Ohio State University

NIH Research Projects · FY 2025 · 2022-09

OVERALL MULTI-COMPONENT NEI P30 PROPOSAL abstract The Ohio State University Vision Sciences Research Core Program (OSU-VSRCP) has established the expanding vision research scientists across five academic units (i.e., College of Medicine (COM), College of Optometry (COO), College of Engineering (COE), College of Veterinary Medicine, College of Arts and Sciences) and newly engaged Nationwide Children’s Hospital. Program Director (PD) Dr. Moroi has commitment from Deans and Chairs to purchase equipment (i.e., confocal microscope), support data science, assign scarce space, and increase collaborations. The leadership and scientists are aligned with the NEI PAR- 20-051 ‘to enhance the capabilities of participating NEI-funded investigators and the institution for conducting vision research.’ Synergy of this community has been established with monthly ViSOR (Vision Sciences OSU Research) seminars. Synergy between Cores has been defined by the Steering Committee composed of the PD, Core Directors and Co-directors, who represent Dept. Ophthalmology and Visual Sciences (DOVS), Dept. Neuroscience, Dept. Biomedical Informatics, Dept. Computer Science (COE), and COO. Synergy between Cores will coincide with monthly ViSOR meetings. In addition, an Advisory Group will provide guidance twice a year to the Steering Committee. Based on a survey of 61 scientists, three scientific cores are proposed, which are re-organized in response to the prior review led by a Director and Co-director, with at least one of the leaders holding an NEI R01. Core A: Structural and Functional Assessments (SFA) Core A provides technical expertise and well-maintained state-of-the-art equipment for functional and morphological assessment of cells and animal models used in vision research. Dr. Moroi arranged the added value of machine shop services with an agreement with Executive Director Mr. Nate Ames (see letter) of The OSU Center for Design and Manufacturing Excellence (CDME) to enhance funded research projects. Core B: Biostatistics, Bioinformatics and Genetic Analysis (BBGA) Core B was re-organized to consolidate services for traditional statistics and statistical genetics. Users can obtain assistance in research design and traditional statistics, as well as bioinformatics, pathway analysis, and large-scale genomic data mining that require advanced computational analytics. Core C: Image Analysis and Data Science (IADS) Core C was re- organized in response to the growing need for image processing, analysis and data science expertise including machine learning and artificial intelligence (AI) and development of a Data Commons Architecture for the OSU vision community. The expected outcome is increased collaboration for successful new proposals with the shared overarching goal to prevent blindness, restore vision and develop cures for eye diseases.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT Glaucoma affects about three million Americans and is a leading cause of blindness worldwide. Patients suffer from progressive optic neuropathy, for which intraocular pressure (IOP) induced mechanical insults at the optic nerve head (ONH) play a central role. Current treatments all aim to lower IOP. While these treatments are beneficial, many patients continue to lose vision with persistent optic nerve damage. There is a great need to identify other modifiable risk factors, based on which novel treatments may be developed to combat this public health problem. Biomechanically, the level of IOP-induced mechanical insults (i.e., stresses and strains) at the ONH are not determined by IOP alone. Computational studies have shown that peripapillary sclera (PPS) modulus and thickness are among the most influential factors. Interestingly, PPS biomechanical changes are implicated in older age, African American race, and high myopia, which have increased glaucoma risk. However, there is a knowledge gap in understanding the biomechanical interplay between ONH and PPS. For example, what PPS biomechanical properties are optimal and how PPS can be modified to mitigate IOP-induced mechanical insults at ONH remain poorly understood. We propose to use a high-resolution ultrasound elastography technique to resolve the complex mechanical responses of the ONH and PPS through full tissue thickness, and to begin to fill the knowledge gap. Using this technique, we will quantify ONH and PPS deformation in normal human donor eyes, those with PPS remodeling, and those with experimental modification of PPS properties. We will also further develop this technique for in vivo biomechanical imaging of the ONH and PPS in an animal model. Specifically, we propose the following aims: 1) test the prediction that ONH deformation is correlated with PPS deformation and different in older age and African American race, 2) test the prediction that ONH deformation is different in eyes with PPS remodeling, 3) test the prediction that ONH deformation is altered after biochemical stiffening or softening of the PPS, and 4) test the feasibility of in vivo ONH and PPS ultrasound elastography in a pig model. Successful completion of the proposed studies will establish a clear understanding of the biomechanical interplay between ONH and PPS, a key contributor to an individual eye’s mechanical susceptibility to IOP. Combined with the development of an in vivo biomechanical imaging technique, this knowledge will lay a foundation for novel diagnostic and treatment strategies to reduce glaucoma vision loss.

NIH Research Projects · FY 2025 · 2022-09

Project Summary Sulfur mustard (SM) and nitrogen mustard (NM) are potent chemical threats that cause damage to the cornea, including acute photophobia and corneal lesions followed by loss of limbal stem cells (LSCs) and prolonged ulceration and vascularization. Therapeutic approaches targeting both the acute and prolonged phases of SM/NM toxicity can potentially provide effective measures to counteract corneal injuries. We provide novel findings that support the benefits of MG53, a tissue repair protein, in treating vesicant-induced corneal wounds. Compared with wild type mice, mg53-/- littermates show delayed corneal re-epithelialization, increased vascularization and conjunctivatization following NM exposure, all hallmarks of LSC deficiency. Further, transgenic mice with sustained elevation of MG53 are resistant to NM-induced corneal injury. We find that the recombinant human MG53 protein (rhMG53) protects against injury to LSCs and corneal epithelial cells to preserve cornea integrity during NM exposure. We also know that MG53 protein is naturally present in the tear film and aqueous humor, supporting the physiology of MG53 in corneal homeostasis and the safe nature of using rhMG53 to treat corneal injuries. The goal of this U01 project is to develop rhMG53 as a potential effective protein therapeutic to mitigate the acute and prolonged phases of vesicant corneal injury. We will formulate rhMG53 for ocular application as a first-aid medicine that can be stockpiled as a medical reserve and rapidly deployed to affected patients in the event of chemical threats. In vitro and ex vivo studies will be performed to elucidate the mechanistic action of MG53 in protecting against NM-induced injury to LSCs and corneal epithelia. Validation studies will be conducted with rhMG53 in mouse and rabbit models of vesicant-induced corneal injuries to determine the therapeutic efficacy and safety windows of rhMG53 in rescuing cornea function. Overall, this U01 program provides a unique opportunity to advance the biology of MG53 into an important counteract therapeutic.

