Ohio State University

NIH Research Projects · FY 2025 · 2025-07

Project Summary Pediatric Traumatic Brain Injury (pTBI) impacts half a million children each year, leaving over 20% with long- lasting cognitive deficits that negatively impact their quality of life. Children are especially vulnerable to pTBI because their brains are still developing at the time of injury. A major factor associated with poor outcomes following pTBI is a life history of early life stress (ELS), such as poverty, abuse, and natural disasters. ELS increases the risk for pTBI and increases chronic attentional, impulsive, and social deficits. Despite this established association, the mechanisms underlying how ELS and pTBI generate these neurocognitive impairments remain poorly understood, leaving these kids with few therapeutic options to improve symptoms. My laboratory uses lateral fluid percussion injury (LFPI) to model pTBI in rats at postnatal day (P)15, which is developmentally equivalent to toddler age. Early life injury generates behavioral phenotypes in adult rats that resemble pTBI symptoms in humans, specifically cognitive alterations and social impairment. Given that cognitive deficits are the most common lasting symptom of pTBI, this proposal builds upon these findings to further investigate how pTBI impacts brain development and resulting cognition. I will combine this model with maternal separation stress and assess development of the medial prefrontal cortex (mPFC), as it is a major hub for cognitive function. Microglia are the brain’s resident immune cells, regulate brain development, including synaptic patterning, and are highly sensitive to stress and injury. Thus, microglia may be key to programming stress and pTBI outcomes. I hypothesize that ELS primes mPFC microglia, enhancing their response to pTBI, and leading to excessive synaptic pruning in mPFC, reduced structural complexity, and impaired cognition. The objectives of this proposal are to define acute neuroimmune changes in the mPFC following ELS+pTBI, determine how these early life insults impact cognitive function in adulthood, and investigate the association between these acute molecular and chronic behavioral phenotypes. In Specific Aim 1 I will use a) engulfment analysis and Golgi staining to examine microglial pruning and resulting mPFC neuronal organization, and b) the 5-choice serial reaction time task to assess complex cognitive phenotypes, including executive function, impulsivity, and attention. In Specific Aim 2 I will use a) transcriptomics to interrogate the role of microglia in these phenotypes and b) pharmacological intervention to shift microglia towards a more homeostatic phenotype following pTBI in an attempt to block the development of neurocognitive deficits later in life. Overall, the findings of these studies will clarify the role of the mPFC and microglia in ELS and pTBI interactions and provide possible insights into novel treatment options for the long- term cognitive consequences of these early life insults.

NIH Research Projects · FY 2025 · 2025-06

ABSTRACT Astrocytes express abundant voltage-independent leak-type K+ channels to make the membrane highly permeable to K+ ions and to have a hyperpolarizing membrane potential. These are two requisites for astrocyte function in brain homeostasis. The leak K+ channels generate a characteristic ohmic behavior, commonly called passive, K+ conductance in astrocytes. While the research over the past decades identified several inwardly rectifying K+ channels, such as Kir4.1, to contribute to passive K+ conductance, the molecular identity of a major leak K+ channel, a K+ channel that follows the Goldman-Hodgkin-Katz (GHK) equation to show constant field outward rectification, remains elusive. This proposal aims to solve this longstanding puzzle by examining the functional expression of a small conductance Ca2+-activated K+ channel, SK2 (KCNN2), as a GHK rectifier K+ channel, in astrocytes. Further, this proposal will examine the interaction of SK2 with adrenergic signaling for dynamic regulation of astrocyte passive K+ conductance. The premise underpinning this proposal includes a high expression of SK2 mRNA in freshly dissociated hippocampal astrocytes, the presence of a large portion of passive K+ conductance that is sensitive to a highly selective SK2 inhibitor, apamin, and responsiveness of astrocyte passive K+ conductance to Gq-coupled adrenergic a1 receptor (a1-AR), known to be expressed by astrocytes. These observations compellingly show the SK2 as the long-sought GHK rectifier K+ channel engaged in astrocyte passive K+ conductance. Extending from these preliminary studies, this proposal aims to achieve three specific objectives. First, to correlate the apamin-sensitive passive K+ conductance with the SK2 channel gene (Kcnn2) through inducible astrocytic Kcnn2 knockout (Aldh1l1-Cre/ERT2;Kcnn2fl/fl;Ai9). Second, to validate the observation that Kir4.1 and SK2 work in concert to generate astrocyte passive K+ conductance through inducible Kcnj10/Kcnn2 double gene knockout from astrocytes (Aldh1l1- Cre/ERT2;Kcnn2fl/fl;Kcnj10fl/fl;Ai9). Third, to test a hypothesis that adrenergic signaling modulates K+ passive conductance through the interaction of astrocytic a1-AR and SK2. This project will for the first time correlate SK2 to the long-sought for GHK rectifier K+ channel in astrocyte passive K+ conductance. The results of the interaction of SK2 with adrenergic signaling have the potential to vertically change the “passive” view of astrocyte K+ conductance in brain homeostatic function. Second, through comparative analyses of SK2 and Kir4.1 KO astrocytes, we expect an outcome that would advance the notion that Kir4.1 and SK2 work in concert to implement the K+ uptake and release in the process of [K+]e buffering. Third, the resultant knowledge and validated animal models from this project should facilitate future studies of leak-type SK2 and Kir4.1 in astrocyte physiology and pathology.

NIH Research Projects · FY 2026 · 2025-06

Abstract Anti-tumor therapies (e.g., anthracyclines, biologic, and immunotherapy) are the standard treatments for most breast cancer patients, and dramatically improve survival rates. However, up to 20% of breast cancer patients treatment with these therapies will develop some form of serious cardiovascular disease (CVD), such as heart failure, myocarditis, or cardiac arrhythmia. Emerging data suggest CVD is now the leading non-malignant cause of death during or after the treatment stage of breast cancer. If clinicians can accurately predict treatment-related cardiotoxicity during the treatment stage or shortly post-treatment, they can then adjust their anti-tumor therapy selection or prescribe interventions that reduce the risk of serious CVD. However, our preliminary data show that clinicians face several challenges in predicting these serious events, including the unpredictable nature of cardiotoxicity, the lack of specific clinical guidelines, and the low sensitivity of diagnostic tests. Recent advances in artificial intelligence and machine learning (AI/ML) have shown great potential to support clinicians in making early decisions about CVD. For example, our and other predictive AI/ML models that were trained and evaluated on cancer patients’ historical electronic health record (EHR) data to predict the risk of a future CVD onset, have yielded promising results. Yet, these existing AI/ML models for risk prediction have inherit limitations, as their predictors are limited only to sparse EHR data; whereas clinicians in practice rely on additional modalities for key signals such as patient-reported symptoms (e.g., discomfort in breathing) from non-clinical settings such as at home, and change in anti-tumor treatment (e.g., increase in dose). To date, these signals are entirely missing in existing risk prediction models for CVD of breast cancer patients. Our primary objectives are: to complement EHR data with multimodal data collected using digital health technologies and to develop a better AI/ML risk prediction model for breast cancer treatment-related cardiotoxicity based on the EHR data and the multimodal data. In aim 1, we will recruit stakeholders, design and develop a human-centered smart system with wearable sensors and a conversational large language model (LLM) chatbot for passive collection of multimodal data. In aim 2, we will recruit breast cancer patients in active treatment, and will collect heart rate variability (HRV) using wearable devices and capture the symptoms potentially related to cardiotoxicity using the LLM chatbot in the home setting. In aim 3, we will first create a deidentified dataset with complete visits and long-term EHR history for patients with breast cancer, corresponding chemotherapy treatments, and potential cardiotoxicity risk. Then, we will develop early treatment-related cardiotoxicity prediction model with large-scale sparse EHRs, and fine- tune the cardiotoxicity prediction model with additional small-scale dense signals. In aim 4, we will update the human-centered AI system to include the dynamic cardiotoxicity risk score in the physician-facing dashboard and evaluate the updated home-based smart system with physicians. Our findings are expected to innovate and improve treatment-related cardiotoxicity risk prediction and facilitate clinical decision making.

