Ohio State University

NIH Research Projects · FY 2025 · 2021-01

Influenza A virus (IAV) is responsible for seasonal epidemics that results in severe respiratory illness and deaths worldwide, costing billions of dollars annually in the U.S. alone. Cancer patients are at increased risk of developing a secondary pneumonia after influenza, which can lead to significant complications. Influenza infections pose serious challenges due to the lack of effective therapeutic interventions, frequent appearances of new strains of the virus, and rapid development of drug resistance. New approaches to control infection may stem from cellular factors or pathways that directly or indirectly interact with viral proteins to enhance or inhibit virus replication. One of the emerging concepts in the field of IAV is that host cellular factors and pathways are required for maintaining IAV genome integrity, which is essential for viral replication. Our preliminary data show that a deficiency of a host cellular protein, Bik, is associated with significant reduction in IAV replication. Our major findings found that Bik deficiency reduces viral protein levels and viral replication in infected airway epithelial cells. Furthermore, bik-/- compared to bik+/+ mice exhibit less severe lung inflammation, reduced lung viral load, and a significant increase in survival rate after infection with IAV. Similarly, a single nucleotide polymorphism (SNP) in the BIK gene (G→A) that increases Bik expression levels significantly increases viral NP level and replication in primary normal human bronchial epithelial cells (NHBEs). Furthermore, data from an IAV- infected human cohort showed that the AA variant of BIK SNP is a risk allele associated with influenza disease severity. Bik disrupts the interaction of Bcl-2 with IAV-encoded nucleoprotein (NP) and form a Bik/NP complex that may help assemble viral proteins. The goals of this proposal are to define the role of a host cell protein Bik in promoting viral replication. Our central hypothesis is that IAV increases host cell Bik protein expression, which interacts with and disrupts Bcl-2/NP interaction to allow NP to assemble components of viral ribonucleoprotein (vRNP) and facilitate efficient viral replication. To test this hypothesis, we propose two Specific Aims. Aim 1 identifies the Bik-binding domain of viral NP required for IAV replication. Aim 2 determines whether a BIK SNP associated with increased Bik expression is a risk factor for influenza disease severity in humans. Studies are designed to identify the sites of Bik/NP interaction that may serve as potential drug targets in the future. This study may identify underlying host genetic risk factors contributing to influenza susceptibility and severity and may have potential implications in regard to targeted prevention and treatment based on susceptibility factors. The proposed studies will have significant impacts on the field by dissecting key mechanisms that promote IAV replication. In the long term, developing peptides or small molecules that disrupt Bik/NP interactions may improve therapy by reducing IAV replication. Further, this study will identify genetic factors contributing to IAV disease severity, which can have a broad public health significance.

NIH Research Projects · FY 2025 · 2021-01

Project Summary/Abstract A recent critical analysis of biologically active molecules and reactions most often used for their preparation suggests that fraction of saturated carbons and presence of chiral centers correlate with success as a compound moves from discovery, through clinical trials to an approved drug. About a third of the compounds had at least one chiral center. In addition, practical aspects of manufacturing still need to be addressed to market a cost effective drug. Thus discovery of fundamentally new catalytic reactions, especially enantioselective ones, showing high turnover frequencies (i.e., substrate/ catalyst/unit time), that use readily available precursors, will have a significant impact on medicinal and process chemistry. Through an approach that relies heavily on mechanistic insights we strive to discover new enantioselective reactions of alkenes and alkynes. For example, use of low-valent chiral (L*)cobalt complexes has enabled heterodimerization between a broad range of 1,3-dienes, and, ethylene and alkyl acrylates, which are feedstock materials. The products of these reactions are synthetically valuable chiral 1,4-skipped dienes (produced in >90% yield and ee) which can be turned into pharmaceutically relevant classes of compounds. Examples cited include anti-microbial and anti-tumor and antifungal agents, GABA analogs, and metalloproteinase inhibitors. On-going mechanistic studies strongly suggest the intermediacy of a cationic {[P~P)Co(L)]+}X– species in these exceptionally selective C-C bond-forming reactions that proceed under ambient conditions. Most remarkably, we recently (2018/2019) found that the chiral cationic Co(I) complexes with custom-designed ligands catalyze enantioselective [2+2]-additions of alkynes and vinyl-X derivatives, opening, arguably, the best route to enantiopure 3-substituted cyclobutenes, potential precursors other valuable compounds. In sharp contrast to 1,3-dienes, 1,3-enynes form, initially, vinylcyclobutenes and then, in a tandem fashion, highly functionalized cyclobutanes with an all-carbon quaternary centers. Such reactions are highly efficient and uncommon. Preliminary results also indicate that chiral cationic Co(I)-complexes catalyze at least 4 other types of reactions (hydroboration, hydroacylation and hydrosilylation of prochiral 1,3-dienes, and, cyclizaion/HV of 1,6- enynes). We plan to explore how many of the combinations of reactions can be run in tandem, in attempts to exploit the full potential of the new cobalt chemistry in organic syntheis. Historically some of the reactions we work on had been carried out using precious metals. We expect, when fully devloped, cobalt (which is 100 to 200 time cheaper than Rh for example), will be able to catalyze some of these basic reactions. The interdisciplinary nature of the work proposed here provides outstanding opportunities to train future scientists at every level of their education.