NIH Research Projects · FY 2024 · 2022-09

Project Summary Type 2 diabetes (T2D) in pregnancy increases the risk of adverse outcomes for both the mother and infant. Over 1 in 3 infants born to individuals with T2D will experience an adverse outcome, including large for gestational age at birth, preterm birth, birth trauma, neonatal hypoglycemia, and stillbirth. Strict maternal glycemic control throughout pregnancy is key to optimizing perinatal outcomes. This is possible with insulin pharmacotherapy, vigilant glucose monitoring, lifestyle modifications including diet and exercise, and team-based prenatal care. Medicaid-enrolled pregnant individuals with T2D experience non-medical social needs that limit their ability to achieve glycemic control, including lack of reliable transportation to attend prenatal visits, access to resources to engage in diet and exercise changes, and convenient methods to log self-monitored glucose values and adjust insulin dosing. A multi-faceted provider-patient based approach is needed with proven strategies to improve glycemic control. We propose “ACHIEVE: Successfully achieving and maintaining euglycemia during pregnancy for type 2 diabetes through technology and coaching.” Our intervention is multi- component, including a mobile health (mHealth) application (app), provider dashboard, DEXCOM continuous glucose monitoring (CGM), and care team coaching for medical and social needs. This intervention empowers Medicaid-enrolled pregnant individuals with T2D and their healthcare providers to achieve and maintain glycemic control, improve access to care, and provide patient education and support. Each sub-component of the proposed intervention is grounded in Social Cognitive Theory (SCT), and emphasizes on individuals’ skills, knowledge and beliefs, and self-efficacy to achieve glycemic control. We propose three aims: AIM 1: Develop the tailored ACHIEVE mHealth app and provider dashboard for Medicaid-enrolled pregnant individuals with T2D and their healthcare team through active stakeholder engagement; AIM 2: Conduct an RCT and measure the effect of the intervention (mHealth app with CGM, provider dashboard, and care team coaching) compared to current standard care (prenatal visits, self-monitored blood glucose, and certified diabetes care and education specialist) on achieving glycemic control (hemoglobin A1c <6.5% in the third trimester). We hypothesize a 25% absolute increase in the proportion of participants in the intervention group who will meet the target hemoglobin A1c <6.5% in the third trimester compared to the standard care group; and AIM 3: Identify multi-level patient and provider barriers and facilitators to satisfaction, engagement, and use of the intervention and its subcomponents.

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT The widespread availability of synthetic opioids (fentanyl) has fueled the rapidly rising rates of unintentional over dose (OD) fatalities. Policy makers, state and local agencies, and investigators have focused on the Ohio experience as a bellwether for the experiences of other states because of the representativeness of Ohio’s demographics. The lack of timely geospatially-linked longitudinal data sources has impeded the ability of communities and state agencies to pivot allocation of resources to regions where they are needed most. Limited integration of environmental risk factors such as sociodemographic characteristics fail to support identification of new targets for intervention or new approaches to emerging threats from changes in local drug supply. We believe that agile data systems and informatics tools that can be used to demonstrate the utility of predictive analytics and machine intelligence approaches on how to enable data-driven decision making will ultimately prove translatable across the country and diverse localities. Our proposed Opioid and Substance Use Disorder Data Enclave (O-SUDDEn) will provide a novel and transformative approach to support rigorous and reproducible research on the opioid and substance use crises. O-SUDDEn will fill several existing gaps in data infrastructure and prediction models that include machine learning, geospatial analyses, and community context. The specific aims for O-SUDDEn are as follows: Aim 1: Data linkage with establishment of O-SUDDEn. We will develop a geospatially-sensitive, individual-level secure data lake that integrates multiple disparate data sources that meets the requirement of a coded-limited set under HIPAA. New data sources include real-time individual-level longitudinal data from urine drug testing (UDT) and community contextual data based on the Ohio Opportunity Index, an area-level social determinants of health developed and used by our team. We will develop query and use tools for data harmonization and integration, prepare and release data sets for dissemination and secondary data analyses; and facilitate secondary use of related administrative data to generate evidence that informs targeted opioid interventions. Aim 2: Develop Predictive Models and Surveillance algorithms. Geospatial and machine learning will be used to model the contribution of opioid, cocaine, and stimulant use on OD, OD death and opioid use disorder/substance use disorder (OUD/SUD); temporal relationship of real time data including UDT and demographic and contextual variables to identify high- risk populations and subpopulations or geographic locales. We will validate model performances and predictive power and then disseminate surveillance and forecasting algorithms through the O-SUDDEn portal for end-user access. Aim 3: Deploy a human-centered platform and actional informatics. Applying co-design principles with a human-centered work group consisting of end-user stakeholders (community, researchers, and state policy makers/agencies), we will develop and deploy an end-user tailored portal and effective user-friendly tools to provide actionable insights to inform opioid treatment and targeted harm reduction strategies.

NIH Research Projects · FY 2025 · 2022-09

Project Summary Nasal sinus disease is one of the most common medical conditions in the US, affecting an estimated 13% of adults, or some 30 million people, and responsible for $5.8 billion in health care expenditures annually (National Health Interview Survey 2009, CDC). Nasal obstruction and smell loss are two of the major symptoms of the disease; however, the field currently lacks a clear, objective understanding to the mechanisms causing these symptoms, which thwarts effective treatment. For example, patients’ complaints of nasal obstruction correlate poorly or inconsistently with objective measurements of actual physical obstruction. Olfactory loss is widely believed to be induced in part by airflow blockage that prevents sufficient ambient odor from reaching the olfactory region; however, no tool has been able to evaluate and target such conductive causes. Without validated clinically tools, current treatment of these symptoms relies primarily on the patient’s subjective feedback and the doctor’s personal training and experience, which can lead to inconsistent and unsatisfactory outcomes. Through a series of preliminary studies, we demonstrated that the symptom of nasal obstruction may be caused not by obstruction per se but by poor sensing of airflow during breathing, through the trigeminal cool-sensitive (TRPM8) pathway, and that such sensing may be worsened by impaired trigeminal function. However, which trigeminal sensory regions and what nasal airflow anomalies are most critical to disrupt the sensing of airflow are still unknown. To establish a more direct link, in Aim 1 of this proposal, we will examine the critical trigeminal sensory regions and critical nasal airflow distortions that may better predict airflow perception and obstruction symptoms. TRPM8 is a major component of the cool afferent pathway that is also activated chemically, which offers a unique dual investigatory tool to broaden our understanding of chemosensory function in nasal sinus disease and open up new therapeutic directions. So in Aim 2, we will investigate the efficacy of a novel patent-pending “nasal aid” to improve patients’ symptoms by modulating nasal airflow and trigeminal sensory feedback and to improve future treatment outcomes based on what we have learned and will continue to learn about the airflow trigeminal perception mechanisms. We have also shown in a series of published studies that complicated relationships exist between nasal obstruction and olfactory function. Based on these findings, in Aim 3 we propose to explore how to potentially improve olfactory function in patients with likely conductive olfactory loss, by enhancing nasal odor/air flow to the olfactory region (another pending US patent), analogous to hearing aids or eye glasses that amplify peripheral sensory stimuli. The outcomes from this research may potentially validate several novel clinical tools to better identify factors that most affect patients’ obstructive symptoms and to relieve symptoms by modulating nasal airflow patterns. The ultimate goal is to assist patients and clinicians in planning effective, well-informed, personalized treatment strategies, potentially saving millions of health care dollars annually while improving patient satisfaction.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY/ABSTRACT There are currently limited treatments available to treat non-operable brain cancers, and none that meaningfully extend the lifespan of patients. Imaging these diffuse tumors is also a challenge, and current fluorescent probes emit in wavelengths with high biological background fluorescence. This proposal describes the development of novel dye molecules that emit in the near-infrared II (NIR-II)/shortwave infrared (SWIR) region (1000 – 2000 nm). Within the NIR-II/SWIR region, higher resolution images are found at longer wavelengths. No small molecule emitters have peak emission beyond 1400 nm and only one known molecule has peak emission >1250 nm. We have preliminarily synthesized two fluorescent materials with emission maxima conservatively projected at ~1700 nm and >1900 nm. These dyes offer the ability to see further into the SWIR region than any other reported organic small molecules where image resolution is the highest. Additionally, we proposed to synthesize materials with shorter wavelength emission than these materials >2000 nm where imaging depth and contrast both are suggested to continually improve based on the current literature. In order to effectively deliver the dye molecules into the brain, we have to encapsulate them into nanocarriers. Linear-dendritic block-copolymers (LDBCs) represent a highly functionalizable material for drug delivery vehicles. Its dual linear/dendritic nature makes it excellent at encapsulating a variety of molecules. We use biocompatible ionic liquids (ILs), molten salts comprised of asymmetric cations and anions, to `tune' the affinity of nanoparticles to different cell types. Using this strategy, we have developed an IL that promotes nanoparticle `hitchhiking' on erythrocytes to deliver them to the brain, and achieves cell-selective targeting of microglia once delivered to the central compartment. Preliminary data in rats demonstrate ~48% of injected nanoparticles accumulating in the brain within 6 hours, a vast improvement over current nanoparticle delivery strategies. To this end, we will (Aim 1) generate a library of novel NIR-II candidates, in addition to our current leads, that show peak emission at 1700 – 2000 nm, package them into LDBCs, and coat the nanoparticles with ILs. We will measure their photophysical properties and confirm the preference that ILs confer to murine and human blood components as potential cargo carriers. (Aim 2) We will assess the safety (subacute, acute, subchronic, reproductive, mutagenic) and biodistribution of up to 5 leading formulations in rats, and capture high-resolution live brain imaging. (Aim 3) Lead candidates (based on CNS distribution and photophysical properties) will be assessed in vitro and in vivo in a xenografted glioblastoma rat model.