NSF Awards · FY 2025 · 2025-06

This award supports participation at the Stochastic Partial Differential Equations (SPDEs) Workshop at the Ohio State University on June 3-5, 2025. It gathers well-established researchers, as well as those new to the field of SPDEs, and aims to provide a stimulating and learning environment for all to share their results and obtain recognition for their work. One of its main goals is to offer sufficient time for the participants to conduct in deep discussions of their results and find possible collaborators. By adding a term representing the “noise” and what cannot be controlled in the system, SPDEs offer more realistic versions of the classical, deterministic and well-known equations studied in Physics. This workshop focuses on recent developments regarding the well-posedness and asymptotic behavior of solutions to such equations and discusses some of their applications in queuing theory, finance and population models. There are 24 confirmed speakers and about 15 other participants who have registered or have expressed interest in joining the workshop. The group consists of senior researchers, postdocs and graduate students and aims to provide the setting for all, regardless of rank, to explore topics in the field of SPDEs and find new problems to pursue. With the permission of each speaker, each talk will be recorded and made available online on the workshop’s website for the mathematics community to benefit from. All related information on this workshop may be found on its website: https://u.osu.edu/spdeworkshop/ This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-06

Project Summary The proposal is focused on the physiological characterization of Chloride intracellular channel 2 [CLIC2, a channel listed in FOA: RFA-RM-21-012 (Pilot Projects Investigating Understudied Ion Channels)]. CLIC2 was identified as XAP121 in an attempt to characterize the 1200-kb telomeric region of Xq28. The region was associated with hypertrophic cardiomyopathy and X-linked intellectual disability (XLID). Patients with mutations in CLIC2 showed early onset of symptoms with death in infancy of some of the affected males and others at later age points due to cardiomegaly. Though CLIC2 has been directly associated with X-linked pathological conditions and episodic ataxia since 1997, information on its physiological roles and biophysical properties is not yet established. In our preliminary experiments, we discovered that CLIC2 is essential for cardiomyocyte differentiation. In its absence human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) differentiate at a slower rate and differentiated cardiomyocytes have abnormal function. We have discovered an unusual truncation mutation in CLIC2 in XLID patients who have reported dilated cardiomyopathy. In these patients, a mutation in the clic2 gene leads to premature truncation of CLIC2 at leucine 92 (CLIC2 Δ92). Therefore, we hypothesize that the novel mutation resulting in the truncation of C-terminus CLIC2 decreases the affinity of CLIC2 for RyR2 which worsens cardiac function in HCM patients by increasing SR Ca2+ leak through RyR2 and abnormal cardiomyocyte differentiation. We also discovered a unique peptide from CLIC2 that can rescue the function of cardiomyocytes lacking CLIC2. We have the following specific aim, 1) to establish the role of CLIC2 Δ92 in the differentiation and function of early human cardiomyocytes, and 2) to establish the role of CLIC2 in the regulation of cytosolic calcium homeostasis. In Aim 1 we use a combination of genetic and imaging approaches to elucidate the impact of CLIC2 mutations on cardiomyocyte differentiation and function. In Aim 2 we will rescue the function of hiPSC-CMs lacking CLIC2 by a unique peptide and also screen the FDA-approved small molecule library available at OSU. The proposal will enhance our understanding of CLIC2 protein by establishing its mechanism in cardiomegaly. CLIC2 mutations are also associated with autism, XLID, episodic ataxia, and learning disorders and the information obtained in our proposal could also increase our understanding of CLIC2 in other pathological conditions.

NIH Research Projects · FY 2026 · 2025-06

Project Summary Heart diseases, including myocardial infarction (MI), heart failure (HF) and cardiac arrhythmias are the leading causes of morbidity and mortality within developed nations. However, our limited understanding of the mechanisms leading to cardiac dysfunction in HF has hampered the development of effective treatment strategies for these patients. Activation of CD4+ T-cells post-MI promote wound-healing and scar formation. However, we have shown that by 8 weeks post-MI, CD4+ T-cells undergo a temporal phenotypic switch that promotes pathological left-ventricular (LV) remodeling and the development of ischemic HF. Importantly, we have shown that during HF, splenic CD4+ T-cells are enriched with antigen-experienced and central memory T- cells, and their adoptive transfer (AT) to naïve mice induce cardiac dysfunction and LV-remodeling, suggesting that CD4+ T-cells contribute to cardiac dysfunction in HF. However, the mechanisms by which HF-activated CD4+ T-cells induce cardiomyocyte (and cardiac) dysfunction are unknown. Our preliminary data show that upon AT, significantly higher numbers of HF-activated CD4+ T-cells (compared to sham T-cells) infiltrate the myocardium of naïve mice (almost 80-85% of all CD4+ T-cells), and induce significant cardiac dysfunction, arrhythmic events, myocyte hypertrophy and LV remodeling in naïve mice. Importantly, co-culture of adult mouse cardiomyocytes with HF-activated T-cells alter electrophysiological function of cardiac myocytes through pro-arrhythmic changes in cardiac currents. Notably, HF-activated T-cells form functional connexin43 gap junctions (Cx43 GJs) with cardiomyocytes and, we demonstrated that changes in currents induced by HF-activated T-cells are contact- dependent. This, contact-dependent alteration of cellular electrophysiology and overall cardiac dysfunction induced by pathological CD4+ T-cells represent a heretofore-unappreciated mechanism contributing to HF and arrhythmias . Thus, we will test the overall hypothesis that HF-activated T-cells promote LV remodeling, cardiac dysfunction and arrhythmias during chronic HF through Cx43 mediated contact with cardiomyocytes. We will test this hypothesis using the following aims: 1. To delineate the pathophysiological role of ischemic HF (IHF) activated CD4+ T-cells on cardiac dysfunction. 2. To determine electrophysiological changes in cardiomyocytes resulting from HF T-cells. 3. To delineate the role of gap junctions in mediating pathological effects of T-cells on cardiomyocyte/cardiac function. These studies will identify mechanisms that mediate contact-dependent pathological effects of HF-activated T-cells on cardiomyocyte electrophysiology and overall cardiac dysfunction, thereby furthering our understanding of the cellular basis for inflammation in this disease. PIs are trained scientists in cardiomyocyte electrophysiology and cardiovascular T-cell biology, and we are collaborating with experts in gap junctions, computational modeling and arrhythmia mechanisms, making us an exceptional team to conduct these studies.

