributes to the immune dysfunction observed in these patients. Activin A is also a negative regulator of muscle growth and we are proposing that it alters the function of key enzymes in skeletal muscle leading to oxidative stress and low energy levels thus, contributing to the post-exertional fatigue characteristic of patients with ME/CFS. Trafficking of EBV dUTPase containing exosomes to the brain and TLR2 ligation on target cells results in microglia activation, disruption of the BBB, neuroinflammation and altered synaptic plasticity ultimately leading to cognitive impairment in these patients. Finally, these physiological effects of the EBV dUTPase are enhanced by chronic stress. The results of this study, will demonstrate that the EBV/HHV-6 dUTPases may act as drivers of the immune activation that occurs in ME/CFS. It may also identify EBV/HHV-6 dUTPase proteins as diagnostic biomarkers for identifying a subset of patients with ME/CFS. Finally, these studies will demonstrate that engagement of EBV/HHV-6 dUTPase proteins with TLR2 is essential for inducing neuroimmune dysfunction and thus, this interaction can be used as a novel target for the development of alternative therapeutic approaches.

NIH Research Projects · FY 2025 · 2010-02

Abstract Acute respiratory Distress Syndrome (ARDS) is a devastating disorder with a high mortality. Prior studies have focused mainly on its hyper-inflammatory state and yet anti-inflammatories for ARDS have not shown benefit. Mounting data suggest that immune suppression partakes in this disorder, the molecular mechanisms of which remain unclear. This application investigates a unique molecular model whereby we discovered an immunosuppressive protein called Fbxo24, that disposes of a key transcriptional protein, called ELF2, that is indispensable for critical cytoprotective functions of epithelia including innate immune function and preservation of cell proliferative activity. By targeting the C-terminal molecular signature present in Fbxo24, we designed, synthesized, and tested a novel small molecule Fbxo24 antagonist that restores ELF2 levels and innate immune responses in ARDS models. Our hypothesis is that Fbxo24, in part, mediates immunosuppression in experimental ARDS through ubiquitin-mediated degradation of ELF2, a protein essential for host epithelial cell innate immune and reparative responses. Hence, in this application we will first elucidate if Fbxo24 targets ELF2 for its ubiquitin-mediated proteolysis in experimental ARDS (Aim 1). We will specifically elucidate the biologic relevance of reduced Fbxo24 levels in preclinical models of ARDS as an immune suppressor using gene transfer in our Fbxo24 knockout mice and the mechanisms by which Fbxo24 mediates ELF2 ubiquitination and degradation in a site-specific manner. Next, we will optimize the pharmacologic design and test a novel small molecule that exhibits distinct, and yet complementary cytoprotective and innate immune properties in ARDS models (Aim 2). We will employ complementary murine and 2-hit models of immune suppression and an ex vivo isolated human lung system. These studies will provide a new pathobiologic model of epithelial injury that will serve as a platform for generating small molecule modulators that optimize cellular repair and modulate immunity in subjects with severe critical illness.

NIH Research Projects · FY 2025 · 2009-09

Sepsis is a devastating disorder and a leading cause of death in the US. Prior studies have focused mainly on its hyper-inflammatory state and yet anti-inflammatories for sepsis have not shown benefit. Mounting data suggest that immune suppression partakes in this disorder, the molecular mechanisms of which remain unclear. This application investigates a unique molecular model whereby we discovered an immunosuppressive protein called Fbxo24, that disposes of a mitochondrial synthetic protein, called DARS2, that is indispensable for critical cytoprotective functions of epithelia including innate immune function and preservation of cell proliferative activity. Our hypothesis is that Fbxo24, in part, mediates immunosuppression in experimental sepsis through ubiquitin-mediated degradation of DARS2, a secreted protein essential for host epithelial cell innate immune and reparative responses. Hence, in this application we will first elucidate if Fbxo24 targets DARS2 for its ubiquitin-mediated proteolysis in experimental sepsis (Aim 1). We will specifically elucidate the biologic relevance of reduced Fbxo24 levels in preclinical models of sepsis and organ injury as an immune suppressor using gene transfer in our Fbxo24 knockout mice and the mechanisms by which Fbxo24 mediates DARS2 ubiquitination and degradation in a site-specific manner. Next, we will determine if DAR2 is a crucial extracellular host defense protein in experimental sepsis (Aim 2). Here we will elucidate mechanistically how DARS2 is essential to maintain innate immune responses and cell proliferative activity through its regulated secretion from epithelia in vitro and in vivo. We will employ complementary murine and 2-hit models of immune suppression and an ex vivo isolated human lung system. These studies will provide a new pathobiologic model of immune dysregulation. This work serves as a platform for generating genetically engineered proteolytically stable DARS2 proteins that optimize epithelial cytoprotective functions in subjects with severe immune suppression in critical illness.