NIH Research Projects · FY 2025 · 2022-09

There are an estimated 50 million Americans with chronic kidney disease (CKD), and the care provided to people with CKD and end stage kidney disease exceeds $114 billion annually. Despite these numbers, recent data indicates that there is a significant workforce shortage in the field of nephrology and that the total number of grants submitted to the NIH focused on kidney and urologic diseases and disorders has decreased over the past decade. This dichotomy creates a significant need to reverse the current trends and increase the number of trainees interested in pursuing a career in nephrology and urology that includes an NIDDK-related research focus. To begin to address these important issues, we propose the development of a new Student Urinary Tract Program in Education and Research (SUPER) Summer Program for undergraduate students. This program will provide new educational, laboratory and clinical experiences for undergraduate students promoting a better understanding of kidney and urinary tract diseases as well as careers in Nephrology and Urology. In addition, the SUPER-Summer Program is designed to integrate into a wide range of pre-existing training programs at The Ohio State University and Nationwide Children’s Hospital providing a seamless NIDDK-focused workforce pipeline. We strongly believe that creating this innovative and well-structured SUPER-Summer Program focused on nephrology and urology related topics will capture student interest early in their career development - thereby increasing the potential workforce population and creating a strong foundation for the next generation of NIDDK-research focused clinicians and scientists.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT Mutations in the PHEX gene cause X-linked hypophosphatemia (XLH), the most common form of hereditary rickets. In XLH, elevated fibroblast growth factor 23 (FGF23) causes renal phosphate (Pi) wasting, hypophosphatemia, reduced 1,25-dihydroxyvitamin D (1,25D), and secondary hyperparathyroidism, all contributing to mineralization disturbances in the skeleton and dentition. Yet current treatments lack efficacy and no treatments are available to specifically improve associated dentoalveolar defects that substantially affect oral health and quality of life in individuals with XLH. Limited efficacy of treatments to date is in part related to the complex etiology of mineralization defects in XLH, including local perturbations that have been overlooked and gone unaddressed. Conventional therapy for XLH, consisting of oral 1,25D and Pi, shows limited improvement of skeletal and dental defects. A recent FGF23-neutralizing antibody (FGF23Ab) treatment targeting excess FGF23 is poised to become standard-of-care. Neither preclinical nor clinical trials of FGF23Ab evaluated dentoalveolar effects. In a pilot study, we found FGF23Ab made limited improvements similar to 1,25D in the Hyp mouse model of XLH. The inability of FGF23Ab and 1,25D therapies to resolve XLH mineralization defects reflects gaps in knowledge about functions of PHEX and pathological mechanisms of XLH, preventing effective treatments. Two mineralization regulators disturbed in XLH are not addressed by current treatments and likely contribute to persistent defects by acting locally in bone and tooth extracellular matrices. PHEX cleaves and inactivates mineralization inhibitor, osteopontin (OPN). Increased OPN in bones and teeth in XLH inhibits mineralization. Additionally, increased production of inorganic pyrophosphate (PPi), a potent mineralization inhibitor, occurs in Hyp mice in association with increased ANK and ENPP1, and decreased tissue-nonspecific alkaline phosphatase (TNAP). Thus, disruptions at both systemic (high FGF23, low 1,25D and Pi) and local (increased OPN and PPi) levels contribute to XLH-associated mineralization disorders. Local factors have not been targeted by treatments to date. TNAP promotes mineralization in local ECM by both reducing PPi and dephosphorylating and inactivating OPN. This project is designed to provide new insights into local mineralization defects in dentoalveolar tissues using a mouse model of XLH, and to test novel treatment approaches to prevent and ameliorate those defects. We hypothesize that correction of OPN and/or PPi in XLH is required to effectively normalize dentoalveolar mineralization and improve oral health. We will test this hypothesis by three aims: (1) To establish the contribution of OPN to dentoalveolar mineralization defects in XLH; (2) To determine the pathogenic role of PPi in dentoalveolar mineralization defects in XLH; (3) To define effects of combined OPN and PPi reduction on Hyp mouse dentoalveolar healing. Expected outcomes include new insights into dentoalveolar mineralization defects in XLH, positively impacting how these may be targeted for improving treatment effects in XLH and other pathological conditions the future.