NSF Awards · FY 2025 · 2025-06

This award will provide funding support for a conference entitled “Geometry and Topology of Polyhedral Complexes” taking place at Ohio State University, Columbus, Ohio on May 26–30, 2025. The conference will cover topics in geometric group theory, geometric topology, and metric geometry, and feature some of the most recent developments in these fields. The conference will also serve to provide an environment for participants to engage in discussions and initiate collaborations. The award will cover travel expenses for US based participants with priority given to graduate students and postdocs. A significant portion of speakers will be in their early careers and will have an opportunity to advertise their work and raise their profiles. The main theme of the conference is the study of polyhedral complexes in geometry and topology. Recent developments in geometric group theory and geometric topology have led to new ways of thinking about these complexes, and ways to use them to build examples in geometry, topology, and group theory. The list of topics covered by the conference include notions of non-positive curvature on polyhedral complexes and its implications in the context of group actions; rigidity properties of groups acting on polyhedral complexes; fibering of complexes and groups; Artin groups, Coxeter groups and hyperplane arrangement complements. This conference invites geometric group theorists, geometers, and topologists who are interested in polyhedral complexes to communicate major recent developments, in the hope of stimulating further research in this direction. The conference website is https://sites.google.com/view/gtpc2025/ This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-06

The International Conference on Scalable Scientific Data Management 2025 is a key event for the community performing research and development in managing scientific data efficiently. The conference is for experts, researchers, practitioners, and developers who want to share and discuss the latest research, tools, and techniques in this field. This NSF student travel award will support participation of students from US universities to attend the conference and to participate in a student poster competition. The SSDBM 2025 poster competition gives students a chance to present their latest research in data management, get feedback from experts, and gain recognition for their work. Participation in an international event such as SSDBM will enable the students to get a global picture of the developments happening in the rapidly evolving scientific data management domain. Their participation will help them to enter the next-generation high-performance computing (HPC) and artificial intelligence (AI) workforce with increased expertise on data management, software design and reuse, and sustainability. Managing massive amounts of scientific data has been crucial for accelerating scientific discoveries with the ever-increasing rate of data generation by scientific simulations, experiments, and observations. This flood of data is both a challenge and an opportunity for groundbreaking discoveries. Efficient data management ensures faster analysis, smoother collaboration among researchers, and better integrity of the data that enhances reproducible science. Modern science creates not only statistical data, but also spatial, temporal, and streaming data. Students attending this conference receive exposure to cutting-edge research in scalable scientific data management, enhanced presentation skills, valuable networking opportunities, career development, open-source software development exposure, software optimization training, and interactions with leading professionals in data management research. Attending SSDBM 2025 better prepares students for their careers in national laboratories, HPC centers, cloud companies, and academia, bridging the gap between academic research and real-world applications. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-06

PROJECT SUMMARY Large protein and protein-nucleic acid complexes and assemblies play key roles in human health and disease, and understanding their three-dimensional structures, conformational dynamics and interactions at the atomistic level is essential for understanding their function and associated biological mechanisms. High-resolution structural and dynamic studies of such large biomacromolecular systems have generally come with significant challenges due to their inherently complex nature. However, by integrating the most recent advances in experimental and computational methodologies many of these obstacles can now be overcome. We develop and apply advanced spectroscopic and microscopic techniques, most notably multidimensional magic-angle spinning solid-state nuclear magnetic resonance and cryo-electron microscopy, in combination with complementary biochemical, biophysical and computational approaches to provide atomic-resolution insights into the structure, dynamics, interactions and function of large protein and protein-DNA systems of major significance in biology. The systems of primary interest in our studies include: (i) nucleosomes and large nucleosome arrays mimicking chromatin, a supramolecular complex of DNA with histone proteins that regulates essential genome functions such as transcription, replication and repair through dynamic changes in its structure, and their complexes with chromatin-binding proteins and (ii) filamentous amyloids formed by mammalian Y145Stop prion protein variants that exhibit strain and cross-seeding barrier phenomena akin to those that underlie the pathogenesis of prion and other neurodegenerative diseases. For chromatin and its complexes we aim to provide quantitative information on functionally-relevant conformational dynamics of histone tail and globular domains as a function of different chromatin parameters including nucleosome positioning and post- translational modifications, which modulate nucleosome plasticity and gene activity, and histone protein interactions with two representative chromatin-binding proteins including a histone reader corresponding to the histone acetyltransferase and ZZ-type zinc finger domains of human p300 and a yeast pioneer transcription factor Cbf1. Combined, these studies will advance the atomic level understanding of critical events that regulate gene transcription. For mammalian Y145Stop prion protein amyloids our studies will decipher the structural basis of amyloid strains and species- and strain-dependent cross-seeding barriers with atomic level detail and furnish insights into the impact of specific Gerstmann-Straussler-Scheinker disease linked amino acid mutations on the core structure of Y145Stop prion protein amyloid fibrils. Collectively, the insights provided by these studies have significant implications for the understanding of prion strains and seeding barriers, prion conformational switching and prion strain selection, which are all of fundamental importance in the pathogenesis of prion and other neurodegenerative disorders.