NIH Research Projects · FY 2026 · 2009-04

Project Summary The purpose of the training program outlined in this renewal application is to provide short-term intensive research experiences to professional veterinary medical students. The short-term goal is to stimulate an interest in the pursuit of hypothesis-based research that examines mechanisms, treatment, and prevention of disease. The long-term goal is to increase the number of veterinary students who embrace research as part of their career, with a focus that ranges from basic science/discovery to translational and epidemiological studies. These individuals fill a unique niche in the biomedical community, combining a comparative medical education with investigatory skills which are essential to advancing human and animal health. The program is based upon a research-intensive summer experience that is part of a larger Summer Research Program. First- and second-year veterinary students select mentors from graduate faculty with primary appointments in Ohio State’s Colleges of Veterinary Medicine, Medicine, Public Health, and Food, Agricultural and Environmental Sciences. Projects are developed in collaboration between student and mentor, assuring that the project reflects student interests and ideas. Development of the proposal and preliminary training activities occur prior to summer, and presentation and publication of research results are emphasized in the period following summer. The latter includes an end-of- summer research symposium, where students make oral presentations of research results, and poster/platform presentations at the CVM Research Day the following spring. The most meritorious projects are selected by an Executive Steering Committee based upon proposals submitted to and ranked by the CVM Council for Research. This approach maximizes quality of students and projects, with an average of 25 applications for 10 T35 positions. The faculty mentor: student ratio is 3.3:1, providing many training options that ensures a fit with student interests. Summer seminars emphasize science communication, commercialization and intellectual property, and career development. We have implemented a journal club that will now be led by a T35 co-director to reinforce concepts in scientific rigor and reproducibility. Topics reflect the breadth of summer projects and individual sessions will include moderation of student presentations by a faculty subject matter expert. Program success is reflected in significant increases in the number of former T35 trainees in research-oriented careers relative to national employment data for veterinarians, representing a greater than two-fold increase in academic, government and industry employment. This reflects leading indicators that include graduate program enrollment (36%) and publications emanating from research projects over the life of the program; 40% of T35-supported students publish, and 31% of the publications are 1st authored by the student. To build upon this trajectory, the program will now establish a formal relationship with the Career Areas of Emphasis component of the 3rd and 4th year veterinary medical curriculum, developing a certificate program in Comparative Biomedical Research, emphasizing research career experiences and opportunities under the guidance of an external advisory committee.

NIH Research Projects · FY 2025 · 2008-09

The Ohio State University (OSU) is proud to submit this renewal application to the Paul Calabresi Career Development Award for Clinical Oncology (K12) mechanism. The overall goal of this renewal proposal is to effectively mentor and train faculty level investigators in basic science and clinical approaches to translational research so they may have successful careers in cancer experimental therapeutics and other therapeutic modalities including radiation oncology, surgical oncology and cancer prevention, control and survivorship research. Aim 1 is to provide individualized career development support to ensure a cadre of physician scientists and cancer clinicians who collaborate to design and conduct hypothesis-driven clinical cancer research. Aim 2 is to provide scholars with educational opportunities and scientific training to enhance their knowledge base and ability to conduct hypothesis driven cancer clinical research. Multi-PIs William E. Carson III, MD and Rosa Lapalombella, PhD will guide this program into its second decade of existence and continue their oversight of early career investigators who will dedicate their careers to the prevention and treatment of cancer. A customized mentorship team will be developed for each K12 Scholar and they will guide the Scholar in their development of an Individual Development Plan. Each Scholar is required to join the laboratory of an accomplished Translational Research Mentor for the 2-3 year period of their appointment. So-called “dry lab” opportunities in population sciences and health outcomes research are encouraged. This research experience will be the source of the preclinical data that will support subsequent investigator-initiated trials (IITs). A Clinical Preceptor will provide guidance on clinical translation and a newly instituted Peer Mentor program provides support from a committed colleague. The educational curriculum has three distinct components: 1) Fundamentals of translational oncology; 2) Essential skills necessary for academic success; 3) Career-building activities and integration into the professional sphere. Scholars are encouraged to enroll in an MPH in Clinical Translational Science. A rigorous process for clincial trial development and implementation is in place and Scholars have benefited from new grant- writing courses such as the R Club. The evaluative process has been redesigned resulting in changes to the program’s educational offerings (Genomics Workshop), mentorship structure (Peer Mentors) and community- building approach (K Breakfast). The Scholar selection process has identified a diverse group of early career investigators (36% minority, 36% female) that have exhibited drive and energy. 14 Scholars have generated 18 IITs and published over 200 K12-related manuscripts. 8 of 8 graduated Scholars have peer-reviewed funding as a PI (7/8 NIH) and half have R01 awards. Drs. Carson and Lapalombella will utilize the extensive educational, translational and clinical trial resources that are available at The Ohio State University to create a cadre of highly trained clinicians dedicated to the development of new treatments, targeted therapies, diagnostics and social strategies that will benefit patients with cancer and lead to longer life.