NIH Research Projects · FY 2025 · 2022-09

The overall goal of this proposal is to develop and advance behavioral assessment methods (BAM) to measure spontaneous reach and grasp in infants and toddlers with and without hemiparetic cerebral palsy. Reach and grasp are critical to promoting healthy development and active engagement with the environment. This proposal focuses on the key period from 8 – 36 months of age when infants rapidly develop upper extremity skills, mobility, cognition, and language; and when hemiparesis-specific treatments, such as constraint-induced movement therapy, can be started. BAM will advance scientific knowledge about typical movements of the arms and hands as well as altered movements in children with hemiparetic cerebral palsy. This will yield a standardized, objective metric that quantifies the distance between impaired and typical development and will expand the precise measurement of treatment-induced recovery. This project includes prospective longitudinal data obtained from typically developing infants and toddlers and leverages video-sharing and support from StrokeNet’s Phase III randomized controlled trial of constraint-induced movement therapy. In AIM 1 we will develop the BAM Index using reach and grasp behaviors in 80 typically developing infants/toddlers and 240 infants/toddlers with perinatal arterial ischemic stroke and hemiparetic cerebral palsy. Videos will be coded for spontaneous reach and grasp frequency, duration, and exploratory behaviors with a common set of objects. Multiple statistical models will be employed to develop four standardized BAM Indices. In AIM 2 we will (a) evaluate the changes of four BAM Indices with 1040 longitudinal videos from the cohorts and (b) establish psychometric properties of the BAM Indices using: the Pediatric Stroke Outcome Measure (Neurological deficit and function); Gross Motor Function Measure-66 (Gross Motor), Bayley Scales of Infant and Toddler Development 4th edition (Fine Motor, Gross Motor, Language, and Cognition subscales), mini- and Assisting Hand Assessment (paretic hand); parent-reported outcome measures (Infant Motor Activity Log, MacArthur-Bates Communicative Developmental Inventories); and a combined clinical/parent outcome measure (Emerging Behaviors Scale). This project has the potential to advance pediatric rehabilitation research by affording a novel, reliable, precise, and sensitive measure of reach and grasp – applicable to hundreds of thousands of children with infant stroke and hemiparetic cerebral palsy. Furthermore, the novel use of data sharing and video coding are imperative for scientific reproducibility, reduction in cost, and will support the ability to improve health and physical function in infants and toddlers with cerebral palsy and other physical disabilities.

NIH Research Projects · FY 2025 · 2022-09

Ischemic stroke is a devastating health problem, affecting approximately 795,000 patients in the US every year, making it one of the leading causes of death and disability in the country. Recent clinical advances have shown great promise in acute stroke therapy, with the use of mechanical endovascular thrombectomy (EVT), with or without standard of care thrombolysis, significantly improving outcomes. Despite these promising advances, long-term neurologic sequelae persist in the post-stroke patient population. Therefore, the use of neuroprotective agents in combination with current methods of reperfusion provides renewed hope for the improvement of stroke outcomes. Indeed, >1000 drugs have been shown to reduce stroke injury in experimental stroke models, but have failed to translate to clinical benefit. The Stroke Therapy Academic Industry Roundtable (STAIR) convened in 1999 and provided important guidelines to improve the rigor of pre-clinical models to improve translational success. More recently, STAIR IX-X provided updates in light of endovascular therapy, advising increased research into adjunct therapies to be combined with EVT reperfusion. The current study is a pre-clinical study that follows the STAIR criteria to characterize a novel neuroprotectant to be utilized in combination with EVT following large vessel occlusion (LVO). The STAIR group identified multiple factors contributing failure to translate, chief among them being over- reliance on acute histological measurements of outcome and poor correspondence between experimental and clinical study designs. To address long-term functional outcomes in our rodent model, we have moved beyond measurements of motor deficits and add cognitive recovery to our outcome measures to assess therapies that may provide real-world improvements in ‘quality of life’ outcomes. Experimental evidence from our group, and others, show that tMCAo induces synaptic derangements in various brain regions, including the hippocampus. This, coupled with the increasing evidence of cognitive impairments and memory loss following AIS (post-stroke cognitive impairment: PSCI), makes synaptic dysfunction (synaptoprotection) a novel new target for neuroprotective strategies. We have developed a drug that 1) provides acute neuroprotection and 2) causes sustained synaptoprotection that enhances long-term cognitive recovery. We focus the current proposal on the interaction between acute injury, delayed neuronal cell death, conversion to chronic dysfunction and therapeutic approaches aimed at synaptoprotection to provide sustained functional benefit. The overarching premise of this proposal is that ischemic stroke causes acute injury within the MCA territory (cortical/subcortical), delayed diffuse neuronal injury and syanptotoxicity which contributes to the conversion to chronic cognitive decline. We will assess dosing regimen of our novel agent, tat-M2NX, that provides optimal long-term functional recovery following tMCAo and assess the mechanism(s) of tMCAo-induced activation of TRPM2 channels.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT In the time it takes to read this application, 20 older adults (age≥65 years) will die of pneumonia in the United States. Annually over 500,000 older adults received treatment in emergency departments (ED) for pneumonia. Unfortunately, ED physicians cannot accurately diagnose pneumonia in older adults because of atypical symptoms, chest x-ray inaccuracy, comorbidities, failure of pulmonary clinical prediction rules established with younger adults, and poor accuracy of available biomarkers. Emergency physician’s inability to diagnose pneumonia in older adults leads to delayed diagnosis, inadequate treatment, worsening infection, longer lengths of stay (6.6 days vs. 5.4), and mortality. Pneumonia can be caused by bacterial and viral pathogens alone or in combination. Bacterial pneumonia alone causes the adverse outcomes and faces the diagnostic challenges just described. The presence of viral pneumonia further complicates diagnosis. Bacterial and viral co-infection in all adults increase odds of death by 2.1 with expected greater deleterious effects on older adults. Unfortunately, when viral sources are detected our current diagnostic approach fails to reliably identify bacterial sources in the event of co-infections. This can lead to inappropriate care and highlights the importance of ensuring fast, accurate diagnosis of both bacterial and viral pneumonia. Unfortunately, available tests (serum, imaging) and patient presentation (symptoms, exam, and history) are unreliable for diagnosing pneumonia in older adult ED patients. Our previous results reveal that novel tests may improve diagnostic accuracy of pneumonia (antimicrobial peptides [AMPs] and monocyte distribution width [MDW]). AMPs are a part of the innate immune system and respond in minutes to bacteria and viruses. Monocyte distribution width measures the distribution of size of leukocytes and increases in ED sepsis. This project seeks to build on previous investigations to improve the diagnostic accuracy of pneumonia in older adult ED patients with the long-term goal of improving clinical care and decreasing the morbidity and mortality associated with pneumonia. Aim #1 examines the potential for novel tests (AMPs and MDW) to diagnose pneumonia alone and in combination with patient presentation/symptoms and existing diagnostic studies. This aim will consider pneumonia caused by bacterial pathogens, viral pathogens and the combination separately to create and determine the accuracy of a diagnostic pathway. Aim #2 will employ group concept mapping guided by the Theoretical Domains Framework to engage emergency physicians to identify facilitators and barriers to implementation of a diagnostic pathway in emergency medicine to inform future studies. Aim #3 pilots the Aim #1 diagnostic pathway. If successful, this proposal will produce a diagnostic pathway for pneumonia in older adult ED patients and provide the groundwork for a successful validation and implementation study of this diagnostic pathway.