NSF Awards · FY 2025 · 2025-06

Scientists assess potential earthquake hazards along known faults by studying past earthquakes that have occurred along those faults. Because earthquake recurrence intervals may be hundreds to thousands of years for any given fault, the number of earthquakes directly observed on that fault in recorded history is typically one or two at most. Paleoseismologists (geologists who study past earthquakes) can dig further back in time by looking at the geologic record of ancient earthquakes: evidence of past slip events that have disturbed rocks and sediment around the fault. This is an expensive and time-consuming process that involves excavating parts of a fault, mapping out geologic structures, and determining the absolute dates of materials disturbed by past ruptures. An alternative approach is to study indirect evidence of past earthquake ruptures preserved in the fractured and pulverized rocks surrounding faults in the so-called fault “damage zone”. A fundamental question in this research project is whether fault damage zones contain information about the maximum earthquake size a fault can host (Mmax) in terms of type, style, extent, width and degree of damage. This project will develop criteria to distinguish damage related to earthquake rupture from damage accrued over the longer-term growth of the fault, and to use these criteria to test the hypothesis that the style and intensity of damage on faults that experience earthquake magnitudes greater than ~Mw6.6 to 6.8 can be clearly distinguished from that of faults experiencing smaller magnitude events. This project will include a combination of field-based structural geology of crustal scale faults in southern California, cutting edge rock mechanics experiments, and theoretical rock and fracture mechanics to provide a roadmap for identifying uniquely seismic features preserved in damage zones, and to test the overarching hypothesis that the maximum earthquake size a fault can host can be estimated by examining the damage zone structure of active strike slip faults. Mmax is a critical component of probabilistic seismic hazard assessment (PSHA) as it limits the maximum size of earthquakes considered in a seismic hazard model. Slip rates of faults are the main drivers of hazard, but Mmax controls the upper end of moment release. If Mmax is large, then a significant proportion of the long-term seismic moment release is accommodated by rare large earthquakes. In PSHA, this decreases hazard, compared with moderate earthquakes, which also generate strong shaking but have higher recurrence rates. Hence, quantitative information on Mmax is a significant aspect of quantifying hazard to critical facilities. Current approaches for determining Mmax can be strengthened by developing independent criteria that allow for Mmax determination without knowing the full paleoseismic history. This research will lead to the development of criteria to distinguish damage related to earthquake rupture from quasi-static damage accrued over the longer-term fault evolution, and to use these criteria to test the hypothesis that the style and intensity of damage on faults that experience earthquake magnitudes greater than ~Mw6.6 to 6.8 can be clearly distinguished from that on faults experiencing smaller magnitude events. This will be accomplished by carefully documenting the shallow expression of damage zone structure of crustal scale faults in Southern California and examining the unique characteristics of brittle damage that varies as a function of known historical and paleoseismic earthquake magnitudes. The difference in damage state is likely to be explained by increased energy dissipation by off fault deformation above a critical moment magnitude threshold, and understanding this relation yields the potential for estimating Mmax for active faults with incomplete historical and paleoseismological records. This collaborative study will use field-based structural geology, cutting edge rock mechanics experiments, and theoretical rock and fracture mechanics to provide a roadmap for identifying uniquely seismic features preserved in damage zones, and to test the overarching hypothesis that Mmax can be estimated by examining the damage zone structure of active strike slip faults. This project has the potential for developing an independent, deterministic criterion for Mmax on individual active faults by examining the damage zone structure. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-06

Non-Technical Abstract: The Polar Rock Repository (PRR) at The Ohio State University provides a unique resource for researchers studying the polar regions by offering free access to geological samples and data. This project seeks support to continue expanding and managing the collection, which is vital for scientific studies and planning fieldwork in Antarctica. Over the next five years, the repository plans to add tens of thousands of new samples and images, making it easier for researchers to study polar geology without the high cost and environmental impact of traveling to remote Antarctic locations. The PRR also supports education and outreach by providing hands-on resources for schools, colleges, and the public, including a "Polar Rock Box" program that brings real Antarctic samples into classrooms. This work ensures the preservation of important scientific materials and makes them accessible to a broad community, advancing understanding of our planet’s polar regions. Technical Abstract: The Polar Rock Repository (PRR) at The Ohio State University serves as a critical resource for polar earth science research, offering no-cost loans of geological samples and comprehensive metadata to the scientific community. This proposal seeks funding to support the continued curation, expansion, and management of the PRR, alongside its educational and outreach initiatives. Over the next five years, the PRR anticipates acquiring approximately 15,000 new samples, including those from major drilling operations (RAID, Winkie drill cores) and polar cruises. The repository also aims to significantly grow its archives of images, petrographic thin sections, and mineral separates. By preserving these physical and digital assets in a discoverable online database, the PRR fosters transparency, reproducibility, and accessibility in polar research, fulfilling Antarctic data management mandates. The intellectual merit lies in enabling cutting-edge scientific analyses through freely available samples and metadata. Broader impacts include reduced environmental costs of Antarctic research, enhanced educational opportunities, and outreach to a diverse audience through initiatives like the "Polar Rock Box" program. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-05

This I-Corps project focuses on the development of a positioning system that provides reliable vehicle localization without relying on satellite-based or network-based positioning. The system addresses the challenge of guiding vehicles safely in regions where conventional positioning signals are weak, unavailable, or vulnerable to cyber-attacks. All current methods of vehicle localization depend on satellite signals prone to signal disruption and 3D mapping that is costly to produce and maintain, limiting their coverage to select areas. This new method ensures positioning using vehicle's on-board sensors and two-dimensional, widely available maps while a global positioning system (GPS) signal is not available or intentionally blocked by a cyberattack. This resilient approach enhances public safety, supports mobility across urban and rural areas, and bolsters economic productivity by enabling broader adoption of advanced transportation technologies. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of the technology. This technology is based on the development of a sensor-driven localization framework that integrates vehicle kinematic dead reckoning with widely accessible, two-dimensional map information. The framework employs a kinematic dead reckoning methodology to estimate vehicle position from on-board vehicle sensors such as velocity, steering rate, steering angle, and yaw rate. To address the inherent drift associated with dead reckoning, an arc-length-based map-matching algorithm synchronizes the predicted trajectory with spatial features derived from map data. By merging temporal kinematic predictions with spatial map details, the system maintains high accuracy in environments where satellite-based positioning is unreliable or compromised. This technical innovation significantly advances positioning by offering a robust and reliable solution under challenging conditions. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-05

This I-Corps project is based on the translation from lab to market of a novel, flexible, biopsy instrument that can collect full thickness samples from tumors growing in tubular (hollow) organs in the body. Some examples of such organs include: the tube connecting the kidneys to the urinary bladder (ureter), ducts and organs within the gastrointestinal system (pancreas, colon, esophagus), and the windpipe (trachea and bronchi). With this device, it will be possible to get a precise and accurate estimation of cancer depth of invasion (T stage). This solution addresses tubular cancers that are hard to reach and sample properly. Current devices can only grab surface cells; however, this device is capable of obtaining a full-thickness sample. The top 6 cancers diagnosed in the U.S. originate from tubular organs systems (head and neck, gastrointestinal, and respiratory tract), and almost 25-50% are inaccurately staged. The commercialization of this technology has the potential to benefit society by improving cancer staging and decision-making, ensuring greater treatment accuracy, and improving outcomes for cancer patients. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of a novel biopsy instrument that obtains full thickness biopsies of target organs. Cancer staging is performed in combination with imaging and histopathological information using the tumor, node, metastasis (TNM) system. This technology has the ability to perform a tru-cut core-biopsy using a long, narrow-caliber, flexible biopsy instrument that is compatible with existing endoscopes. The benefits of this approach include precise and adequate tissue sampling, accurate treatment selection, appropriate utilization and management of resources, lower healthcare costs, and improved patient outcomes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-05