NIH Research Projects · FY 2025 · 2007-07

OVERALL PROJECT SUMMARY In this Program Project Grant (PPG) renewal application, the applicant group is representative of three primary institutions, the Ohio State University (OSU), the University of Illinois at Chicago (UIC), and the University of North Carolina at Greensboro (UNCG). The participants have combined their vast experience in the isolation, structure elucidation, and biological evaluation of natural products, to the development of a consolidated, integrated program for the discovery of novel anticancer agents of diverse origin for potential utilization as cancer chemotherapeutic agents. Plant materials to be studied in Project 1 (OSU) have been collected in tropical countries by established botanists, and also accessed from the Natural Products Repository of the National Cancer Institute. Lichens and their fungal associates (Project 1), cyanobacteria (Project 2), and filamentous fungi (Project 3; UNCG) will also be accessed. Organisms acquired will be extracted and evaluated in a diverse battery of relevant mechanism-based, cell-based, and tumor-growth related assays currently operational at OSU (Project 1), UIC (Core 1), Columbia University (through Project 3), and via other external collaborators (through Core A at OSU). Dereplication of known active compounds will be accomplished at OSU, UIC, and UNCG using computerized literature surveys and LC-MS coupled to bioassays. Bioassay-directed fractionation will be employed in Projects 1-3 for the elucidation of the active principles. Lead development of active natural products via medicinal chemistry and pharmacokinetics-related studies will be conducted at OSU (Project 1 and Core 2), facilitated by the OSU Biostatistics group (Core A). Novel, active compounds thus discovered will be further evaluated in our panel of in vitro and in vivo bioassays (Projects 1 and 3, Cores 1 and 2) and by some external collaborators. Group decisions will be made regarding the further development of agents for potential use as anticancer agents. The more advanced stages of biological and toxicological testing will be aided through consultation with the Drug Discovery Institute of the OSU Comprehensive Cancer Center (through Core A). The Consortium will work with the involvement of the NCI Program Director in the discovery process, and plans to hold regular meetings of key scientific personnel (inclusive of our External and OSU Internal Scientific Advisory Boards) to enhance communication and decision-making processes, to be organized by Core A. Excellent facilities for the isolation, structure determination, chemical modification, synthesis, and in vitro and in vivo biological evaluation, and overall project data management are available. The overarching goal of this PPG is to identify lead compounds that ultimately have therapeutic value for the treatment of cancer.

NIH Research Projects · FY 2024 · 2006-04

Influenza is a leading cause of death in the US with a staggering economic burden. Interferons serve as a critical response to this virus triggering elaboration of host defense molecules within alveolar macrophages. A relatively new and unchartered area in interferon biology involves interferon lamda (IFN) acting through its cognate receptor, IFNLR1, to mediate anti-viral defense. Loss of IFNLR1 leads to viral dissemination and death in experimental influenza. The mechanistic platform of this proposal resides on our discovery of a unique molecular model whereby a protein, Fbxo45, rapidly impairs host defense by mediating ubiquitin-driven disposal of this crucial cytoprotective, anti-viral receptor, IFNLR1. Hence, in this application we will first elucidate how short-term influenza infection depletes IFNLR1 through Fbxo45, thereby accentuating experimental viral lung injury (Aim 1). We will specifically elucidate how Fbxo45 targets IFNLR1 for its degradation using complementary in vitro and in vivo genetic models. Next, after sustained influenza infection we observed that IFNLR1 mRNA levels increase in macrophages, perhaps as a compensatory host defense mechanism. Here we will assess novel post-transcriptional mechanisms mediated by microRNA acting on the 3’UTR of the IFNLR1 gene (Aim 2). These studies will provide a new pathobiologic model of lung injury that will serve as a platform for unveiling new molecular insight into the IFN- IFNLR1 axis that is indispensable to resolve inflammatory injury in subjects with severe virally-driven critical illness.