NIH Research Projects · FY 2025 · 2022-09

We propose a summer internship experience titled: the Interdisciplinary Summer Research Experience (ISRE) in the Department of Biomedical Informatics at The Ohio State University. The ultimate goal of this project is to encourage and support students who are interested in careers in biomedical informatics and data science. We take a unique approach to the internship in two ways. First, we focus on interdisciplinary dual mentorship. This means that each student will have two mentors from different fields with different research experiences. The goal is to help the student gain a broader perspective of the field by exposure to different viewpoints. The second innovation as part of this grant is to offer a mentored experience in an artificial intelligence challenge competition instead of a traditional research experience. AI competitions foster teamwork, creativity, and quick thinking. We will study whether this experience has the same impact as the traditional mentored research experience. We have a supportive departmental environment, institution, and dedicated and engaged faculty members.

NIH Research Projects · FY 2026 · 2022-09

Apolipoprotein E (APOE) genotype strongly impacts several major pathological features of Alzheimer’s disease (AD), including extracellular β-amyloid (Aβ) deposits, intracellular tau tangle formation, and microglial dysfunction. The metabolism and signaling of ApoE in the brain are controlled by members of the lipoprotein receptor superfamily, and genetic manipulation of ApoE receptors has been shown to significantly impact AD pathology. Hence, the pathways modulating ApoE receptors in the brain represent promising targets for the therapeutic intervention in AD. Previously, we have identified the inducible degrader of the LDLR (IDOL), an E3 ubiquitin ligase, is a major post-translational regulator of three ApoE receptors: low-density lipoprotein receptor (LDLR), very low-density lipoprotein receptor (VLDLR), and ApoE Receptor 2 (ApoER2). Each of these ApoE receptor plays key role in modulating ApoE actions and impacting AD pathogenesis in the brain. We showed that both genetic deletion and therapeutic reduction of IDOL increases brain ApoE receptors levels, decreases Aβ levels, and improves cognitive functions in mouse models of Aβ amyloidosis. Our recent mechanistic research revealed IDOL knockdown markedly increases microglial phagocytosis of fibrillar Aβ in vivo, and the subpopulation of disease-associated microglia (DAM), a phagocytic microglia population associated with Aβ plaques. Our research also suggests that LDLR, an IDOL substrate, plays an important role in facilitating metabolic reprogramming of microglia during phagocytosis likely by mediating the uptake of ApoE lipoproteins. Furthermore, IDOL regulates the expression of ApoER2, a receptor that is enriched in the postsynaptic membrane of excitatory synapses. ApoER2-mediated signaling is known to increase glutamatergic neurotransmission and antagonize Aβ-induced suppression of synaptic functions. We showed that manipulation of IDOL expression in neuron is sufficient to modulate synaptic transmission. Based on these results, our goals of this proposal are to delineate molecular mechanisms by which IDOL-ApoE receptor pathway modulates ApoE actions and impacts Aβ pathology. Aim 1 is to define the role of IDOL in facilitating microglial response to Aβ and impacting the progression of Aβ pathology. Aim 2 is to elucidate the mechanisms of how IDOL-LDLR axis facilitates metabolic reprogramming and ApoE signaling in microglia. Aim 3 is to delineate the role of neuronal IDOL in enhancing ApoER2-mediated signaling and protecting against Aβ-induced synaptic dysfunction and cognitive deficit.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY The overall goal of The Ohio State University (OSU) Accrual to Clinical Trials (ACTs) project is to increase the referral and accrual of participants to NCI’s National Clinical Trials Network (NCTN) prevention/control and treatment trials at the OSU Comprehensive Cancer Center (OSUCCC). This research is grounded in the socioecologic model developed by the Centers for Population Health and Health Disparities (Warnecke, et al. Am J Public Health 2008) and utilizes the theoretical model, Accrual to Clinical Trials (Paskett, et al. Clin Adv Hematol Oncol 2003). The OSUCCC serves the catchment area of the state of Ohio where over 95% of our patients with cancer reside. Working closely with the OSUCCC Center Community and Engagement (CCOE), OSUCCC National Outreach Network, community partner organizations, community providers in the OSUCCC referral area, James Hospital Network sites, NCI Community Oncology Research Program (NCORP) sites in Ohio, and the OSUCCC Clinical Trials Office, our goal will be accomplished by completing the following specific aims: 1) Conduct a baseline assessment of referral patterns and accrual of participants to clinical trials at OSUCCC by cancer disease group (breast, gastrointestinal, genitourinary, thoracic, hematologic, and others) and examine factors at the system (i.e., eligible clinical trial protocol, clinic context and culture), provider (trial discussed with patient), and patient level (agreed or refused participation) that influence referral and accrual (Phase I); 2) Implement a multi-level intervention in a stepped wedge design in referring practices in 9 counties with high counts of cancer cases in the OSUCCC catchment area using the Accrual to Clinical Trials framework (Paskett, et al. Clin Adv Hematol Oncol 2003), in Phase II. The intervention will include an outreach component, directed at community members and community practices, and an in-reach component, involving patients, providers, and the hospital system (at both referral centers and the OSUCCC) that directly addresses problems identified in Phase I; and 3) to evaluate the impact of the intervention on referral (primary outcome) and accrual patterns (secondary outcomes) in Phase III to clinical trials. Both qualitative and quantitative methods will be used. Dissemination of the key findings of our multi-level intervention is a high priority of this project.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT Francesca Cottini, MD, is a Tenure-eligible Assistant Professor in the Division of Hematology, Department of Internal Medicine (70% research, 30% clinical) at The Ohio State University Comprehensive Cancer Center. Dr. Cottini’s career goal is to become an independent and productive physician scientist whose research will combine aspects of multiple myeloma (MM) pathogenesis and tumor immunology to develop tailored therapies for MM patients. MM is an incurable disease that affects vulnerable adults causing high healthcare costs and poor quality of life. No tailored therapies exist to treat patients with MM, despite major differences in terms of genetic abnormalities, gene expression profiles, or immune signatures. To fill this gap, Dr. Cottini has identified a surface marker, named CD56, which is present in 70 percent of patients and is associated with poor prognosis. Thus far, Dr. Cottini has demonstrated the feasibility of her project with strong preliminary data, showing that CD56 promotes MM growth and tumor escape from the immune system. The main objective of Dr. Cottini’s K08 proposal is to characterize the mechanisms associated with CD56 protumoral phenotype in terms of: 1. MM growth; 2. resistance to anti-MM therapies; 3. regulation of oxidative stress; and 4. escape from natural killer (NK) cell-mediated cytotoxicity. The final step of Dr. Cottini’s proposal is to find strategies to promote CD56 degradation in MM and induce tumor regression. This knowledge will lead to science-driven clinical trials and improve outcomes in high-risk CD56 positive MM patients. To support her pathway to independence, Dr. Cottini has established a mentoring committee consisting of: Drs. Don Benson MD, PhD (Primary Mentor: expertise in MM biology, tumor immunology, and translational and clinical science), Yiping Yang MD, PhD (co-Mentor: expertise in tumor immunology, grant writing, and leadership skills), Bei Liu, PhD (Advisory Committee Member: expertise in MM murine animal models), and Natarajan Muthusamy, DVM, PhD (Advisory Committee Member: expertise in signaling and translational science). She will also take advantages of two additional collaborators, with experience in genomics (Dr. Pearlly Yan) and drug development (Dr. Gerard Hilinski). She formulated a career development plan with objectives of (1) learning skills in tumor immunology, drug development, and animal models; (2) developing knowledge in the analysis and interpretation of genomic data and design of correlatives for clinical trials; (3) improving expertise in leadership, grant writing, and team management. These objectives will complement Dr. Cottini’s current knowledge to help achieving independence as a physician scientist in the field of MM. To conclude, Dr. Cottini’s studies have the potential to identify therapeutic options based on disease characteristics and hence improve outcomes and reduce toxicities in patients.