ABSTRACT Neurofilaments (NFs) are abundant cytoskeletal polymers in neurons that function as space-filling structures to expand axonal caliber, which is a critical determinant of axonal conduction velocity. NFs assemble in the neuronal soma and are transported into axons, where they accumulate excessively in many neurodegenerative diseases, leading to axonal swelling and enlargement. In addition, mutations in one of the NF subunit proteins, NFL, cause the hereditary sensory and motor neuropathy known as Charcot-Marie-Tooth disease type 2E (CMT2E). Most CMT2E mutations are dominantly inherited missense mutations. Here we propose three aims to elucidate the disease mechanism of CMT2E and develop a pre-clinical therapeutic strategy. Aim 1 is to establish the effect of CMT2E mutations on NFs. Overexpression of CMT2E mutant NFL in cultured cells has been reported to disrupt NF assembly. However, observations on human nerve biopsies and an NFLN98S/+ knock- in mouse model of CMT2E have revealed accumulations of NF polymers, which suggests an impairment of NF transport. We hypothesize that when expressed at physiologically relevant levels, CMT2E mutant NFL assembles into NFs that have altered transport kinetics. We will test this using biochemical and imaging approaches in neurons differentiated from patient-derived and gene-edited human iPSCs. Aim 2 is to elucidate the mechanism of NF accumulation in CMT2E disease. Ultrastructural studies on the NFLN98S/+ knock-in mouse model of CMT2E have revealed massive accumulations of NF polymers in the cell bodies and proximal regions of myelinated axons of motor and sensory neurons. Distally, these axons lack NFs entirely and have a reduced caliber and impaired nerve conduction. We hypothesize that the proximal accumulations represent NF “logjams” which arise due to an impairment of NF transport, preventing NF movement into distal axons. We will test this hypothesis by performing volumetric reconstruction of axons in NFLN98S/+ mice using immunofluorescence array tomography, and by live imaging of NF transport during the formation of NF accumulations in iPSC-derived neurons from CMT2E patients. Aim 3 is to establish a therapeutic strategy for CMT2E in NFLN98S/+ mice. Preliminary data point to a dominant negative mechanism of action. Thus, we hypothesize that the disease can be rescued by a knockdown-and-replace gene therapy strategy using recombinant adeno-associated viral vectors. We will compare the efficacy of this approach to simply overexpressing wild type NFL. An advantage of this approach is that it will be applicable to all forms of CMT2E, independent of the specific mutation, thus broadening the therapeutic applicability. Our goal is to restore normal NFs to neurons, permitting NF delivery to distal axons during postnatal development. The proposed research leverages more than three decades of experience studying NF assembly and transport in the PI’s lab as well as the complementary expertise of co- investigators and collaborators at UCSF and Ohio State University, who have had proven success with iPSCs, gene editing, RNAi, viral vectors, electrophysiological assessments of neuromuscular function, and the translation of viral gene therapy from mice to patients.

NIH Research Projects · FY 2026 · 2025-05

Abstract Human noroviruses (HuNoVs) account for more than 95% of non-bacterial acute gastroenteritis worldwide. Currently, there are no vaccines or antivirals against HuNoVs. This is due, in large part, to the lack of a robust cell culture system and a small animal challenge model. In general, live attenuated viral vaccines induce strong systemic and mucosal immunity and provide durable protection. However, it is not possible to generate a live attenuated vaccine for HuNoV because of its inefficient replication in vitro. In this situation, a live viral vectored vaccine platform represents a feasible strategy for development of a “live” HuNoV vaccine. Rotavirus (RV) vaccine (RotaTeq) and measles/mumps/rubella (MMR) vaccines are the two most successful live attenuated vaccines in human history, approved for use in children in 2006 and 1971, respectively. The goal of this project is to develop multivalent, live-vectored mucosal HuNoV vaccines using the FDA-approved RV and MMR vaccine platforms. We hypothesize that RV and MMR-based multivalent HuNoV vaccines will induce strong systemic and mucosal immune responses that confer broad protection against different HuNoV genogroups and genotypes. The major capsid (VP1) gene and protrusion (P) domain of VP1 gene of the most prevalent HuNoV genotype GII.4 and other important genotypes (e.g. GI.1, GII.1, GII.3, and GII.6) will be inserted into five re- assortant strains of the RotaTeq vaccine. RVs expressing VP1, P, double VP1, and double P will be generated and formulated into multivalent RV-NoV vaccines expressing 5-10 VP1 or P proteins. In parallel, these VP1, P, double VP1, and double P will be inserted into MeV, MuV-Jeryl Lynn 1 (JL1), and MuV-JL2 strains of the MMR vaccine, and multivalent MMR-NoV vaccines expressing 3-6 VP1 or P proteins will be generated. The immunogenicity of these multivalent RV-NoV and MMR-NoV vaccines will be screened in mice (for RV-NoV) and hamsters (for MMR-NoV). The two most immunogenic RV-NoV and MMR-NoV vaccine candidates will be chosen for oral (for RV-NoV) or intranasal (for MMR-NoV) immunization of gnotobiotic piglets, the only small animal challenge model for HuNoV. HuNoV-specific serum IgG, mucosal IgA, and their neutralization activities, gut- resident T cell immune responses, and their breadth will be characterized. The immunized gnotobiotic piglets will be orally challenged with different HuNoV genogroups and genotypes, and their protection efficacy will be determined. Finally, we will determine whether multivalent RV-NoV and MMR-NoV co-expressing VP1/P and T cell epitopes (such as nonstructural proteins NS1 and NS6) of HuNoV can enhance the immune responses and breadth of protection against HuNoV infection. Upon the completion of this project, we will have developed two mucosal multivalent HuNoV vaccines, the oral multivalent RV-NoV vaccine and the intranasal multivalent MMR- NoV vaccine that are safe, highly efficacious, and broadly protective. These vaccine candidates will directly lead to trials in non-human primates and humans.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY/ABSTRACT Auditory Neuropathy Spectrum Disorder (ANSD) is a clinical diagnosis that is characterized by abnormal cochlear nerve (CN) function as indicated by absent or abnormal auditory brainstem responses in conjunction with some normal hair cell function as evidenced by the presence of cochlear microphonics and/or otoacoustic emissions. Current intervention options for ANSD include the use of hearing aids (HAs) and cochlear implants (CIs). Auditory abilities among patients with ANSD are extremely diverse and cannot be predicted based on the severity of hearing loss. Overall, ANSD remains a mystery despite decades of research. The current clinical paradigm for managing ANSD solely depends on reliable behavioral responses from patients, which is impossible in infants and many children with ANSD due to their young age and/or comorbidities. As a result, even though early identification of ANSD through effective newborn hearing screening programs is possible, implementing appropriate interventions for individual patients is delayed, which can have lasting detrimental effects on communication skills development. The proposed study aims to translate scientific findings in objective measures into clinical tools to address the following unmet, urgent clinical needs for managing patients with ASND: 1) how to determine whether the CN responds to acoustic stimulation in clinical settings, 2) how to determine the degree of hearing loss, 3) how to determine appropriate CI programming settings, and 4) how to accurately assess whether individual patients are making appropriate progress with HAs or CIs in a timely manner. In Aim 1, we propose to establish the electrocochleography recorded at the tympanic membrane as a noninvasive, clinical tool to evaluate frequency-specific CN function in patients, including children with ANSD. In Aim 2, we propose to establish the onset cortical auditory evoked potential (CAEP) as a clinical tool to objectively assess ear- and frequency-specific, audiometric thresholds in children with ANSD and children with conventional sensorineural hearing loss, as well as to validate the degree of cortical neural synchrony as an early identifier of the patients with ANSD who need to transition from HAs to CIs. In Aim 3, we propose to establish the clinical applications of the electrically evoked onset CAEP and the stapedial reflex threshold to assist in the CI programming process and to establish the degree of peripheral neural synchrony as a robust indicator to predict CI benefit for individual children with ANSD. This study has tremendous clinical significance because 1) it will shift the clinical paradigm for ANSD management from solely relying on behavioral response to a synergistic approach that includes both objective and behavioral measures, and 2) it will improve clinical care of children with SNHL who cannot provide reliable behavioral responses.