NIH Research Projects · FY 2025 · 2021-01

PROJECT SUMMARY Skeletal muscle is central to the development of metabolic dysfunction during type 2 diabetes (T2D) and obesity. In addition, these conditions are often accompanied by accelerated muscle loss despite the presence of nutrient excess. This suggests uncoupling of nutrient sensing mechanisms with the molecular pathways that control muscle plasticity. For instance, depletion of intramuscular nicotinamide adenine dinucleotide (NAD) is linked to skeletal muscle loss and dysfunction, while strategies that restore or increase its levels can reverse this pathogenesis. Particularly, genetic or pharmacological inhibition of poly(ADP-ribose) polymerases 1 (PARP1), a major NAD consumer, improves muscle fitness through increases in NAD availability and the activation of NAD-dependent deacetylase sirtuin-1 (SIRT1). Thus, identifying physiological pathways that link energy metabolism to the regulation of PARP1 activity can lead to the development of innovative therapies for the prevention or treatment of muscle degeneration and metabolic dysfunction. Preliminary data suggest that direct sensing of circulating glucose by sweet taste receptors (STRs) regulates PARP1 activity to control the adaptive potential of skeletal muscle. Specifically, whole body or skeletal muscle-specific deletion of T1r2 gene of STRs (T1R2-KO) enhances mitochondrial function, oxidative capacity, exercise tolerance, and induces mild increases in myofiber size. These improvements are linked to attenuated PARP1 activity, increased NAD pool, and enhanced glucose utilization towards nucleotide biosynthesis. Consequently, T1R2-KO mice are protected from metabolic derangements associated with diet-induced obesity, including muscle mass loss. Thus, it was hypothesized that the T1R2 receptor is a constitutive sensor of glucose availability to adjust intracellular pathways that control the metabolic basis of skeletal muscle plasticity. This hypothesis is tested through comprehensive studies using mice with constitutive or inducible muscle-specific deletion of the T1r2 gene to: 1) Elucidate the role of T1R2 signaling network in the regulation of muscle bioenergetics and function. Specifically, a) probe signaling pathway leading to PARP1 regulation and NAD bioavailability, b) identify downstream effectors of NAD-dependent activation of SIRT1 and 2, c) assess contributions of STRs in the regulation of substrate utilization, and d) determine interactions between STR signaling and established intracellular energy sensors (i.e. AMPK, mTORC1, Akt). 2) Investigate contributions of T1R2-mediated glucose sensing in the regulation of muscle mass. Specifically, a) assess physiological effects of inducible deletion of STR signaling in adult skeletal muscle to mimic longitudinal effects of pharmacological treatments targeting STRs, b) define contributions of STR signaling to muscle mass adaptations in response to treatments that induce muscle hypertrophy or atrophy, c) spatiotemporal expression of T1r2 gene during muscle development and growth using muscle-specific reporter mice, and d) contributions of STR signaling during postnatal muscle growth through the assessment of morphological, signaling and functional muscle adaptations. .

NIH Research Projects · FY 2025 · 2021-01

PROJECT SUMMARY Women at elevated risk for breast cancer should complete genetic counseling and may require more frequent screening or additional tests (e.g. breast magnetic resonance imaging [MRI]). Despite guidelines emphasizing the importance of genetic counseling as part of the genetic testing process, opportunities to provide genetic counseling for women at elevated breast cancer risk are often missed. Conventional genetic counseling, consisting of separate pre- and post-genetic test sessions, is not patient driven, and is labor and time intensive to meet increasing demand (workforce burden). Our overall goal is to improve the genetic counseling experience and adherence to the National Comprehensive Cancer Network (NCCN) recommendations for women at elevated breast cancer risk. The proposed randomized controlled trial (RCT) is our next step to reach our goal. A well-established interdisciplinary team will build on past work to test a novel genetic counseling patient preference (GCPP) intervention integrated within an electronic health record (EHR) portal that allows patients to indicate their preferences while directly receiving genetic test report information and post-genetic test counseling. The RCT will be conducted among 1,000 women at elevated risk for breast cancer who agree to participate in the study. Women will be randomized to: 1) GCPP via EHR patient portal; or 2) conventional genetic counseling. The efficacy of the GCPP intervention compared to conventional genetic counseling will be determined for: adherence to NCCN guidelines for having a clinical encounter every 6-12 months and an annual mammogram (and breast MRI with contrast if recommended) (Aim 1); adherence to additional NCCN recommended cancer screening (Aim 2); and accurate breast cancer genetic knowledge and perception of breast cancer risk, breast cancer-specific worry, post-test/counseling distress, and satisfaction with genetic counseling (Aim 3). An Exploratory Aim will assess patient preferences for receipt of post-genetic test counseling (e.g. in-person, phone, video-based Skype). The proposed study is innovative because it will test a novel EHR-based genetic counseling intervention in a randomized controlled trial. The study is significant because it will determine the efficacy of the GCPP intervention in a clinical care setting to address many of the limitations of conventional genetic counseling (e.g. not patient driven). The proposed research is relevant to public health by determining the degree to which a novel genetic counseling approach influences medical outcomes for women at elevated breast cancer risk. The study results may change how genetic counseling is delivered to women with elevated breast cancer risk and address the increasing burden on the genetic counseling workforce.

NIH Research Projects · FY 2025 · 2021-01

Project Summary: There is a rapidly growing body of evidence that Müller glia can are a source of retinal progenitors to promote neural regeneration. Many studies have demonstrated that Müller glia can become proliferating progenitor cells in the retinas of different vertebrate species. Most reports have studied Müller glia-derived progenitors in acutely damaged retinas. However, little is known about the mechanisms that stimulate neurogenesis from Müller glia-derived progenitors in undamaged retinas or retinas undergoing slow, progressive degeneration. Furthermore, the regeneration of retinal neurons in warm-blooded vertebrates is limited compared to that seen in cold-blooded vertebrates. Therefore, the identification of the secreted factors and signaling pathways that block or stimulate neural regeneration from Müller glia-derived progenitors is crucially important to developing new therapies to treat degenerative diseases of the human retina. We have obtained compelling novel preliminary data indicating that Fatty acid-binding proteins (FABPs) and endocannabinoids impact the de-differentation and reprogramming of Müller glia into proliferating, neurogenic retinal progenitors in chicks and mice. We will investigate how the phenotype and plasticity of the Müller glia are regulated by FABPs and endocannabinoids in normal, damaged and growth factor-treated retinas. We will use a combination of pharmacological and genetic approaches to selectively activate or inhibit FABPs and endocannabinoid-signaling. We will compare and contrast how FABPs and endocannabinoid-signaling impacts the formation of Müller glia-derived progenitors in chick and rodent model systems with different inherent capacities for retinal regeneration. We expect that the completion of the experiments described in this proposal will provide significant new information regarding how mature Müller glia can be reprogrammed into Müller glia-derived progenitors that regenerate retinal neurons. Identification and understanding of the mechanisms that enhance the neurogenic potential of Müller glia is required to develop new therapies for sight- threatening diseases, such as glaucoma, retinitis pigmentosa and macular degeneration that involve the loss of retinal neurons.