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT My previous work showed specific mutations in mRNAs activate initiation at non-canonical start codons (e.g., GUG, ACG) resulting in expression of neurotoxic proteins that cause multiple human disorders. However, non- canonical translation is not restricted to atypical start codons or necessarily connected to pathology; cells rely on alternative mechanisms to respond to specific states to translate mRNAs with spatiotemporal precision. Our basic understanding of non-canonical translation is incomplete, and the long-term goal of this research program is to understand how and why non-canonical translation occurs in cells. We will fill gaps in our understanding of non-canonical initiation by addressing two fundamental questions. What mechanisms enable alternative initiation factors to support translation? Which aminoacyl tRNAs other than Met-tRNAiMet are used for initiation? Our previous and current work has also discovered unconventional translational regulatory mechanisms that use ribosome queuing and non-canonical RNA-binding domains (ncRBDs). We will establish how unconventional regulatory mechanisms such as ribosome queuing are used as cellular sensors of elongation to drive apoptosis, and how proteins with ncRBDs regulate translation. My research program will shed new light on how the translation machinery is used to create a diverse repertoire of initiation and regulatory mechanisms. In doing so, we will expand our understanding of the coding potential of the genome and how alterations in protein synthesis lead to human disease.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT The remarkable functional versatility of the actin cytoskeleton stems from its ability to assemble into a variety of diverse structures – branched networks, meshes, and bundles. This architectural complexity is orchestrated by actin-binding proteins, whose activity is delicately regulated in response to internal and external signals. Our long-term goal is to contribute to human health and well-being by advancing the understanding of the actin cytoskeleton organization by actin-bundling proteins and their contribution to pathologies (e.g., congenital diseases and metastatic cancers). Plastin/fimbrin family of cytoskeleton organizers are conserved proteins that promote assembly of actin filaments into bundles involved in cell migration, adhesion, cytokinesis, and formation of stereocilia and microvilli structures of the inner ear, intestinal and kidney epithelia. Of three human plastin (PLS) isoforms, PLS1 deletion results in deafness, PLS2 contributes to pathologies of the immune system and the development of aggressive metastatic cancers, while mutations in PLS3 lead to severe osteoporosis with bone fragility and other connective tissue disorders. Despite the importance and a long-lasting interest of the research community to these proteins, understanding of their interaction with actin and their regulation is superficial, whereas published structural and biochemical data are incomplete, scattered, and sometimes contradictory. The overall objective of the current proposal is to fill these major gaps by providing a thorough characterization of the molecular and cellular mechanisms governing the function of plastins and to demonstrate how this improved understanding can contribute to explaining the pathology of plastin-related diseases. We propose that the unique domain organization of plastins enables several regulation modes interconnected via a central allosteric mechanism that confers multifaceted contribution to various actin-governed cellular processes. Biochemical characterization of plastin isoforms will reveal mechanisms of their regulation and function at the molecular level (Aim 1a,b); high-resolution cryo-electron microscopy (EM)/cryo-electron tomography (ET) reconstruction will provide structural details of plastin interaction with actin (Aim 1c); structural analysis and atomistic molecular dynamics (MD) simulations will generate a model of the auto-inhibition allowing to predict functional outcomes of congenital mutations (Aim 2); while Aim 3 will focus on understanding functional significance and implications of the allosteric auto-inhibition of plastins and its role in cooperation with other actin- binding proteins. These approaches, supported by single-molecule speckle (SiMS), total internal reflection fluorescence (TIRF), and bulk epi-fluorescence microscopy, will unveil plastin dynamics, cooperation with protein partners, and contribution to actin-dependent processes in living cells. The proposal will result in a breakthrough in the understanding of the actin-dependent cellular events controlled by the plastin/fimbrin family of cytoskeleton organizers, uncover molecular mechanisms behind plastin-linked congenital (deafness, osteoporosis, and diaphragmatic hernia) and acquired (cancer) diseases, opening opportunities for their specific therapeutics.

NIH Research Projects · FY 2024 · 2022-09

Abstract Alzheimer’s Disease (AD) is the most common cause of dementia and a major cause of morbidity in the United States, yet there remains no disease-modifying therapy as the mechanism of disease is incompletely understood. AD is defined by the accumulation of two protein lesions in the brain, amyloid-β plaques and neurofibrillary tangles. Neurofibrillary tangles, which are composed of aggregated tau protein, are a better marker of disease progression than amyloid-β, correlating with neuron loss and cognitive decline. Notably, tau tangles spread through the brain in a stereotypical fashion defined by Braak staging, starting in the locus coeruleus and spreading along networked synapses. This suggests that misfolded tau is propagated across the synapse, templating normal tau to become misfolded as well and generate new lesions. However, some regions never develop tau lesions despite parallel synaptic exposure to the locus coeruleus, suggesting selective vulnerability of different regions to tau lesions. Although some cases of AD are due to dominant single gene mutations, the vast majority of AD cases are sporadic with no clear genetic cause. One approach to such complexity is to study the gene expression response to disease in order to capture functional interactions between genes. Most transcriptomic studies have limited their analysis to the disease response in affected areas of the brain, comparing diseased individuals to normal controls. In contrast, our analysis incorporates the selective vulnerability of specific brain regions to developing tau lesions, comparing a lesion-affected area of the brain (prefrontal cortex) to a lesion-protected area (cerebellum) in both diseased and control individuals. According to the premise that both regions receive the same anterograde tau insult, but differential expression uniquely protects the cerebellum, this comparison will highlight the drivers of neuroprotection in areas that never develop lesions. This approach has yielded a list of candidate drivers of disease neuroprotection, notably enriching for chaperone proteins that regulate protein folding. Our analysis also identified several transcription factors (TF) candidates, such as the core clock regulator BHLHE40. This aligns with observations of several circadian phenotypes observed in AD, such as the increased risk of AD among patients with sleep disorders and vice versa. This proposal aims to test our candidate driver genes through several approaches. Aim 1 will test the identified chaperone proteins for functional inhibition of tau misfolding in both a biochemical model of induced recombinant tau fibrillization and in vitro with a cellular biosensor of tau aggregation. Aim 2 will test TF candidates for modulation of tau aggregate accumulation in vitro with a cellular biosensor of tau aggregation. Finally, Aim 3 will test how a circadian TF, BHLHE40, modulates tau spreading in a mouse model of misfolded tau seed injection. Together these aims will create new insight into mechanisms of protection from AD tauopathy and provide multiple new avenues for development of disease-modifying therapies.