NIH Research Projects · FY 2025 · 2005-04

PROJECT SUMMARY In all organisms, proteins are synthesized by ribosomes, large two-subunit enzymes that use aminoacyl- tRNA substrates to translate messenger RNA. Each ribosome is composed of several large RNA molecules (rRNAs) and more than 50 distinct proteins, with rRNA accounting for around two-thirds of the overall mass. Tremendous progress has been made in elucidating the structure of the ribosome and the molecular mechanisms that underpin protein synthesis. Yet, how ribosomes are made in the cell and how components of the ribosome can regulate protein synthesis remain important unresolved questions. The long-term goal of this project is to understand the mechanisms of ribosome biogenesis and regulation in bacteria. Aim 1. In bacteria, the three rRNAs are co-transcribed in long operons. Sequences flanking each rRNA are complementary and form leader-trailer helices (hLTs) in assembly intermediates. These hLTs are absolutely essential for subunit assembly in the cell but dispensable for subunit assembly in the test tube. The proposed work will investigate the cellular function of these key elements. The findings may hold broad relevance for RNA folding and RNA-protein complex assembly inside cells. Aim 2. Protein S21 contributes to the mRNA exit channel of the small subunit. Some bacteria lack S21, other bacteria encode multiple versions, and many bacterial viruses (bacteriophages) encode S21 homologs. The proposed work will investigate the ability of natural S21 variants to substitute for the primary S21 on the ribosome and globally regulate translation. The findings may uncover a widespread mechanism of translational control in bacteria. Ribosomes are a main target of antibiotics, and defects in ribosome biogenesis cause many inherited human diseases (termed ribosomopathies). Insight gained by this project may ultimately lead to the development of novel antimicrobial drugs and/or treatments for one or more hereditary diseases.

NIH Research Projects · FY 2024 · 2003-07

ABSTRACT Heart failure (HF) continuous to be a major health care challenge. Altered myocyte calcium (Ca) signaling is an essential part of the pathophysiology of HF and of critical relevance in the search for new effective therapies. Despite progress in the elucidation of Ca-dependent processes occurring on rapid time scales, mechanisms whereby Ca modulates slow cardiac processes, including long term adaptations to physiological and pathological stress, remain poorly understood. This critical barrier to progress is attributable to our poor understanding of foundational aspects of cardiomyocyte biology, including sites and mechanisms of protein synthesis, processing and delivery. This is compounded by the lack of technological tools for probing and tracking slower / long-lived molecular process in living myocytes. Store-operated Ca entry (SOCE), wherein depletion of intracellular Ca stores prompts extracellular Ca entry into the cytosol, has recently emerged as an important component of cardiomyocyte Ca signaling. SOCE is mediated by the stromal interaction molecule (STIM1), which, upon sensing sarco/endoplasmic reticulum (SR/ER) Ca depletion, interacts with and activates the sarcolemmal Ca- release activated channel protein (ORAI1). STIM1 has been reported to play a critical role in maladaptive hypertrophy. However, the mechanism whereby STIM1 contributes to hypertrophy and its role in adaptive hypertrophy (exercise-induced) remain to be elucidated. Recently, we discovered that SOCE and its molecular machinery are localized at the cell-to-cell contact sites, the intercalated discs (IDs). Based on preliminary results, we put forth a novel hypothesis that SOCE promotes myocyte longitudinal growth through facilitation of localized protein synthesis from a dedicated pool of mRNAs at the IDs. Indeed, SOCE in the normal heart may be optimally tuned to achieve a “Goldilocks zone” of adaptive hypertrophic response, as induced by exercise. In contrast, pathological dysregulation of SOCE may prove deleterious. Specifically, SOCE over-activity in disease may underlie maladaptive hypertrophy, thus leading to phenomena such as stress-induced cardiomyopathy (SCM). In this proposal, we will use cutting-edge cellular physiology and molecular techniques (including super- resolution microscopy, novel cellular reporter systems) and novel genetic mouse models to test these hypotheses and determine key cellular micro- and nanodomains, as well as molecular steps involved in SOCE- driven myocyte growth. We will also examine the possibility of targeting key components of the SOCE machinery (specifically, STIM1L, the long splice variant of STIM1) that mediate maladaptive hypertrophy. To this end, we propose the following specific aims: 1) Define the role of SOCE in adaptive and maladaptive hypertrophy. 2) Define subcellular and molecular mechanisms underlying modulation of hypertrophy by SOCE; and 3) Define the role and mechanism of SOCE in stress-induced hypertrophic cardiac disease. These studies will yield new insights into the mechanisms underlying physiological and pathological hypertrophy and provide a foundation for new mechanism-based therapies for abnormal cardiac structure and function.