NIH Research Projects · FY 2025 · 2020-12

ABSTRACT Tumor hypoxia reduces the effectiveness of anti-cancer treatment with radiotherapy, some chemotherapy and immune checkpoint blockade therapy. For radiotherapy, biophysical measures show that hypoxic cells require 2.8-fold greater dose to achieve the same cell kill as those that are fully oxygenated. For immunotherapy, hypoxia has been shown to contribute to immune evasion and even accelerate T cell exhaustion. For these reasons, many groups have tried to deliver more oxygen to tumors as an adjuvant to increase tumor sensitivity. Unfortunately, this approach has met with disappointing clinical results. We have looked at tumor oxygenation differently, as a supply and demand mismatch, with the supply being inadequate to meet the demand of the growing tumor mass. Therefore, if we could reduce oxygen demand rather than increase supply, we could effectively reduce hypoxia and sensitize tumors. Because mitochondria are the major sink for oxygen within a cell, we propose that novel mitochondria inhibitors would reduce oxygen demand to match the limited supply. We have identified papaverine (PPV) as an FDA-approved molecule with the ability to inhibit mitochondrial function at clinical doses. Published studies from our group showed that in mouse tumors that papaverine can radiosensitize through inhibition of mitochondrial function, producing “Metabolic Radiosensitization”. Papaverine was originally isolated from the poppy and used as a smooth muscle vasorelaxant presumably due to inhibition of phosphodiesterase 10A. This activity makes it an effective drug for cerebral vasospasm, but causes a systemic drop in blood pressure and potential adverse cardiovascular effects. We therefore propose in this application to synthesize and evaluate new small molecule derivatives of papverine that we have designed to remove its activity as a phosphodiesterase inhibitor, but retain its activity as a mitochondrial complex 1 inhibitor. Using these PPV derivatives, and sophisticated mouse models of cancer, we intend to prove that inhibition of mitochondrial function is an effective strategy for removing hypoxia in solid tumors without affecting well oxygenated normal tissue. Preliminary data supports the overall theory that mitochondrial inhibitors increase tumor oxygenation and sensitivity to radiotherapy and immune checkpoint blockade therapy.

NIH Research Projects · FY 2026 · 2020-12

Developing an exceptional biomedical research workforce requires attracting the best scientific minds. This is particularly important for neuroscience, as significant challenges remain in treating neurological disorders. Many individuals discover neuroscience too late in their career decision process, missing opportunities to gain the rigorous research experience necessary for careers investigating neurological diseases. The Explorations in Neuroscience Research Summer Internship addresses this challenge by providing substantive summer research experiences in neuroscience, neurological injury, and neurodegeneration under trained mentor supervision. Experienced instructors deliver complementary workshops enhancing research understanding, neuroscience education, and professional development to prepare interns for future research experiences in college and beyond. Networking sessions and site visits provide additional inspiration and career exploration. Rigorous assessment ensures program accountability and efficacy. Evaluation demonstrates that participation in the internship enhances cognitive factors known to promote persistence in research, with many participants subsequently choosing neuroscience majors and pursing undergraduate research. The program’s popularity has grown dramatically, now attracting hundreds of applications for only twelve positions. Continuing to offer the Explorations in Neuroscience Research Summer Internship will cultivate a strong cohort of emerging scientists dedicated to advancing research on neurological disease.

NIH Research Projects · FY 2025 · 2020-12

ABSTRACT The purpose of the smoking machine adaptor design project is to develop a standardized and validated adaptor, or family of adaptors, for attachment to existing smoking and vaping machines to ensure the accuracy and reliability of scientific data obtained from the study of the physical and chemical properties of electronic nicotine delivery systems (ENDS), cigars, and heated tobacco products (HTPs). Equally important, the project will produce a set of protocols for the generation and collection of mainstream yield data for these four product types. For the proposed research efforts, the Ohio State University (prime contractor) will collaborate closely with the Food and Drug Administration’s Center for Tobacco Products (CTP), and with our proposed team members, including our Particle and Aerosol Characterization Laboratory, the Centers for Disease Control and Prevention Tobacco Products Laboratory (CDC-TPL); our smoking and vaping machine industry partner, Cerulean; and former Borgwaldt KC USA linear smoking machine design implementation engineer, Jeremy Jones, President, Produced Better. The project is comprised of four main phases: 1) Feasibility, 2) Prototype Design and Testing, 3) Adaptor Validation, and 4) Continued Stakeholder Support. Once the validation of the adaptors is complete, our team will be responsible for the manufacture, sale, and continued device support, including continuous design improvement, of the USMA in the final phase of the project and after CTP sponsorship has concluded. The project will provide a public benefit by ensuring that stakeholders can generate accurate scientific data and reduce measurement variability to help fill current scientific gaps regarding the chemical and physical properties of ENDS, cigars, and HTPs. These data will assist FDA in their mission to protect Americans from tobacco-related death and disease by regulating tobacco products and by educating the public, especially young people, about tobacco products and the dangers their use poses to themselves and others.

NIH Research Projects · FY 2024 · 2020-09

Summary of Parent Project (4U54CA260582-02) Stemming the spread of COVID-19 will require research that cross-cuts basic, translational, and applied sciences. The Center for Serological Testing to Improve Outcomes from Pandemic COVID-19 (STOP-COVID) is proposed as a transdisciplinary entity to understand the interface between exposure risk, transmission, immune responses, disease severity, protection, and barriers to testing/vaccination, with the goal of improving population health and clinical outcomes. The Center will utilize state-of-the-art serological and molecular tests, developed at OSU, in a longitudinal study of first responders, a group at continual high risk of SARS-CoV-2 exposure, as well as their household contacts. Through the proposed work, STOP-COVID investigators will understand critical aspects of: (i) transmission in both asymptomatic and symptomatic individuals, (ii) immune, host, and viral determinants of disease outcome, and (iii) factors associated with immune protection. Center investigators will also identify best practices for communication of test results and information about COVID-19 to improve understanding of risk, transmission, and protection, while reducing access barriers to testing. The Center to STOP-COVID will: Aim 1 Develop Institute Infrastructure through three shared resource cores: 1. An Administrative Core that provides overall direction and leadership, coordinating all Center activities as well as Project–Core–SeroNet interactions; 2. A Testing and Biorepository Core, whose role is to perform first-tier serologic and viral testing during our longitudinal study using high throughput ELISA and neutralization assays developed at OSU, and cost-shared by OSU; and 3. A Data Management and Analysis Core that will provide project investigators with a centralized resource for biostatistics, bioinformatics, epidemiology, and psychometrics expertise. Aim 2: Conduct three innovative research projects to address: Project 1: Parallel serological and viral testing to determine COVID-19 prevalence, transmission, and protection in extended first responder cohorts. This project will also generate serology data for vaccines or mAbs, once available to this presumably high-priority group; Project 2: Serologic and molecular determinants of COVID-19 severity and immune protection. This project will evaluate COVID-19 serological responses in the context of SARS-CoV-2 and common cold CoV (CCCoV) antibodies, using novel assays specific for a panel of antigens. Project 2 also will employ transcriptomics to understand how host genetics, CCCoV, other respiratory viruses, and immune responses contribute to pathogenesis; and Project 3: Responding to changing serological and viral information around COVID-19. This project will incorporate results from Projects 1 & 2 and SeroNet to inform best practices in risk communication, provide behavioral guidance to decrease transmission, and enhance protection from disease. Aim 3: SeroNet Participation and Sharing of Data and Best Practices. We will leverage STOP-COVID infrastructure to share data, results, reagents, and best practices with SeroNet, which will drive new discoveries and their translation into actionable strategies for implementation across all groups affected by COVID-19.