NIH Research Projects · FY 2026 · 2025-05

Project Summary Cerebral Palsy (CP) is the primary motor disability of childhood. Over half of all children with CP have upper extremity (UE) deficits. Children with unilateral UE deficits benefit from intensive motor practice using the weaker or affected arm while the dominant or unaffected arm is constrained in a splint or cast. This form of therapy, pediatric constraint induced movement therapy (pCIMT), is one of the most effective treatments for improving UE motor skills, but it is not available in many areas of the country. Telehealth may make pCIMT accessible for families who live in rural areas, under-resourced settings, far away from pCIMT programs, or those who face barriers to in-person visits (e.g., transportation). Early-stage pediatric research trials are exploring telehealth interventions (mostly in infants and young children), but most still require in-person pre- and post- assessments. For telehealth to truly reduce the health accessibility gap, scientists need to 1) determine if telehealth pCIMT is effective in school-aged children, 2) compare telehealth and in-person UE assessments, and 3) measure adherence to protocol dose for any parent-delivered components of treatment. This proposal adds aims to a funded pilot efficacy trail (n=10) of intensive (60 hours in 4 weeks) telehealth pCIMT study, CHAMP-T2, to address each of these needs. First, wrist-worn accelerometers will measure changes in amount, magnitude, and symmetry of UE use. Accelerometers have been successful in measuring change in UE movement and are highly correlated with functional measures. CHAMP-T2 participants and an additional 25 subjects will be enrolled in a sub-study to compare the scores of in-person and telehealth administrations of the Melbourne Assessment-2 and the Assisting Hand Assessment. If telehealth administrations of these assessments have high agreement with in-person assessments, they may be suitable for measuring change in future telehealth trials. Finally, because CHAMP-T2 depends on an on-site parent to facilitate the child’s motor practice through a combination of video-conferencing sessions and at-home practice, accelerometry watches will be used to quantify adherence to pCIMT treatment dose (e.g., frequency, time, and type of intervention). If successful, this offers a low-burden alternative to activity logs or diaries for monitoring adherence to dose during at-home practice. The applicant identifies training goals to advance expertise in: 1) all phases of clinical trials, 2) remote collected UE assessment, 3) training parents in motor intervention principles, and 4) stakeholder-led research. In addition, the applicant will complete lab rotations, workshops, courses, and seminars to meet these training goals and enable the completion of the research plan. The applicant is supported by an interdisciplinary team of mentors in pediatric rehabilitation (physical and occupational therapy), engineering, and medicine, parent stakeholders, and a biostatistician.

NIH Research Projects · FY 2026 · 2025-05

Project Summary/Abstract Falls among older adults represent a significant public health issue in the United States. Falls and fall-related injuries impact approximately 28-49% of the older adult population each year and falls are the primary cause of accidental death in older adults over the age of 65. Fall related injury and mortality have considerable impact on healthcare costs. This research seeks to elucidate the interplay between age-related auditory and vestibular deficits and their effects on gait and spatial navigation. Age-related hearing loss (ARHL) and age-related vestibular dysfunction are both associated with increased fall risk, yet their influence on gait and spatial navigation remains underrepresented in the literature. This project aims to address this gap by investigating how changes in auditory and vestibular function correlate with spatiotemporal gait characteristics and spatial navigation abilities. We propose a novel approach by employing comprehensive assays of auditory and vestibular function, including objective and subjective measures of hearing ability as well as vestibular perceptual thresholds, to evaluate the impact of age-related changes in these systems on gait and spatial navigation. Participants aged 18-89 will undergo a battery of assessments: auditory tests (including pure-tone audiometry and speech recognition in noise), vestibular perceptual threshold testing, instrumented gait analysis, and the triangle completion test to assess spatial navigation. By correlating auditory and vestibular thresholds with gait variability and spatial navigation performance, this study aims to identify key predictors related to fall risk and impaired mobility. This research is expected to contribute to a deeper understanding of how ARHL and age- related changes in vestibular function affect gait and spatial navigation, potentially guiding the development of targeted interventions to mitigate fall risk and improve quality of life for older adults. The innovative integration of continuous measures of auditory and vestibular function with dynamic gait and spatial navigation assessments represents a significant advancement in the field toward the reduction of fall risk in older adults.

NSF Awards · FY 2025 · 2025-05

This Faculty Early Career Development (CAREER) award supports research investigating the reuse and recycling of feedstock in the laser directed energy deposition metal additive manufacturing process in the context of a circular economy where resources are used as long as possible. This process allows for fabrication or extension of a component’s service life through remanufacturing and repair, specifically for large components for energy applications, like hydropower turbines. This award aims to support research that attempts to reveal how reused and recycled metals can introduce unique chemistries, structures, and properties for improved large components. The research is expected to provide an understanding of how manufacturing can overcome challenges in the qualification and certification of components, leading to more reliable parts, and fueling the US economy. Educational activities will contribute to workforce development for graduate research students and for local high school students so they can succeed in a competitive global market. These activities include development of videos on imaging science, international research collaborations, and engagement through a local recycling center in Columbus, Ohio. The research objective is to reveal how characteristics of reused and recycled feedstock influence melting and solidification in the laser directed energy deposition additive manufacturing process, specifically on how tramp elements and the morphology of feedstock influence melting, oxidation, particle segregation, intermetallic phase formation, and overall microstructure. The research approach includes in situ and operando experimental methods, including synchronized high-speed synchrotron X-ray imaging and diffraction to capture phase transformations during solidification in real-time and at multiple scales. The scientific objectives address the following: (1) Melt flow changes from reused and recycled material, where increased oxidation and tramp elements from feedstock exhibit lower surface energy in the laser-induced liquid melt pool, reversing Marangoni flow and increasing melt pool flow velocities; (2) Melt flow changes from reused and recycled material physical characteristics, where increased irregularity in shape introduces melt pool flow turbulence during deposition, which breaks up intermetallic phase formation and refines grain growth during solidification; (3) Solidification changes with reused and recycled material resulting from melt flow changes and particle segregation for refined grain growth. Addressing these objectives intends to: create a framework for feedstock reuse and recycling for metal additive manufacturing, extend reuse to material and process systems where material recycling rates low, and elongate the service life of repaired or remanufactured components. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-05