NIH Research Projects · FY 2026 · 2003-02

All living cells possess mechanisms that partition the chromosomal DNA into actively transcribed, accessible domains, and transcriptionally silent domains densely packed by DNA-bound proteins. In Escherichia coli, nucleoid-associated proteins (NAPs) assemble into nucleoprotein filaments that cover several kilobase-long regions of DNA, silencing expression of horizontally acquired xenogenes, virulence factors or enzymes needed for utilization of exotic nutrients. While silencing of promoters, frequently by exclusion of RNA polymerase, is well studied, silencing during RNA chain elongation has only recently come to light. E. coli H-NS and its homolog StpA are NAPs that directly bind to AT-rich DNA and inhibit transcription initiation and elongation. The available data show that the transcription elongation complex is involved in both maintenance and relief of NAP-mediated silencing. Recent data implicate the ω subunit of RNA polymerase in regulation of global DNA topology and transcription of xenogeneic regions. A universally conserved elongation factor, NusG, and termination factor Rho, which are associated with RNA polymerase genome-wide and stop synthesis of RNAs that are not actively translated, cooperate with H-NS to silence xenogenes and other inactive genes. Conversely, we showed that a specialized NusG paralog, RfaH, which is required for expression of xenogeneic operons, excludes NusG and Rho from the transcribing RNA polymerase and counteracts NAP-mediated silencing. We propose to elucidate molecular mechanisms which control the accessibility of bacterial chromatin, focusing on poorly understood regulation during transcription elongation. In Aim 1, we will investigate effects of the ubiquitous ω subunit on RNA polymerase structure and activity. We will identify cellular factors that interact with ω using genetics and proteomics, characterize ω-induced changes in transcription complexes, and investigate ω effects on in vitro RNA synthesis. In Aim 2, we will study regulation of Rho- dependent termination. We posit that hyperactive Rho may be harmful during slow growth or translational stress and will investigate mechanisms by which Rho activity may be globally downregulated, e.g., by changing Rho conformation, promoting the formation of inactive Rho filaments, or blocking Rho binding to RNA. In Aim 3, we will identify new factors that contribute to maintenance of E. coli heterochromatin; determine contributions of different NAPs, Rho, and ω to silencing; and elucidate the molecular mechanism by which RfaH counter-silences NAPs in vitro.

NIH Research Projects · FY 2024 · 2002-09

Project Summary The following aims are developed as the logical next step based on published and unpublished findings from the parent grant (initiated by the late Dr. Traystman) to assess sex-specific signaling following pediatric (juvenile mice) cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Pediatric cardiac arrest is surprisingly common and remains poorly understood and understudied. We made significant progress on the major aims of the previous grant cycle and obtained important new preliminary data that form the foundation for the current aims. We take advantage of our novel juvenile mouse cardiac arrest and cardiopulmonary resuscitation (CA/CPR) model to assess functional outcomes and recovery following CA/CPR. Emerging evidence from our laboratory, and others, indicate that alterations in the surviving functional networks contribute to cognitive deficits. Synaptic plasticity, in the form of strengthening following physiological stimuli (long-term potentiation; LTP) is a well-established cellular model of learning and memory. Deficits in hippocampal LTP correlate with memory impairments in adult and juvenile mice and therefore, we focus on therapies that target reversing synaptic plasticity deficit to enhance functional recovery (neuro-restoration). We recently made the remarkable observation that juvenile mice exhibit endogenous neuro-restoration; recovery LTP and memory function 14-30 days after CA/CPR, which we do not observe in adults exposed to the same injury. Our data indicates that the impairments and endogenous recovery of synaptic plasticity and memory function in juvenile mice correlates with expression of brain derived neurotrophic factor (BDNF). Further, we show that stimulation of BDNF-TrkB signaling facilitates recovery of hippocampal function. The recovery in hippocampal function we observed in juveniles corresponds with hormonal maturation that occurs between PND28-56. Our preliminary data indicates that gonadectomy of juvenile male (CAST) and female (OVX) mice prevents recovery of LTP (and recovery of BDNF levels) following CA/CPR. Further, we observed that replacement of sex steroids (estrogen in females and testosterone in males) restores endogenous neuro- restoration in CAST/OVX juvenile mice. Importantly, we observe that estrogen stimulates BDNF expression in juvenile females but not males and that brain estrogen does not facilitate recovery of LTP in males. Therefore, our overarching hypothesis is that 1) increased steroid levels in the brain during puberty facilitate endogenous neuro-restoration following juvenile CA/CPR through activation of sex-specific signaling (Aim 2 male-specific androgen signaling and aim 3 female-specific estrogen receptor signaling) that converges on BDNF and other plasticity gene expression to enhance synaptic plasticity. The proposed research will contribute to our understanding of the mechanisms of functional impairments and recovery following cardiac arrest in the pediatric age group, an understudied population. In particular, this project extends our long-standing research focus regarding sex-specific signaling and the interaction between age, sex, sex steroids and outcomes following brain injury. Further, our studies will extend our focus on developing therapeutic strategies to restore synaptic function within surviving brain networks, rather than attempting to protect neurons from ischemic injury, which may impact treatments of patients of all ages.