NIH Research Projects · FY 2025 · 2020-09

Project Summary/Abstract Acute pancreatitis (AP) is an inflammatory disease that can lead to long-term complications, including diabetes which is estimated to occur in >25% of patients. Research progress to date has been hindered by limitations due to study design and case ascertainment for diabetes. The DREAM study, an ongoing, prospective cohort study with serial assessments of glycemic status, undertaken by the Type 1 Diabetes in Acute Pancreatitis Consortium (T1DAPC), has been designed to directly investigate the incidence, etiology and pathophysiology of AP-related diabetes. The Ohio State University Clinical Center (OSU CC), one of the inaugural 10 clinical centers of the consortium, is a multi-disciplinary team (pancreatology, diabetology, radiology, and nutrition science) of nationally recognized experts that has worked collaboratively with the other T1DAPC CCs. Over the past four years, the OSU CC has been actively engaged to develop and contribute leadership to the T1DAPC organizational infrastructure and has been committed to enrolling and following up participants into the DREAM study. Overall goals of the current proposal are for OSU CC to continue its servant leadership to the T1DAPC over the next five years, foster research collaboration, and contribute to studies to understand the incidence and mechanisms of AP-related diabetes.

NIH Research Projects · FY 2024 · 2020-09

Project Summary/Abstract Many studies have shown that providing care for a spouse with dementia can be quite stressful, leading to a heightened risk for depression, multiple negative health outcomes, frailty, and early mortality. Stress- and depression-related immune system alterations are seen as a key pathway to poorer health in caregivers. However, the health impacts of caregiver stress have been questioned in recent years, based on newer evidence that caregiving may benefit health and extend lifespan. Furthermore, even though caregivers have typically had poorer immune function than noncaregiving controls, the clinical significance of these differences has been questioned. These discrepant findings reflect both methodological and conceptual issues that this project will address. Three molecular aging biomarkers (telomere length, p16INK4a expression, and epigenetic age) have each been associated with multiple diseases and disorders. Their combined use will provide an innovative way to quantify the long-term health risks of caregiving, allowing us to ask novel questions: Does caregiving accelerate aging? Can caregiving-related distress propel molecular aging and shorten health span (the length of time that a person is healthy—not just alive)? We will also assess three stress-sensitive pathways relevant to molecular aging: inflammation, intestinal permeability, and cytomegalovirus serostatus and reactivation. Drawing on behavioral, immunological, and molecular aging research, this transdisciplinary study will assess concurrent and prospective relationships related to key caregiving risk-related dimensions (gender, social relationships, caregiving intensity/burden, and benefit finding), and these aging biomarkers. Spousal dementia caregivers and sociodemographically-comparable married noncaregivers will be evaluated at study intake and then again one and two years later. This design will provide longitudinal data to assess changes in caregiving, depression, key risk behaviors, aging biomarkers, and the stress-sensitive pathways related to molecular aging. We have three specific aims: 1) To characterize the concurrent and prospective differences between caregivers and noncaregivers on the molecular aging biomarkers, inflammation, and mood. 2) To assess the relationships among the molecular aging biomarkers. 3) This exploratory aim addresses the relative contributions of key risk-related dimensions to depression, accelerated increases in aging biomarkers, and inflammation. This proposal describes a distinctly novel methodology that will provide a way to test innovative and original hypotheses about the ways that spousal dementia caregiving impacts lifespan and health span. The interactions between behavior and molecular aging represent an important new frontier for understanding how caregiving (and other chronic stressors) can accelerate or slow aging. This cutting edge research will help illuminate the mechanisms through which caregiving and depression influence health and longevity.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY Microbial phosphonic acids are a class of understudied natural products with significant utility in medicine. The antimicrobial, antiviral, and antimalarial activity of many useful phosphonic acids derives from potent and specific inhibition of metabolic enzymes through chemical mimicry of their natural substrates. These properties, along with the trove of novel biosynthetic gene clusters encoded within microbial genomic datasets, highlight their potential of phosphonic acid natural products new antimicrobials. In this project we focus our efforts on realizing their genomic potential of these compounds by establishing fundamental genetic and biochemical principles that define their biosynthetic and bioactivity landscape. Filling these gaps in knowledge will provide a systems-level understanding of natural product biosynthesis necessary to improve discovery and engineering of new phosphonic acids. Specifically, we investigate three recently discovered phosphonic acid peptides to uncover unusual hydroxylation, reduction, amination, and amino acid ligation enzymes, and the molecular basis of their antimicrobial activity. We expand and refine the framework for phosphonic acid natural product genomics through the isolation of new compounds from cryptic gene clusters, discovery of new pathways and enzymes for C-P bond formation, and the development of a classification scheme to improve prediction of phosphonic acid gene clusters and their chemical products.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY/ABSTRACT This innovative T32 proposal addresses a critical need to train emerging postdoctoral scientists to become leaders in cardiometabolic science. At the intersection between cardiovascular disease and metabolic disorders lies excess morbidity and mortality, best addressed by successful scientists and research integrated in these areas. Our proposal addresses 3 aspects of the training need: First, these scientists require training from both cardiovascular and metabolic researchers. Second, training must occur in an environment where relevant interdisciplinary collaborations among successful mentors are already underway. Third, the advancement of women scientists must be actively pursued by both men and women to maximize the talent pool. Drs. Hsueh and Raman, internationally-recognized, established investigators in diabetes/metabolism and cardiovascular medicine, have brought together a team of NIH-funded cardiovascular and metabolic researchers at the Ohio State University (OSU), with a dual mentorship training design that gives trainees essential cross-disciplinary scientific and professional guidance. OSU’s environment for cardiometabolic training is unparalleled, with faculty in the Davis Heart and Lung Research Institute and the Diabetes and Metabolism Research Center (Hsueh, Director) engaged in NHLBI-funded research across basic, translational, and clinical disciplines. To advance women in cardiometabolic science, this T32 leverages a number of programs across OSU including a predoctoral T32 program for diversity in cardiovascular science led by co- investigator Dr. Rafael-Fortney. Faculty mentors have been chosen specifically both for their productive track records and for research publication productivity and NIH award success of their trainees. We will enroll 2 new postdoctoral trainees per year for 2 years’ training, with a 3rd slot supported by OSU College of Medicine (COM, PhD) and Department of Internal Medicine (DOIM, MD or MD-PhD) funding. Recognizing that physician scientists may be less competitive for a first K award due to inadequate research time, a third year of postdoctoral training, covered by DOIM funds, is provided for physician trainees. OSU’s success in attracting physicians willing to invest the needed time in research training is evident by such successful entities as the Physician Scientist Training Program (PSTP). Highlights of this T32 include clear milestones, development of a formal course in Cardiometabolic Science that distinguishes this program as an independent discipline, regulatory sessions, and effective efforts across many institutional layers to change culture towards advancement of women in cardiometabolic science. Individualized development plans are assessed by metrics such as publications, career development awards, completion of coursework and workshop, and transition to research and academic careers. Our faculty, infrastructure, leadership, trainee pool, and unique scientific focus will deliver male and female cardiometabolic scientists and fill a critical postdoctoral training gap.