NIH Research Projects · FY 2025 · 2022-09

Project Summary/Abstract The 14 million cancer survivors living in the US clearly demonstrate continued improvements in anti- cancer treatment efficacy; yet, this success has been tempered by a parallel rise in the incidence of cancer treatment-related cardiotoxicity, leading to morbidity and mortality. A prominent example of this conundrum involves Tyrosine Kinase Inhibitors (TKIs), first-line therapy in kidney cancer, the 16th most common cause of death worldwide. Renal cell carcinoma (RCC) accounts for approximately 90% of all cases with ~143,000 deaths/year. The incidence and prevalence of RCC have been increasing over the last 50 years, and with the growth of the US elderly population, these numbers will only continue to increase. Mounting data support that TKIs can modify and inhibit cardiac voltage-gated Na+ channel Nav1.5, and in general play a key role in cardiac excitability. At the same time, TKIs have been shown to increase reactive oxygen species (ROS) in cardiomyocytes. In turn, ROS is known to activate the multifunctional Ca2+/calmodulin- dependent kinase II (CaMKII), which resides at the hub of a pro-arrhythmia signaling hub in cardiac myocytes. In previous work, we have shown that CaMKII promotes arrhythmia in part through direct phosphorylation of Nav1.5 at Ser571 with a concomitant increase in INa,L. Notably, INa,L has importance in regulating contractility in normal heart, thus of all the potential ion channels to target for cardioprotection, INa,L inhibition could prevent arrhythmias and adverse structural remodeling in patients taking TKIs. Based on these data, we will test the hypothesis that TKI-induced arrhythmia acts in part through oxidative activation of CaMKII and increased excitability cardiac myocytes. Thus, we propose INa,L is an attractive target to prevent TKI induced cardiotoxicity Results will inform clinical decision making regarding drug-induced arrhythmias, inform mechanistic approaches to prevent Ca2+ overload, and define an innovative approach using drugs readily available on the market as cardioprotective agents for patients during TKI therapy. We propose to: 1) Determine the role of TKIs in modulating cardiac myocyte excitability 2) Define the impact of TKIs on cardiac phenotypes, and 3) Define potential therapeutic strategies that mitigate TKI-induced cardiac dysfunction.

NIH Research Projects · FY 2024 · 2022-09

Project Summary/Abstract Large bone defects caused by trauma, infection, or cancer lead to thousands of amputees and millions of dollars in costs. Recently, a two-staged surgical regimen, Masquelet’s Induced Membrane Technique (MIMT), has presented a revolutionary way to reconstruct critical-sized defects that is more ideal than the current standards and could serve a wider patient population. More importantly, it presents a unique opportunity to discover new bone regeneration biology which could be applied to other bone formation situations (i.e. non- union, fusions) and possibly other tissues. The key feature of MIMT is an autologous foreign-body membrane that forms around an implanted bone cement spacer. Weeks to months later during a second surgery, the spacer is removed and the membrane compartment is filled with morselized bone graft. The technique can heal defects as large as 25 cm, more than triple the traditional maximum volume treatable via grafting without the membrane. However, MIMT’s regeneration mechanisms are completely unknown. All that is certain is that the membrane is necessary. Its critical functions have not yet been defined, so there is no evidence to improve its clinical application or harness the biological principles for other tissue regeneration scenarios. A critical barrier to investigating MIMT’s mechanisms is that it has only been thoroughly established in rats and larger animals. The number of genetic tools and reagents available for these species are far fewer than those available for mice. Thus, establishing a mouse-based MIMT model would be very powerful and allow much more in depth study and manipulation. To date, only one study has used a mouse for MIMT, but the second stage was not attempted and the first stage study design did not mirror well what has been done in other species. The goals of this proposal are to establish a mouse-based MIMT model, compare/contrast this model with what is known in other species, and use tools only available in mice to answer some fundamental MIMT questions. We hypothesize that a mouse model is feasible and that host cells, specifically osteoblasts, are mainly responsible for new bone generation. To test this hypothesis, we will first compare/contrast membrane formation and bone regeneration dynamics in normal C57BL/6J mice with what is already known from other species – most specifically rats. After establishing that a mouse MIMT model is feasible, we will use transgenic C57BL/6J mice to determine the contributions of host/graft cells to regeneration. Information gained from these experiments will be combined to target specific cells/genes/pathways in host/graft mouse tissues in a future R01.

NIH Research Projects · FY 2025 · 2022-09

Project Abstract Unlike the sporadic exposure of the general population in wildfire prone areas, exposure of wildland firefighters (WFFs) to WF smoke is recurrent, and has recently become more so due to the increase in the acreage of land burned by wildfires and prescribed (managed) fires. WFFs are exposed to elevated levels of WF smoke while working at wildland fires. The airborne concentrations of the reactive particles in WF smoke at the fireline are at least an order of magnitude higher than the health-based air quality standards in the U.S. The inhalation exposure of WFFs at the fireline is exacerbated because they work extended hours on multiple days per year at the fireline. Additionally, wildland firefighting is conducted mostly without any respiratory protection, as no respirator is currently approved for the profession. Nevertheless, knowledge about the chronic respiratory effects of such exposure is lacking. The proposed study is designed to address NIOSH’s “Public Safety” sector, and its “Respiratory Health” and “Cancer, Reproductive, and Cardiovascular Diseases” cross-sectors by assessing the association between occupational WF smoke exposure and subclinical indicator of pulmonary health impairment and cancer-related molecular changes in the respiratory airways. Therefore, the hypotheses of the proposed study are: 1) that cumulative recurrent WF smoke exposure induces adverse long-term respiratory effects among WFFs, and 2) that a situational use of an air purifying respirator (APR) during periods of peak particulate exposure concentrations will reduce exposure and adverse acute physiological responses. The first hypothesis will be tested by comparing changes in DNA methylation and gene expression in the nasal epithelium and lung function across a three-year period between WFFs and a control group of emergency medical technicians (EMTs) matched by age, sex and ethnicity (N = 50/group). The proposed outcomes are disease precursors and are relevant for characterizing risk of disease that may evolve long after exposure or retirement. The second hypothesis will be tested by comparisons of cross-shift changes in urinary biomarkers of exposure, gene expression in the nasal epithelium, and serum pro-inflammatory cytokines among WFFs (N = 35) between occasions when they wear the APR and when they do not, while working at prescribed burns. The objective of the proposed study is well aligned with NIOSH’s priority extramural research goals to reduce occupational cancer and respiratory disease and exposures causing them. Following the completion of the study, we would have determined the adverse respiratory effects of cumulative occupational exposure to WF smoke and a practical approach to mitigate them. The envisaged outputs from the proposed research, which would include publicly accessible results and publications, would directly inform NIOSH’s priority goal to reduce incidence of exposure and illnesses among wildland firefighters. These outputs, which will also be made accessible to stakeholders via a virtual workshop, will contribute to appropriate risk assessment of WF smoke exposure, the development of exposure and risk mitigation strategies, and methods to test their effectiveness.