NIH Research Projects · FY 2026 · 1999-09

PROJECT SUMMARY: Cardiovascular disease, particularly heart failure (HF), remains a leading cause of morbidity and mortality, underscoring the urgent need for innovative therapeutic strategies. While excitation–contraction coupling (ECC) and calcium (Ca2+) homeostasis are critical for cardiac function, the spatial regulation of key Ca2+-handling protein synthesis in cardiac myocytes remains poorly understood. Traditionally, these proteins were thought to originate in the perinuclear rough endoplasmic reticulum (ER) and then be trafficked to their sites of action. However, our recent single-molecule imaging studies demonstrate that essential Ca2+-handling proteins—such as RyR2, SERCA2a, and Cav1.2—are synthesized locally within the sarcoplasmic reticulum (SR). This discovery reframes the SR as a translation hub, integrating compartmentalized Ca2+ regulation with spatially coordinated protein biogenesis through localized “signaling-translation” modules. Our preliminary data reveal that, in HF, this localized protein synthesis (LPS) becomes severely disrupted, contributing to Ca2+ instability, maladaptive remodeling, and contractile dysfunction. We also introduce the concept of “SR stress” wherein unfolded protein response (UPR) activation exacerbates LPS disruption and further destabilizes ECC. Over the next five years, we aim to: (1) Define the spatial organization and molecular mechanisms of LPS in cardiac myocytes, elucidating how it governs the biogenesis of ECC proteins and maintains Ca2+ homeostasis; (2) Define the roles of LPS in coordinating functionally linked proteins and complexes for ECC; and (3) Define the mechanisms through which LPS disruption and SR stress precipitate HF pathology and test novel LPS-targeted targeted therapeutic strategies. To accomplish these goals, we will employ a cutting-edge nanoscale spatial multi-omics platform integrating high-plex mRNA detection, super- resolution imaging, and live-cell tracking—enabling precise mapping of mRNA localization, translation, and protein distribution in cardiac myocytes. Employing a range of cutting-edge techniques and drawing on nearly three decades of NIH-supported research, our interdisciplinary team is uniquely equipped to advance cardiac science significantly. Through this endeavor, we not only aim to enhance our fundamental understanding of heart function but also to identify novel targets for therapeutic intervention in cardiac disease.

NIH Research Projects · FY 2026 · 1998-05

Project Summary/Abstract The long-term objective of this program is to expand the number of optometrists trained in research within the profession of optometry to ensure a strong pipeline of individuals available to address the visual and ocular needs of the aging population through rigorous clinical and basic research. This program achieves this goal by exposing optometry students to vision research early in their clinical degree program through a short-term training program in vision research. By exposing optometry students to research early in their clinical program, students are still agile to expand their educational goals, such as by subsequently enrolling in a combined OD/MS degree, or even later earning a PhD in vision science. This proposal is a renewal of a successful 25 year short-term training program whose 213 past trainees have been involved in producing more than 250 scientific abstracts and 78 peer-reviewed publications. In addition, 125 past trainees have completed or are pursuing a Master’s Degree in Vision Science, and 10 have completed and 2 are pursuing a PhD in Vision Science at The Ohio State University. The graduate program in vision science at The Ohio State University has a long track record of training optometrists for careers as clinician scientists. The program has yielded many NIH funded investigators, clinical trialists, and significant contributors to the field of vision science. Support is requested for eight training slots per year to provide a 3 month training experience in research for optometry students in the summer months following their first year of the optometry program. The program is housed within the College of Optometry at The Ohio State University and led by the Chair of the Graduate Program in Vision Science. Participating faculty include 20 members of the graduate faculty in Vision Science who each run independent research labs and are involved in the training of MS and PhD students enrolled in the graduate program in Vision Science. The faculty’s specific areas of research include, but are not limited to refractive error, ocular embryonic development, color perception, pediatrics, cataractogenesis, vision rehabilitation, anterior surface and contact lens, adaptive optics, and corneoscleral biomechanics. Trainees appointed to this award will be paired with individual faculty advisors and conduct research projects throughout the course of the training period. Training will also include weekly seminars in responsible conduct of research, bi-weekly attendance at vision science seminars, participation in journal club discussions, and a formal presentation of their research at the end of the program in a public forum. Trainees are also encouraged to submit research findings for presentation at scientific meetings and to publish results following completion of the training period. Continued support of this program and an expansion of training slots from 6 to 8 will contribute to the scientific literature and engage future independent clinician scientists who perform vision research.