NIH Research Projects · FY 2025 · 2020-09

Project Summary Acute kidney injury (AKI) and chronic kidney disease (CKD) are more prevalent in elderly individuals due to the increased susceptibility to injury and diminished repair capability of the aging kidney. Age-related decline of renal function may reflect multicellular dysfunction that leads to reduced capability of the kidney to repair or regenerate in response to stress. Our group previously identified MG53 as a key component of cell membrane repair, which plays a vital role in protection against AKI. We know that renal proximal tubular epithelia (PTE) contain endogenous MG53 protein. In principle, compromised function of MG53 to repair injury to PTE may be an intrinsic mechanism that contributes to reduced kidney function in aging. We also know that MG53's myokine function in tissue repair is compromised in aging. A loss of the crosstalk from muscle to kidney may constitute an extrinsic mechanism leading to the increased vulnerability of the kidney to function properly during aging. This project is centered on testing the hypothesis that MG53 participates in the multicellular process of aging-related AKI and CKD by maintaining the integrity of PTE cells and facilitating muscle-kidney crosstalk. We have made a novel finding that links MG53's myokine function in control of intracellular Ca signaling to modulation of inflammasome activation associated with kidney injury and fibrosis. Thus, we developed a novel concept that engineering of macrophages with tailored secretion of MG53 can enhance renoprotection via harnessing inflammation and fibrotic remodeling associated with CKD. If proven, these findings can have a significant impact on geriatric medicine research, as chronic inflammation and fibrosis occur during the aging process and can impact the function of many organs including kidney.

NIH Research Projects · FY 2025 · 2020-09

Summary Antimicrobial resistance is an increasingly critical threat to human and animal health. In the US alone, >35,000 individuals die each year because of infections with antimicrobial resistant organisms. A common source of resistant bacterial pathogen exposure is food, in particular fresh retail meat products. Most foodborne bacterial pathogens present in retail meat products also colonize the gastrointestinal tract of food animals during production. Contamination of meat products occurs during the harvest process when GI contents, including fecal bacteria, contaminate the carcass. Despite improved food safety, the burden of foodborne illness has remained relatively unchanged for the past decade, affecting 1 in 6 individuals in the US annually. To help address this important public health problem, we propose to continue as a NARMS retail meat and seafood surveillance collaborating laboratory. As our contribution to the NARMS program, we will accomplish the following specific aims: 1) Contribute to national surveillance of foodborne pathogens and indicator bacteria as part of the NARMS retail meat and seafood surveillance program, 2) Support outbreak investigations of foodborne disease by providing field epidemiology and laboratory support to other agencies in Ohio, and 3) Conduct field research to understand the reservoirs for zoonotic foodborne transmission, and the molecular epidemiology of antimicrobial resistant pathogens and indicator bacteria in fresh retail meat products. To accomplish these specific aims, we will serve as a NARMS retail meat and seafood surveillance project contributing laboratory. As a large cluster surveillance site, we will sample retail poultry, beef, pork, and seafood from retail stores within both metropolitan and rural Ohio. All required monthly samples will be cultured for specific pathogens and indicator bacteria. The resulting isolates will be further characterized and shipped monthly to FDA for antimicrobial susceptibility testing, with duplicate isolates maintained in our culture collection. We expect to successfully sample all required packages of retail beef, pork, poultry, and seafood annually that will help to track the current state of antimicrobial resistance among foodborne pathogens and indicator bacteria found in retail meat and seafood but will also impact future FDA policy and regulations and monitor the success of actions and interventions. In addition to our contributions to the retail food surveillance program, as a NARMS participating laboratory, we will be available to support foodborne disease outbreak investigations in Ohio and nearby states as needed.

NIH Research Projects · FY 2024 · 2020-08

Cardiac fibrosis is a grim consequence for almost all myocardial injuries. In myocardial infarction (MI), what starts as a protective scarring process to prevent ventricular wall rupture becomes a pathological remodeling of the tissue with the accumulation of excess extracellular matrix (ECM) proteins. Eventually, this adaptation impedes the mechanical and electrical properties of the myocardium resulting in heart failure. Recently, we showed that periostin (Postn) expressing cells that arise from resident cardiac fibroblasts (CFs) are a potential therapeutic target since they differentiate into the scar associated, matrix-producing cell-type after MI injury. In fact, deletion of these cells after an acute MI injury eliminates interstitial fibrosis but results in ventricular rupture which is a hallmark outcome of impaired ECM deposition during the acute phase of MI. However, if we delete these cells during a chronic injury such as pressure overload-induced cardiac fibrosis model, we detect sustained perivascular fibrosis. Previous studies also report heterogeneity of origin and function for ECM-producing cells associated with different cardiac diseases. Consequently, our inability to identify cell- and state-specific therapeutic targets render cardiac fibrosis yet an incurable disease. Therefore, there is a critical need to determine the cellular composition and functional heterogeneity within ECM-producing fibroblasts. Until very recently, the main limitation has been the inability to accurately interrogate and manipulate the activities of different CF sub-populations differentiated from cells, including pericytes, endothelial cells, resident inflammatory cells in vivo given a lack of cell type-specific genetic tools. Recently, we and others have generated several novel genetic tools that now allow us to investigate all of the matrix-producing cells and their activated forms. Utilizing these new genetic tools in lineage tracing, gain-of-function, and loss-of-function studies, we will interrogate and determine the origin and function of all ECM-producing cell types as well as the molecular mechanisms that regulate CF sustained pathological activation and differentiation after acute or chronic disease models in mice. Our recent work where we effectively interrogated Postn expressing CF lineage in comparison to Postn negative CFs in a single-cell RNA sequencing analysis revealed distinct gene expression profiles between these two populations. Depending on the injury type, such as hearts subjected to MI, TAC, or Angiotensin induced fibrosis, we observed differences in ECM components as well as cellular composition. Finally, our preliminary data showed here identify another cell lineage that involves perivascular fibrosis. Therefore, we hypothesize that pathological ECM deposition resulting in fibrosis comes from disease-specific specialized sub-populations of CFs with distinct gene expressions. The following aims will rigorously interrogate CF subpopulations and the molecular mechanisms that regulate CF activation and ECM composition.