Modified Project Summary/Abstract Section Physician scientists and surgeon scientists comprise a vital component of the biomedical research workforce yet statistics indicate a shrinking physician scientist workforce and reduced pipeline of medical students engaging in basic/translational research. The overall goal of this training program is to expand and strengthen the physician and surgeon scientist pipeline that will become the next generation of immunology and virology trained physician scientists across a breadth of medical specialties. Global infectious pathogens creating current and future pandemics, novel immunotherapeutics with expanding applications in cancer and other diseases, increasing prevalence of allergic and autoimmune disease, and exciting innovations in transplantation necessitate more immunology and virology trained physician and surgeon scientists. Each year an outstanding class of over 200 medical students matriculate into the Ohio State University (OSU) College of Medicine (COM). STRIVE T35 will leverage the OSUCOM medical student talent and the infrastructure of the COM Office of Physician Scientist Education and Training (PSET) to recruit medical students to engage in short-term immunology and virology research training including during the summer between Med I and Med II. The OSU Short- Term Research in Immunology and Virology Experience (STRIVE) will provide a 12 week summer research experience including mentored research, didactics, participation in seminars and conferences, clinical experiences and career development. Medical students will gain knowledge, skills, and abilities in 4 domains: 1) Autoimmune disease, 2) Immune Oncology, 3) Virology and Microbial Immunity and 4) Transplant Immunology. The faculty preceptors are experienced NIH-funded collaborative investigators with outstanding training track records including success in inspiring and training medical students. STRIVE innovations include: 1) pre- T35 training preparation of a mini research proposal and development of individualized training goals and plans 2) rigor and reproducibility lab-based training complemented by didactics, 3) a new short course in Responsible Conduct of Research led by an ethicist, 4) focused clinical experiences to integrate immunology and virology learning with clinical correlations in the 4 domains, 5) participation in seminars, conferences and workshops to highlight cutting edge immunology and virology research and to gain broad exposure to leaders in the field, 6) career development activities and 7) community building and networking with trainees in PSET programs. STRIVE has well defined metrics and a robust program evaluation plan that will leverage OSU and COM trainee tracking tools and program evaluation experts in addition to external review by an expert external advisory committee. This new T35 program offers an unparalleled experience for highly talented OSU medical students at a formative stage to broaden their career support network and to experience the rewards and impact of immunology and virology related physician and surgeon scientist careers.

NIH Research Projects · FY 2026 · 2025-04

ABSTRACT Traumatic spinal cord injury (SCI) causes devastating neurological deficits and long-term disability due to detrimental structural and functional alteration in neuronal circuits. Despite recent progress, no effective disease-modifying treatment is currently available for SCI. This may be because the cellular and molecular mechanisms that cause or contribute to pathophysiological changes in neuronal structure and function after SCI are poorly understood. Many studies, including ours, have demonstrated a remarkable convergence between the structural and functional organization of neuronal circuits and the expression of α2δ subunits of voltage-gated calcium channels (VGCC). Neuronal α2δ subunits positively regulate synaptic transmission by increasing plasma membrane expression of VGCC. However, these subunits may also play a pathological role following axonal injury. Expression of α2δ1/2 increases following axonal injury, resulting in aberrant neuron activities associated with chronic pain and axon regeneration failure. We recently showed that α2δ1/2 pharmacological blockade through systemic administration of gabapentinoids (e.g., gabapentin and pregabalin), drugs used clinically to treat various neurological disorders, promotes axon regeneration and functional recovery after SCI in adult mice. Whereas the beneficial action of gabapentinoids in promoting neurological recovery after SCI is gaining support, systemic administration of this class of drugs can cause adverse side effects. More recently, gabapentinoids' rise as drugs of abuse generates concern. Given that neuronal α2δ1/2 subunits accumulate at the growth cone and presynaptic nerve terminals, targeted interventions could prove to be more effective than systemic delivery strategies. Our preliminary data suggest that localized intraspinal delivery of gabapentinoids through biocompatible polymer-based injectable microspheres favors spinal cord repair while circumventing detrimental side effects and misuse associated with the systemic administration of this class of drugs. Accordingly, experiments in Aim 1 will implement electrospray techniques to optimize conditions for microsphere fabrication, consistent drug loading and homogeneous release profiles. We will further characterize physicochemical properties including porosity, swelling, drug entrapment efficiency and release profile at predetermined time intervals upon reconstitution. We will also test microsphere performance and behavior in vitro using time-lapse microscopy of primary neuronal and macrophage cultures. Aim 2 will test whether localized gabapentinoids delivery at the lesion site favors axon regeneration and SCI repair. Our multi-layered electrosprayed delivery system will facilitate the development of novel and more effective strategies creating favorable conditions for neurological recovery after injury to the mammalian spinal cord.

NIH Research Projects · FY 2025 · 2025-04

PROJECT SUMMARY Approximately half of individuals experiencing homelessness or housing instability have sustained at least one traumatic brain injury (TBI) in their lifetime, with up to 90% having sustained their first TBI prior to becoming homeless. Becoming unhoused is often precipitated by socioeconomic disadvantage resulting from job loss, inability to pay medical bills, and/or severing of family ties that provided financial and other supports. Furthermore, cognitive and behavioral impairments due to TBI can make it difficult to complete tasks of daily living and maintain key relationships at work and home. When left unidentified and unaddressed, these impairments can affect a person’s ability to fully benefit from existing homeless and housing service programs meant to facilitate housing access and housing retention, thus contributing to the chronicity of homelessness and housing instability. Neurologic-Informed Care (NIC) is a novel, integrated model of care that could enhance the equitability and effectiveness of services for this population. NIC consists of existing evidence-based interventions: 1) the Ohio State University TBI Identification Method to screen for lifetime exposure to TBI, 2) Adult Symptoms Questionnaire for Brain Injury to identify specific impairments, and 3) neurocognitive accommodations for overcoming these impairments. NIC is a scalable and potentially highly effective model that can be employed by front-line staff in these settings. NIC is now required by the American Society of Addiction Medicine when cognitive impairment is an issue, but it is not specific to substance use treatment. Increasing the uptake, effectiveness, and sustainment of NIC in homeless and housing service settings will take deliberate, implementation efforts to overcome multilevel barriers at the staff, organizational, and system levels. Our prior research has demonstrated the utility of implementation blueprints as an effective implementation strategy for overcoming barriers and scaling-out other interventions in complex treatment settings, but studies have yet to develop a blueprint for implementing NIC in homeless or housing service settings. Grounded in the NINDS Social Determinants of Health and Health Equity Implementation Frameworks, this R34 seeks to address several objectives necessary to prepare for a future hybrid effectiveness-implementation study aimed to increase the uptake, effectiveness, fidelity, and sustainment of NIC in homeless and housing service settings nationally. In Aim 1, we will determine client (n = 20) and staff (n = 15) acceptability of NIC and if adaptations are needed for persons with TBI experiencing homelessness or housing instability. In Aim 2, we will investigate multilevel determinants to NIC uptake using a convergent parallel mixed methods design through interviews (n = 25 staff) and surveys (n = 100 staff across 10 organizations in the United States). In Aim 3, we will co-develop an implementation blueprint with our Community Advisory Board members to address these determinants, connecting specific blueprint strategies to measurable implementation and effectiveness outcomes.