NIH Research Projects · FY 2025 · 2022-09

This study proposes a longitudinal study to assess the effects of opioid prescribing practices on outcomes of patients with Alzheimer’s disease and related dementia (ADRD). The research is responsive to priorities espoused by the National Plans to Address Alzheimer’s disease: Goal 2 Enhance Care Quality and Efficiency to address care needs of ADRD patients due to co-occurring chronic conditions. Chronic pain is common in ADRD, with 90% of affected patients relying on pharmacotherapy, such as opioids, to relieve painful symptoms. Use of prescription opioids in ADRD has doubled over the last decade; among users, over half used opioids chronically or concurrently with other central-nervous-system (CNS) depressant medications, contrary to what current pain guidelines suggest. These guidelines, however, adapt evidence primarily from younger populations or older adults with healthy cognition and whether they are suitable for ADRD patients remains unclear. To inform treatment decisions for pain management in ADRD, there is an urgent need for evidence on the clinical effects of existing opioid prescribing practices, considering outcomes aligned with treatment goals. For older adults who suffer from chronic pain, there is a strong need to understand if opioids improve or worsen cognition to help clarify inconclusive findings in the current literature. To fill these research gaps, this proposed study will leverage nationally representative longitudinal survey and assessment data that are linked to Medicare claims to study opioid prescribing practices on outcomes of ADRD patients residing in communities and nursing homes. Specifically, we will examine the associations between the continuation of chronic opioid therapy with outcomes in patients with ADRD and chronic non-cancer pain. We will also evaluate the extent to which concurrent use of opioids with CNS drugs is associated with outcomes in patients with ADRD receiving chronic opioid therapy. Furthermore, we will assess associations between opioid use and changes in cognitive function among non-demented older adults who had moderate or severe pain. We will consider a range of clinical outcomes, including pain intensity, physical and mental health, and safety outcomes, including fall-related injuries, hospitalizations, and opioid use disorder or overdose. Our study will provide empirical evidence on the effects of common opioid prescribing practices on health outcomes pertinent to patients with ADRD and elucidate the role of opioids on cognition in older adults with chronic pain. Because ADRD populations are rarely included in trials, our data will have great potential to further knowledge of the benefits and harms of opioid treatment and inform optimal use and safe opioid prescribing in patients with ADRD. The long-term goal of this line of research is to improve management of chronic pain in older adults, particularly those with cognitive impairment.

NIH Research Projects · FY 2025 · 2022-08

Today's reality includes threats from emergent microbial diseases, rising opportunistic infections, development of multi-drug-resistant microbes, and inefficacy of existing vaccines due to microbial evolution. These threats to human health necessitate comprehensive interdisciplinary training programs for the next generation of scientists in studies of the microbe-host interface and emerging methodologies. The hub for this training program will be The Ohio State University Infectious Disease Institute (IDI), which is focused on Host-Pathogen Research, Education, and Outreach. IDI brings together a vibrant and dynamic community that fosters a collaborative approach to address critical problems in infectious disease. All the preceptors for the training program are members of IDI and represent a vast array of expertise in host-pathogen interactions. Both PDs (MPD mechanism) have strong research programs and careers dedicated to training and education. Thus the PDs represent an outstanding, established and collaborative team to oversee this broad innovative program which emphasizes: 1) a highly interactive scientific community, 2) a multidisciplinary approach to science, 3) immersion of trainees in the biomedical research community of a large academic health sciences center, 4) integration of the clinical and basic sciences, 5) exposure to experienced and talented scientist educators and mentors, and 6) several added advantages to trainees, including a vibrant externship program. The major thematic areas are 1) Viral pathogens, 2) Host defense, and 3) Microbial communities. These thematic areas represent three of five IDI interdisciplinary programmatic areas, and we have selected the most dedicated members from each area to serve as preceptors for this T32. The program will include a Selection and Oversight Committee, an outstanding and engaged External Advisory Committee, the necessary administrative structure within IDI to execute the program, and a high-quality trainee pool. Emphasis is placed on the recruitment of exceptional trainees and on formal instruction for the responsible conduct of research. We request 3 pre-doctoral, and 2 post-doctoral scholar slots per year. The proposed training experience includes a state-of-the-art curriculum, dedicated faculty, exceptional resources, exposure to a variety of career paths, and mentors and networking combined with sustained institutional support that will prepare the trainees for the evolving landscape of our biomedical workforce

NIH Research Projects · FY 2025 · 2022-08

Summary The therapeutic targeting of cancer cells’ ability to evade immune surveillance has revolutionized the treatment of many cancers. Immune checkpoint inhibitor (ICI) monoclonal antibodies (mAb) reactivate cancer patients’ (pts’) immune systems to attack tumor cells thus eliciting response even in advanced disease. Unfortunately, durable response rates remain relatively low (~25%), and it is currently unclear what limits ICI response. Retrospective analyses of clinical pharmacology data reveal a strong correlation between elevated ICI clearance (CL) and reduced ICI response that is also associated with cancer cachexia, though independent of circulating ICI levels or ICI target receptor occupancy. Suppressive immune populations are elevated in pts with non-small cell lung cancer (NSCLC) and in multiple animal models of cachexia, but how these immune populations differ in numbers or function in cachectic vs. non-cachectic pts is poorly understood. The neonatal Fc receptor, FcRn (FCGRT), is a key mediator of IgG and albumin homeostasis with dual roles in recycling (i.e. slowing the CL of) both IgG and albumin in immune cells. Project Hypothesis: FcRn modulation in myeloid populations, triggered by yet unidentified cachexia-associated signaling, leads to elevated CL and poor ICI response. Preliminary data: 1) murine models replicate increased pembro CL in tumor-bearing cachectic mice relative to non-cachectic tumor-bearing mice and tumor-free controls; 2) increased CL of other mAbs, including anti-murine PD-1 mAb RMP1-14 in cachectic mice relative to non-cachectic mice; 3) decreased Fcgrt in liver of cachectic vs. non-cachectic mice; 4) immunosuppressive immune cell populations are elevated in pts with NSCLC and correlate with poor ICI responses; 5) increased myeloid and dendritic cell populations in pts and in mice with cancer-induced cachexia; and 6) paradoxical apparent elevation of FcRn protein in these immune cell populations in pts and mice. Project Objective: To identify mechanisms linking cachexia, elevated ICI mAb CL and poor response to ICI therapy. Specific Aims: Aim 1. To identify tissues with elevated mAb CL, altered FcRn and macrophages in cachectic mice. We expect to identify tissues/organs, immune cell populations, and FcRn expression/functional differences responsible for elevated CL in cachectic vs. non- cachectic mice. Aim 2. To determine whether cachexia affects myeloid-derived immune cells leading to poor ICI efficacy. We expect cachexia will alter myeloid-derived immune populations and FcRn function resulting in poor ICI mAb anti-tumor responses. Aim 3. To determine how cachexia affects anti-tumor immunity and pembro CL in NSCLC pts. We expect myeloid immune populations from cachectic pts will display modulated FcRn expression and function that drives decreased efficacy and elevated CL of anti-PD-1 treatment. Impact: Despite the remarkable promise of ICI therapies, durable responses remain rare, and causes of resistance unclear. Our project interrogates probable mechanisms linking poor clinical outcomes to ICI clearance and cachexia in NSCLC, which may reveal improved strategies for broadly overcoming ICI resistance.