NIH Research Projects · FY 2024 · 2020-08

MIDAS: Microangiopathy, endothelial Damage in Adults undergoing Stem cell transplantation ABSTRACT Hematopoietic cell transplant-associated thrombotic microangiopathy (HCT-TMA) is a clinical diagnosis based on consensus criteria and associated with high mortality rates (80%). Approximately 9,000 hematopoietic cell transplant (HCT) procedures are performed in the U.S. annually, and reported frequencies of HCT-TMA are highly variable due to lack of routine screening. HCT-TMA is a morbid and potentially life-threatening complication of HCT including microangiopathic hemolytic anemia, renal dysfunction and neurological symptoms. The initiating event of HCT-TMA appears to be endothelial injury, and extensive data indicate decline in endothelial health as people age suggesting that HCT-TMA might be more frequent or severe in older persons. Preliminary data indicate a bimodal distribution of HCT-TMA in adults, with a peak early after transplantation, which is well described in children, but a second later peak 3-6 months after transplant, sometimes associated with a flare of graft versus host disease (GVHD) during taper of immune suppression. There is no reported prospective study of HCT-TMA in adults thus risk factors and outcomes are currently unknown. This is a key gap in current knowledge and we plan to address this gap in our proposal. The need for a prospective adult cohort study of HCT-TMA is urgent as older patients are increasingly eligible for HCT. This study will define clinical phenotypes, risk factors, and possible therapeutic strategies for HCT-TMA. Our overarching hypothesis is that “The etiology and risk factors for HCT-TMA are different in adults than children, and that these differences importantly modify potential diagnostic and therapeutic strategies”. We propose to identify strategies that will define HCT recipients with increased susceptibility to HCT-TMA occurring early after transplantation, and later after establishment of GVHD. Identifying endothelial injury occurring post-HCT at the earliest possible time will allow for prompt clinical intervention and interruption of the cycle of endothelial injury and complement activation. The centers participating in this study are ideal for this work because they are large transplant centers with a strong track record of successful clinical research and study enrollment with a long-standing interest in HCT- TMA, evidenced by previous publications in the area. We will use our prospectively generated, well-annotated clinical database to test hypotheses regarding pathophysiology, for example, that GVHD is a major contributor to HCT-TMA by examining clinical risk factors and biomarkers of endothelial injury. We will measure the financial cost of HCT-TMA, late organ toxicity and will formulate and test a predictive index for HCT-TMA to target monitoring and treatment to highest-risk individuals. In summary, this study will provide essential data to identify persons at highest risk of HCT-TMA to allow testing of future clinical interventions such as studies of endothelial protecting agents and complement or interferon inhibitors for HCT-TMA and development of evidence-based guidelines for screening and diagnosis of HCT-TMA in adults.

NIH Research Projects · FY 2024 · 2020-08

Abstract Cancer genomics aims to improve our understanding and treatment of all cancers by identifying differences in DNA sequence and gene expression between tumor cells and normal host cells. Cancer genomics has contributed to many advances in treating several cancers, but the field is limited by a lack of genomics data. The Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network will promote and support research on direct participant engagement approaches to address these gaps, especially among rare cancers, highly lethal cancers, cancers with an early age of onset, cancers with high disparities in incidence/mortality, and cancers among under-represented minorities. Our team wishes to contribute to the important work of the (PE-CGS) Network by serving as its coordinating center. We have the necessary faculty, resources, and experience to address the needs and goals of the Network by supporting network coordination, promoting effective and equitable outreach and promotion, and establishing and disseminating network best practices. In addition to meeting all the requirements of the RFA, we bring innovation by establishing Participant Engagement Community (PEC) by applying the principles of community-based participatory research and by promoting a diverse pool of future scientists, especially those from underrepresented groups through a Summer Scholar Program and by two post-doctoral positions that will be supported by our comprehensive cancer center. Our proposal for the coordinating center is focused around four specific aims. First, we will effectively manage administrative and scientific coordination of the PE-CGS network. This will include providing administration/coordination, governing all advisory, organizing meetings/site visits, fostering collaboration, dissemination and implementation, and coordinating communication. Second, we will foster effective and culturally appropriate outreach and promotion activities. We will establish a common branded, public relations, communication resources, facilitating interactions, and managing outreach. Third, we will develop and disseminate network best practices and data collection/processing standards. We provide support for participant engagement and cancer genome sequencing activities, establish data standards, ensure data are accessible to the public, data are appropriately shared, and support efforts to make the Network sustainable. Finally, we want to address health disparities and promote equity throughout the Network and ensure there is a diverse pool of future scientists, including those from underrepresented groups, to support future efforts in participant engagement and cancer genomics. We envision that the network will need to evolve to address emerging issues in participant engagement and believe that being based in a university setting will provide us the capacity to anticipate and address these issues as they emerge. We are strongly supported by the OSU College of Medicine, the OSU Comprehensive Cancer Center, and the OSU Center for Clinical and Translational Science.

NIH Research Projects · FY 2024 · 2020-08

Abstract A major concern in cochlear implantation is the loss of residual hearing associated with surgery. Hence, many candidates are faced with the decision to relinquish their remaining acoustic hearing in exchange for electric hearing via the cochlear implant (CI). A potential solution is a stimulation strategy termed Electric acoustic stimulation (EAS), which has been used to describe the ipsilateral combination of electric hearing via a CI and acoustic hearing via a hearing aid. This, however, requires preservation of residual hearing, which has been possible but inconsistent. A new technology to potentially improve hearing preservation, intraoperative electrocochleography (ECochG), has been introduced and it was recently implemented into commercially available CI systems. Studies comparing EAS with conventional CI have were able to demonstrate a performance benefit of EAS. However, these studies have compared conventional CI candidates to EAS candidates with more residual hearing. Thus, the clinical importance of residual acoustic hearing in cochlear implantation (CI) remains unclear. Therefore, the present protocol seeks to answer two critical clinical questions in cochlear implantation: (Specific Aim 1) Are cochlear implant electrode insertions using Electrocochleography (ECochG) feedback better for achieving hearing preservation (HP) and (Specific Aim 2) is combined ipsilateral EAS better than non-HP (conventional) cochlear implantation among CI candidates with substantial residual hearing (EAS candidates). We plan to enroll and randomize EAS candidates in seven large US centers. Patients will be assigned to either intraoperative ECochG monitoring or conventional CI electrode insertions. Hearing preservation and other performance outcomes will be recorded and analyzed between the groups to assess the clinical value of intraoperative monitoring. Further, subjects from both groups will have either useable or no useable residual hearing as the result of surgery. Audiometric and patient reported performance outcomes will be obtained and evaluated for 24 months following initial stimulation. In summary, the present proposal aims to answer two critical clinical questions: Is CI electrode insertion based on ECochG better for achieving HP? and Is EAS better than conventional cochlear implantation among EAS candidates? A positive answer to these questions will inform an evidence-based clinical practice for EAS candidates that uses longer electrodes, broadens the candidate pool by including patients with greater levels of residual hearing, and potentially improves outcomes following CI.