NIH Research Projects · FY 2026 · 1997-09

PROJECT SUMMARY – OVERALL The Ohio State University Comprehensive Cancer Center (OSUCCC) is in its 49th year as an NCI-designated comprehensive cancer center, having received an “exceptional” overall merit descriptor in its last three reviews, and is requesting continued federal support for the next five years. The OSUCCC mission remains to reduce cancer morbidity and mortality through basic, population, translational, and clinical research. Through thoughtful strategic planning, attention to the cancer burden in the catchment area (the state of Ohio), effective organizational capabilities, and targeted investment, the Director and his Senior Leadership Team will enable the OSUCCC to advance collaborative cancer research with local, national, and global partners on initiatives of the highest priority to the OSUCCC. The 323 members are currently served by 12 Shared Resources and are distributed among our five Research Programs: Cancer Biology, Cancer Control, Leukemia and Hematologic Malignancies, Molecular Carcinogenesis and Chemoprevention, and Translational Therapeutics. The OSUCCC fosters collaborative basic research and implements strategies that advance and translate early discovery into clinical and population-based research and addresses the needs of our catchment area through research, engagement, and outreach, from etiology through prevention, treatment and survivorship regarding the major cancers afflicting our catchment area population. The OSUCCC trains the next generation of cancer-focused scientists and clinicians through new and established programs focused on integrating training for collaborative research efforts. Under the leadership of Director Raphael Pollock, MD, PhD, the OSUCCC supports innovative research efforts across three strategic plan interprogrammatic themes: immuno-oncology, cancer engineering, and cancer prevention and survivorship. Since the last CCSG competitive renewal, the OSUCCC has shown tremendous growth demonstrated by: 1) the recruitment of 77 basic, population, and translational science faculty who are OSUCCC members; 2) the addition of 63,230 ft2 research and administrative space under the full control of the OSUCCC Director; 3) a 34% increase in direct cancer-related funding to $101.1M, with $53.6M coming from the NCI; 4) accrual of 18,459 patients to interventional clinical trials, a 23% increase compared to the prior review cycle with 17.4% from individuals from American Indian/Alaska Native, Asian, Native Hawaiian/Other Pacific Islander, Black/African American backgrounds; and 5) increased collaborative and impactful research demonstrated by 4,548 peer-reviewed publications in which 26% are intra-programmatic, 37% are inter-programmatic, and 97% are multi-institutional; 900 are published in journals with an impact factor >10. Efforts are supported by a new funds flow model based on revenue generated by clinical activity in The James Cancer Hospital. With new recruits and strong institutional and philanthropic support in place, the OSUCCC is poised in the next five years to take significant steps toward achieving our strategic plan vision of creating a cancer-free world.