NIH Research Projects · FY 2025 · 2025-04

Abstract A group of 15 investigators from 5 colleges/institutes and 12 departments at The Ohio State University and 1 investigator from Case Western Reserve University is requesting funds to permanently acquire a Bruker timsTOF fleX MALDI-2 quadrupole time-of-flight mass spectrometer. This instrument was originally brought to the Ohio State campus with a one-year, no obligation loan and has already resulted in thirteen publications from users. This instrument empowers NIH-funded users in their tissue imaging studies with three new and needed capabilities: 1) MALDI-2 post-ionization; 2) single-cell spatial resolution; and 3) trapped ion mobility (TIMS) coupled with imaging. These three features are in high demand amongst NIH-funded OSU investigators and no other instrument of this type is available on campus or within Ohio. While there are other imaging instruments on campus, the balance of m/z resolution (at 60,000), scanning speed, imaging speed, and imaging resolution makes the timsTOF fleX MALDI-2 a crucial, research-changing piece of technology for the growing number of interested users at OSU. The instrument provides rapid detection and structural elucidation of a tissue landscape in a non-targeted fashion with the capability of high-throughput MS and MSMS scanning with the use of TIMS before quadrupole mass selection. The added feature of post-ionization with MALDI-2 increases signal intensity for many small molecule metabolites (i.e., glycans, fatty acids, amino acids, and drug-metabolites). Likewise, the diameter of the MALDI laser spot, needed for creating the pixelation of a tissue image, can be adjusted as low as 5 µm, making the imaging spatial resolution the finest on the market and capable of imaging within a single cell. Finally, the instrument can be readily switched between positive and negative modes and has a high m/z dynamic range without the need for labeling, so researchers can overlap different molecular types to acquire imaging overlays of protein and lipids or protein and drug metabolite interactions. This flexibility is critically needed as the research programs of the 10 major users and the 6 minor users that will benefit from this instrument are highly diverse, span two universities, and are funded by 16 NIH grants (spanning 5 NIH institutes: NCI, NIGMS, NHLBI, NIA, NIBIB) as well as the NSF and the USDA. The requested instrument will be housed in the OSU Mass Spectrometry and Proteomics Facility (MS&P) within the Campus Chemical Instrument Center (CCIC), a unit of the OSU Office of Research that provides mass spectrometry access campus wide. Already known for consistent research-driven instrumentation for LC-based proteomics and metabolomics, the CCIC MS&P core is looking to provide the highest quality state-of-the-art instrumentation in imaging mass spectrometry to match and facilitate both the omics already performed in the facility as well as the microscopy research performed by NIH-funded researchers. The CCIC MS&P staff have the expertise and experience to support the timsTOF fleX MALDI-2 and offer these services to a wide range of biomedical researchers at OSU and throughout Ohio.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY The prognosis for patients with metastatic non-small cell lung cancer (NSCLC) remains poor despite recent progress in immune checkpoint blockade therapy. A better understanding of mechanisms for lung cancer immune evasion within the tumor microenvironment (TME) will allow for the rationale development of more effective and durable immunotherapeutic strategies for treating patients with lung cancer. Tumor-associated macrophages (TAMs), a major component of the TME, generally display an anti-inflammatory phenotype and can facilitate tumor growth by promoting angiogenesis, invasion, and metastasis, as well as immune evasion. However, it remains largely undefined exactly how these TAMs regulate anti-tumor immune responses within the TME. We have demonstrated preclinically that hedgehog signaling in TAMs induces intratumoral CD8 T cell dysfunction in addition to regulating the recruitment of CD8 T cells to the TME, and that combining Hh inhibition and PD-1 blockade has synergistic anti-tumor effects in vivo. We plan to test the hypothesis that Hh signaling in TAMs suppresses CD8+ T cell recruitment resulting in pro-tumorigenic state within TME in patients with NSCLC through the following specific aims: 1) Investigate the role of Hh inhibition with anti-PD-L1 therapy in patients with non-small cell lung cancer (NSCLC), and 2) Study the impact of Hh inhibition on TAMs and changes within the TME. To achieve these aims, we will conduct a multi-center phase Ib clinical trial of combination therapy with vismodegib (hedgehog inhibitor) and atezolizumab (anti-PD-L1) in patients with metastatic NSCLC. The objective of this project is to understand signals required for functional polarization of TAMs within the TME and its contributions to immune cell dysregulations, cancer development, and progression, which may lead to the development of novel therapy for patients with NSCLC.

NIH Research Projects · FY 2025 · 2025-04

New therapeutic strategies are urgently needed to improve outcomes for patients with STK11/KEAP1 co-mutant non-small cell lung cancer (NSCLC). We found that concurrent STK11/KEAP1 loss-of-function (LOF) predicts poor (median overall survival of only 7.3 months) prognosis in NSCLC; compared to wildtype or single mutants. STK11/KEAP1 LOF mutations dramatically enhance cell proliferation, invasive potential in vitro, and tumor growth in xenograft lung cancer models. Furthermore, NSCLC cell lines harboring co-mutation of STK11 and KEAP1 showed significant enrichment of pathways suppressing ferroptosis, and co-mutant cells were resistant to ferroptosis-mediated death. CRISPR/Cas9-based screening of these cells identified synthetic lethal interactions specific to the co-mutant state, including a crucial regulator of ferroptosis (SCD1). Our data suggest that ferroptosis is a barrier to tumorigenesis in NSCLC and STK11/KEAP1 mutations provide multimodal ferroptosis protection in co-mutant models. However, the underlying mechanisms of ferroptosis evasion, the impact on immune microenvironment; and the effectiveness of targeting ferroptosis to overcome chemotherapy and immunotherapy resistance in STK11/KEAP1 co-mutant NSCLCs still remain largely unexplored. Our overarching hypothesis is that evasion of ferroptosis is critical to the survival and proliferation of STK11/KEAP1 co-mutant NSCLCs, and therapeutic regimens that induce ferroptosis and inhibit ferroptosis evasion could be effective therapeutic strategy to overcome therapy resistance. Our objective is to delineate the mechanism and establish ferroptosis as a potential target in STK11/KEAP1 co-mutant NSCLCs, with the long-term goal of developing novel therapies for STK11/KEAP1 co-mutant NSCLCs. Aim 1 will define the molecular and immune features associated with the progression or recalcitrance of STK11/KEAP1 co-mutant NSCLCs by (1) determining the role on tumor growth, ferroptosis, metabolic landscape and immune microenvironment in preclinical models; (3) determining the tumor heterogeneity and immune microenvironment changes associated with the aggressiveness and recalcitrance of STK11/KEAP1 co-mutant NSCLC patient tumors. Aim 2 will determine how STK11 and KEAP1 individually regulate invasion, tumor growth, and ferroptosis in preclinical models. We will examine how selective loss of STK11 or KEAP1 affects downstream signaling, promotes proliferation, invasion, ferroptosis evasion, and SCD1 expression in multiple in vivo models. Aim 3 will establish the efficacy and strategy of targeting stearoyl CoA desaturase-1 (SCD1) [with ferroptosis inducers (FINs)] to overcome resistance to chemotherapy or immunotherapy in STK11/KEAP1 co-mutant NSCLCs by (1) determining the mechanisms by which SCD1 regulates tumor growth and survival in vivo; and (2) defining the effectiveness of combining SCD1 inhibition (+/-FINs) to overcome chemotherapy and immunotherapy resistance. Our study will have a significant impact on both our basic understanding of ferroptosis and our ability to target SCD1 or ferroptosis in the most recalcitrant subset of NSCLC, directly supporting the mission of the NCI.