NIH Research Projects · FY 2026 · 2020-08

Project Summary and Abstract The core objective of the proposed research is to develop synthetic methodologies that accelerate molecular diversification of complex molecules and pharmaceuticals. The targeted chemistries constitute challenging C–C and C–X (heteroatom) bond-forming reactions from abundant starting materials and leverage electrochemistry to uniquely control reactions. The resulting transformations will provide chemists with the synthetic tools to ex- plore new regions of chemical space for therapeutics based on new molecular architectures. Synthetic access to these new structures will enable accelerated drug discovery, new treatments, and reduced side effects. Goal 1. To create synthetic platforms for molecular diversification. Persistent and isolable oxidative additive complexes (OACs) will be prepared from abundant alkyl and aryl electrophiles of drug-like molecules. These OACs will serve as synthetic platforms from which a wide range of new cross-coupling reactions can be per- formed. Collaborative research efforts will implement data-science as a tool to thoroughly evaluate the capabili- ties of the developed methods as applied to new chemical space. Ligand architectures for next-generation OACs will be designed that enable challenging or unknown coupling reactions. Finally, OACs will be employed to study reaction mechanisms and benchmark reactivities of electrophile classes at activated metal complexes to facilitate catalytic reaction design. Goal 2. To develop intramolecular cross-electrophile coupling (iXEC) reactions. iXEC methodologies will be developed that serve as new annulation strategies to form aliphatic heterocycles, macrocycles, and strained rings. Ring-closing reactions from combinations of electrophiles (halides, triflates, redox-active esters, Katritzky pyridiniums) will be developed to form C(sp2)–C(sp3) or C(sp3)–C(sp3) bonds. Multiple strategies – guided by planned mechanistic studies – will be pursued to develop these desirable, but rare, intramolecular reactions. Goal 3. To activate new classes of electrocatalysts for reactions of challenging electrophiles. Electrocat- alytic reactions catalyzed by complexes of phosphine or N-heterocyclic carbene ligands will be developed. Cur- rently, redox reactions (echem/photo/chem) are primarily performed with complexes of pyridyl ligands, which limits the scope of substrates that can be modified in redox-driven reactions. Expanding electrocatalysis to the full portfolio of transition metal catalysis will equally expand the breadth of substrates that can be activated. While direct electron transfer to these non-traditional redox catalysts generally fails, we will leverage dynamic ligand exchange to transiently generate redox-active complexes. We will explore combinations of ligands that undergo these exchange reactions and build models for predicting ligand pairings based on the physical properties of the ligands. The identified catalyst systems will be utilized for coupling reactions of C–O and C–Cl electrophiles.

NIH Research Projects · FY 2025 · 2020-07

The acid sensing ion channel1a (ASIC1a) is essential for normal brain function, but initiates neuronal death and contributes to ischemic brain injury. Prolonged reductions in extracellular pH accompany ischemia and ASIC1a inhibition limits neurological damage. Yet, ASICs also play an important role in normal physiology and established models of ASIC-induced cell death make it difficult to develop strategies that specifically inhibit ASIC1a toxicity. Our preliminary data support a newer model of ASIC1a-induced cell death. Specifically, we have discovered that the toxic effect of ASIC1a can be eliminated by modification of the intracellular region of the channel or activation of the delta opioid receptor (DOR). An especially provocative aspect of these findings is that acidotoxicity is inhibited without a reduction in ASIC1a current, thereby suggesting that the toxic and physiological actions of the channel can be separated. Our central hypothesis is that DOR prevents acidotoxicity through signaling cascades, which act on the intracellular domain of ASIC1a to limit protein interactions required for toxicity. To test this hypothesis, we will define the mechanisms governing DOR action on ASIC1a and elucidate their role in ischemic injury in vivo. The outcomes of the proposed work will reveal novel regulatory mechanisms controlling ASIC1a-induced toxicity, suggest new interventions to mitigate ASIC-induced death using existing DOR agonists, and reveal strategies to separate the physiological and pathological actions of ASIC1a. These results will be significant as they are expected to have broad implications for the prevention of brain injury following ischemic stroke as well as other disorders where neuronal acidotoxicity plays a role.

NIH Research Projects · FY 2024 · 2020-07

THE TRANSLATIONAL REGULATION OF PRO-APOPTOTIC GENES PROJECT SUMMARY Inactivation of the Retinoblastoma 1 protein (pRB) is one of the most common alterations in cancer. This is because pRB inhibits the activity of three E2F transcription factors, E2F1-3, that control the expression of numerous critical RB-E2F target genes that are required for cancer cell growth, including cell cycle and metabolic factors. In addition to tumor-promoting processes, E2F1-3 also regulates the transcription of tumor-inhibiting genes that play a central role in apoptosis and necrosis. This regulatory circuit links the expression of RB-E2F proliferation and cell death genes, ultimately preventing uncontrolled cell growth. The widespread loss of pRB in cancer underscores a significant puzzle in the field: why don’t pRB-deficient cells simply die? To understand the regulation of the RB-E2F target genes, we profiled RNA and protein changes following pRB- depletion and found that the pro-apoptotic genes were transcribed, but they were not translated into protein. A search for RNA-binding proteins (RBPs) that bound to and blocked the ribosome occupancy of these genes identified the Pumilio complex as direct translational regulators of RB-E2F pro-apoptotic mRNAs. Furthermore, co-deletion of the two core components of the Pumilio complex, PUM1 and PUM2, provoked the cell death of RB1-/- cancer cells via the translation of pro-apoptotic mRNAs. The human Pumilio complex is comprised of PUM and NANOS (NOS) proteins, however significant functional redundancy between the members of the PUM and NOS protein families has limited cellular and tumor studies of the Pumilio complex. To circumvent this issue, we have engineered human cells to express only a single PUM or NOS protein that we can specifically degrade utilizing a novel Auxin-inducible degron system. This technical advance has enabled us to conduct kinetic analysis of RNA stability, localization and translation initiation in the absence of PUM or NOS and to probe the role(s) of different Pumilio complexes in cellular regulation and tumorigenesis. In this new application we propose to: 1) Determine the mechanism(s) of Pumilio complex translational suppression of RB-E2F target pro-apoptotic genes, 2) Define the mechanism of Pumilio complex regulation in RB1 mutant Small Cell Lung Cancer (SCLC) cells, and 3) Determine the role of the Pumilio complex in the Rb1-/-; Trp53-/- mouse SCLC tumorigenesis model. These studies will identify the mechanism(s) that prevent the production of cell death components in highly aggressive and metastatic SCLC.