NIH Research Projects · FY 2025 · 1995-04

MISMATCH REPAIR AND CARCINOGENESIS PROJECT SUMMARY / ABSTRACT Defects in human mismatch repair (MMR) are the cause of Lynch syndrome aka hereditary non-polyposis colorectal cancer (LS/HNPCC), as well as 10-40% of various sporadic cancers. MMR corrects DNA polymerase misincorporation errors, suppresses recombination between non-allelic partially homologous DNA sequences, and functions as a lesion sensor in DNA damage signaling. The unrepaired errors in MMR-deficient cells lead to increased genomic mutations that drives tumorigenesis, while the lack of damage sensing results in resistance to several common chemotherapeutics. Conversely, MMR defective tumors appear to activate cellular innate immunity that results in strikingly effective PD1/PD-L1-based immunotherapy. Despite decades of study, critical aspects of MMR mechanics remain uncertain, the sequence of events that leads to MMR damage signaling is poorly understood, and the mechanism that connects MMR to innate immunity is largely a mystery. Four MMR genes account for most of the LS/HNPCC mutations and include the highly conserved MutS homologs (MSH) and MutL homologs (MLH/PMS) MSH2, MSH6, MLH1 and PMS2. During the last funding period, we expanded our single molecule imaging capabilities and discovered that the MSH and MLH/PMS proteins interact to form novel cascading sliding clamps on a mismatched DNA. Once loaded by an MSH, the MLH/PMS sliding clamps assist in detecting the error-containing strand and function as a processivity factor for MMR excision activities, while retaining a large enough “donut hole” to transit nucleosomes. The remarkable stability and DNA diffusion properties of the MSH and MLH/PMS sliding clamps clarified our understanding of MMR mechanisms, while provoking new concepts for strand-specific excision and damage signaling. Remarkably, the MSH and MLH/PMS sliding clamps displayed entirely random motions when on the DNA. Deterministic mechanisms have historically underpinned MMR models, where static complexes and well-defined stepwise biochemical sequences are proposed to complete repair events. This renewal application will explore the hypothesis that the entire multi-component multi-pathway MMR process is Stochastic: governed by chance encounters, varied repair intermediates and/or MMR component exchanges that are orchestrated and anchored to the DNA by dynamic MSH and MLH/PMS sliding clamps. Understanding the depth of biochemical randomness during MMR will facilitate similar biophysical studies of more complex DNA repair systems. We propose the following Specific Aims: 1) examine the interactions and competition between human MMR components in real-time, 2) detail the dynamic selection and interchange between strand-specific excision components during MMR, 3) examine fundamental damage recognition and signaling interactions on chromatin substrates, and 4) visualize human MMR component interactions with single molecule resolution in vivo. The overall goal of this research is to detail the MMR mechanisms that lead to faithful repair as well as how MMR defects instigate the genome instability that drives cancer, drug resistance and immune activation.

NIH Research Projects · FY 2026 · 1992-04

This proposal describes the team, environment, and resources of The Ohio State University (OSU) Center that allow it to substantively and meaningfully participate in, and meet the objectives of, the Eunice Kennedy Shriver NICHD Maternal Fetal Medicine Units (MFMU) Network. The OSU Center has demonstrated strong performance and experience in conducting clinical and translational research due to its scientific expertise, excellent infrastructure, and institutional support. The research team for this proposal is led by Maged Costantine, MD, who serves as Division Director for Maternal-Fetal Medicine and PI for the MFMU Network Center, and William Grobman, MD, MBA, who serves as Vice-Chair for the Department of OB/GYN and Alternate PI for the MFMU Network Center. In addition to their productivity within the MFMU Network, both the PI and Alternate PI bring extensive experience in study design, recruitment, data analysis, and dissemination of results. Their research foci on disparities in obstetric care and outcomes, perinatal pharmacology, epidemiology, clinical trial design, and translational research is complementary and will be an asset to the Network. The OSU Center will recruit study participants from racially and ethnically diverse populations at 2 medical centers with a combined total of more than 10,000 annual births, many of which are to high-risk women who receive prenatal care within the two systems. Our Center’s Nurse Coordinator, Anna Bartholomew, MPH, RN, BSN, CCRP, leads a large group of research staff capable of recruiting and retaining patients in the setting of a research organization that has 32 of years of experience in the MFMU Network; demonstrable experience in multiple other cooperative research settings, including the NICHD nuMoM2b Network, NICHD Maternal and Pediatric Precision in Therapeutics (MPRINT), NIH Helping to End Addiction Long-term (HEAL), and the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative; and engagement with other multi-site initiatives such as the North American Fetal Treatment Network, Ohio Better Birth Outcomes, and Ohio Perinatal Research Network. We additionally benefit from a robust bioinformatics structure and versatile Electronic Medical Record System that captures antepartum, intrapartum, and postpartum data and is readily available to authorized research personnel for data query and notification of research subjects’ eligibility; an extraordinary group of obstetrical sonographers and perinatal epidemiologists; and a mature research infrastructure supported by a CTSA grant shared with Nationwide Children’s Hospital. Our satellite site, Miami Valley Hospital in Dayton, has an outstanding record of recruitment in the prior Network cycles, well-established research culture, and ambitious goals for MFMU Network participation. Our strong clinical and research collaboration with OSU neonatology [including in the Neonatal Research Network (NRN)], anesthesiology, pathology, the clinical laboratory, and pharmacology add strengths to our application. We look forward to continuing our tradition of service, strong performance, and innovation in the renewed NICHD MFMU Network, and accept the RFA’s capitation and participatory stipulations.