NIH Research Projects · FY 2025 · 2020-07

PROJECT SUMMARY In humans, microRNAs (miRNAs) are key components of mature RNA-induced silencing complexes (mature RISCs) involved in silencing specific genes. Recent research has uncovered a new class of smaller RNAs called tinyRNAs (tyRNAs), which are shorter than miRNAs and associate with AGO proteins to form tyRNA- induced silencing complexes (tyRISCs). A significant discovery is the existence of a tyRNA biogenesis pathway driven by specific exonucleases, resulting in the production of 14-nt tyRNAs from AGO-associated 21~23 nt miRNAs. Some tyRNAs, known as "cleavage-inducing tyRNAs (cityRNAs)," can catalytically activate Argonaute3 (AGO3). Despite these breakthroughs, the study of tyRNAs is in its infancy, with only a limited number of papers compared to miRNAs. The primary goal is to comprehensively understand the roles of tyRNAs, with three specific aims: Aim 1: Investigate the mechanism of target recognition and cleavage by cityRISC. AGO3 loaded with 14-nt cityRNA cleaved a complementary target RNA at low efficiency. Cleavage was enhanced when the target was extended by 9 nt on its 5' side, suggesting AGO directly recognizes the sequence of the extended target site. This challenges the conventional idea that the guide is essential for target recognition. Structural studies and RNA sequencing will provide insights into this unique target recognition. Aim 2: Explore the structural basis for neurodevelopmental disease-relevant AGO1s (NDD-AGO1s). NDD- AGO1s with specific mutations exhibit abnormal trimming of associated miRNAs. Cryo-EM structures of these mutant AGO1s will reveal structural alterations compared to wild-type AGO1. Additionally, the interaction between AGO1 and poly(A)-specific nuclease (PARN) will be examined to understand the distinct trimming patterns. Aim 3: Determine the silencing ability of NDD-AGO2-RISCs loaded with tyRNA (NDD-AGO-tyRISCs). The study will investigate whether NDD-AGO2 mutants exhibit similar miRNA trimming as NDD-AGO1s and assess the silencing capability of NDD-AGO2-tyRISCs. Co-localization of NDD-AGO2-tyRISC with AGO-binding proteins will be analyzed. Through these aims, the research aims to unravel the mechanisms of target recognition by cityRNAs, understand tyRNA pathology, and characterize NDD-tyRISCs, which may lay the groundwork for potential therapeutic applications.

NIH Research Projects · FY 2024 · 2020-07

PROJECT SUMMARY The objective of this Ohio State University postdoctoral clinical T32 training program entitled: “Training Hematology and Oncology Fellows in Clinical Research” is to provide a state of the art clinical research training experience, specifically for postdoctoral fellows in Hematology and Oncology with an M.D., D.O., or equivalent degree who have demonstrated a firm commitment to patient oriented cancer research. The overriding goal of this training program is to prepare Hematology and Oncology fellows in the OSU Divisions of Hematology and Medical Oncology for academic careers in patient oriented clinical and translational cancer investigation. Progress in cancer therapy and prevention requires strong collaborative efforts, and patient oriented physician investigators provide a critical link with physician-scientists and basic scientists toward this goal. The recent explosive growth of scientific discoveries and the increasing complexity of cancer clinical trials, particularly phase I/II studies of novel therapeutic agents and regimens, make it imperative that trainees in Hematology/Oncology acquire the proper training through appropriate mentoring, to prepare them for careers in clinical and translational investigation. This T32 program will prepare fellowship trainees for productive academic careers by providing an intellectually rigorous curriculum, strong mentoring and support from senior faculty, protected time for academic training during fellowship, “hands on” experience in developing and writing clinical studies and research papers, and ample opportunities to enhance their OSU experience with extramural programs and workshops sponsored by the NCI or other professional academic organizations such as ASCO and ASH. The participating members consist of the 2 Program Directors, Coordinating Committee members, Advisory Committee members, primary mentors, and contributing faculty, who were chosen based on their prior track record of successful mentoring and their demonstrated commitment to clinical and translational research. T32 fellows will commit for two years of training. The strengths of the OSUCCC, primarily in the fields of cancer prevention and experimental therapeutics, is the perfect environment to our planned success. Our T32 proposal is designed to foster and ensure the development of fellowship trainees, who we will train to assume academic clinical research positions as faculty members upon graduation. The T32 program is engineered to empower trainees to become independent clinical and translational investigators. Trainees will have mandatory an elective training in various settings, including the opportunity to obtain one or two master degrees; they will be required to create an investigator initiated clinical study and will start its implementation during training; they will be required to apply for funding for their own study through peer reviewed grant mechanisms; and they will be offered the opportunity to network nationally with the NCI and oncology professional organizations. OSUCCC is also deeply committed to training women and members of underrepresented racial and ethnic groups for academic careers as shown in continuous efforts to recruit and train female and underrepresented minority fellows.

NIH Research Projects · FY 2024 · 2020-07

PROJECT SUMMARY/ABSTRACT The goal of this study is to identify the pathways through which poverty conditions and the early family context contribute to persistent language disorder at age 9 years among young, low-income children. This renewal seeks to continue to follow a sample of 311 children ascertained in the first year of life and followed to age 4 years to determine pathways through which the early family context increase susceptibility to developmental language disorder at school entry. The study is designed to address disparities in the rate of DLD among young children, with low-income children disproportionately affected (Norbury et al., 2017). The proposed longitudinal study addresses three specific aims regarding low-income dyads: (1) to model the language trajectories from ~2 to ~9 years and reading trajectories from ~5 to ~9 years for children from low-income homes as a function of DLD status at school entry; (2) to test the Family Stress Model's applicability for specifying the pathways through which the early home context is associated with persistent language disorder at age 9; and (3) to test the Differential Susceptibility Theory for representing how early environmental adversities can contribute to risk for persistent language disorder among young children with DLD. We theorize that low-income children with DLD have heightened risk for persistent language disorder when they experience significant adversities imposed by poverty, in particular parent psychological distress and disrupted parenting. In our longitudinal research design, 12 assessment sessions conducted in four windows over a 5-year period are used to comprehensively measure children's language and reading skills from 5 to 9 years. We couple these data with robust measurement of children's early family context across five dimensions (economic hardship, economic pressure, caregiver psychological distress, interrelationship conflict, disrupted parenting) and children's linguistic trajectories until 54 months. The study aims are addressed using multi-level growth models (including nonparametric modeling) and multilevel path analyses to examine the interplay among children's language and reading trajectories, DLD status at 54 months and persistent language disorder to age 9, and the early family context.