Ohio State University

NSF Awards · FY 2025 · 2025-04

In U.S. colleges and universities about 25% of undergraduate students and 20% of graduate students with a disability enroll in science and engineering fields. Surprisingly, the economic well-being of persons with disabilities has decreased since the passage of anti-discrimination laws such as the 1990 Americans with Disabilities Act. However, STEM careers offer better financial outcomes for individuals with disabilities. Additionally, economic projections suggest an increasing need to recruit more STEM majors, and students with disabilities are an under-recruited group who could help to meet this national economic need. Undergraduate and graduate students with disabilities may be dissuaded from pursuing STEM careers by instructors and mentors who lack the knowledge to support the students' participation. This CAREER scholar is investigating the barriers and supports encountered by undergraduate and graduate physics students and early career physicists with disabilities in their learning and research experiences. Results of this work provide information to college instructors and professional mentors to make physics more accessible and inclusive for persons with disabilities pursuing physics careers. The Faculty Early Career Development (CAREER) program is a National Science Foundation (NSF)-wide activity that offers awards in support of junior faculty who exemplify the role of teacher-scholars through outstanding research, excellent education, and the integration of education and research within the context of the mission of their organizations. This award is supported through the EHR Core Research (ECR) program. ECR emphasizes fundamental STEM education research that generates foundational knowledge in the field. The goal of this CAREER project is to explore how the attitudes toward and experiences of physics students and early career physicists vary across multiple components, including demographic variables, research experience, and physics sub-field. This research is focusing on individuals with visual, hearing, physical, mental health and/or cognitive-learning impairments, including those with learning and reading disorders, Autism Spectrum Disorder and other executive function disorders. Everyone is conceived to have an ability profile, with strengths and weaknesses along multiple dimensions. Research questions include: (1) How is the existing culture in the physics research and instructional communities towards persons with disabilities shaped by the ability profile and other personal characteristics of the instructor/mentor and the student/mentee? (2) How does the existing culture in the physics research community vary across sub-fields and research types? (3) What are effective strategies for making physics more accessible and inclusive for persons with disabilities? (4) What are effective ways to train university faculty to better support undergraduate and graduate students, and early career researchers with disabilities? In addition to collecting student data, surveys will be administered in collaboration with the American Physical Society to capture a broad population of practicing physicists, and interviews will be conducted with physicists with disabilities and their mentors. The research is integrated with an extensive education plan that includes creating learning communities for faculty interested in persons with disabilities in physics, modifying trainings for graduate teaching assistants and undergraduate learning assistants to include inclusive teaching strategies, conducting workshops to train physics teachers and mentors, and publishing articles for practicing physicists and instructors. Additionally, undergraduate and graduate students working with the researcher will benefit from learning about STEM education research methods and integrating research with educational opportunities for improving physics instruction. 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 · 2025-04

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.

NIH Research Projects · FY 2025 · 2025-04

Abstract Over 12 million people currently suffer from leishmaniasis, and ~2 million new cases occur each year, making it a major global health problem and a WHO classified neglected tropical disease. Visceral leishmaniasis (VL) is a life-threatening form of the disease caused by Leishmania donovani and Leishmania infantum and is characterized by parasite dissemination to the liver, spleen and bone marrow. Second to malaria, VL causes most deaths amongst parasitic diseases. The majority of VL cases caused by L. donovani are reported from East Africa, particularly Kenya, Sudan, South Sudan and Ethiopia. In Sudan, 40-50% of treated VL patients develop post kala azar dermal leishmaniasis (PKDL) which is characterized by proliferation of parasites in the skin leading to macular or nodular dermal lesions. PKDL self-resolves in the majority, but up to 20% of cases become chronic and non-healing. PKDL lesions have recently been implicated as a source of infection in sand flies. VL in eastern Africa is an epidemiologically and clinically diverse disease. in In East Africa, two distinct ecotypes of VL, the northern ecotype (NE-VL) in Northern Ethiopia and eastern Sudan and the southern ecotype (SE-VL) in southern Ethiopia, Kenya, Uganda and Somalia, have been identified based on genetic differences in parasites, and different sand fly vector species and ecological features. Phlebotomus martini (southern ecotype) have a micro-ecological preference for termite mounds (breeding /resting site); and P. orientalis (northern ecotype) depends on black cotton soil cracks. The disease phenotype and clinical outcomes also vary between the two ecotypes and within the northern ecotype. For example, PKDL is common in NE-VL but rare in SE-VL. Furthermore, although north Ethiopia and Sudan have genotypically similar parasites, PKDL is common in Sudan but rare in north Ethiopia. Likewise, there are differences in the therapeutic response to paramomycin and liposomal amphotericin as NE-VL responds poorly to treatment compared to SE-VL. Unlike Asia, VL in East Africa is targeted for control rather than elimination by WHO, partly due to significant knowledge gaps in ecoepidemiology, vector biology, and host and parasite factors driving transmission and pathogenesis. VL transmission is influenced by intrinsic factors such as vector competence, longevity and gut microbiota, and extrinsic factors including reservoir diversity, vector feeding preferences, and vector anthropophilicity, among others. Yet, how these factors promote VL transmission in Eastern Africa and elsewhere is poorly understood. To address these knowledge gaps, in this U01 project we propose to study the eco-epidemiology of VL at 4 sites in East Africa which are endemic for SE-VL (2 sites) or NE-VL (2 sites) and have different ecological and transmission features (Aim 1), determine the relative significance of factors that influence vector behavior and ecology as drivers of transmission (Aim 2), and identify host and parasite determinants of pathogenesis in VL and PKDL (Aim3). Collectively, our studies will contribute to VL knowledge landscape, control and innovation opportunities and discovery of new treatments towards VL and PKDL elimination in East Africa.

NSF Awards · FY 2025 · 2025-04

This project explores a new concept, regulatory scope, in order to inform actions that result in persistent behavior change. The traditional focus on one-off decisions may have limited impact. The idea of regulatory scope is to reduce the psychological distance of future behavioral consequences and current behavior choices by expanding an individual's range of concern or the scope of outcomes an individual considers. This is hypothesized to be achieved by exercises that help an individual recognize behavioral patterns in order to make choices guided by longer term consequences versus shorter term needs. The project tests this theory of regulatory scope on choices made. Expanding regulatory scope has the potential to be applicable to several domains of behavior change, including resilience and personal health. Specifically, this research focuses on expanding regulatory scope: the range of considerations that people account for in their decisions and behaviors to include further off outcomes and possibilities. Through the framework of regulatory scope, the researchers provide a comprehensive account of resilience-related behavior and behavior change, explaining past phenomena and predicting future ones. The primary aims of this proposed project are to (1) assess the relationship between regulatory scope and existing resilience behaviors; (2) determine how regulatory scope manipulations influence resilience behavior intentions; and (3) evaluate the effect of a practical real-world change in regulatory scope on persistent resilience behavior change. These three aims are met through a combination of cross-sectional surveys and longitudinal experiments to test and evaluate regulatory scope and provide guidance for a new class of interventions. 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 · 2025-04

Abstract Paclitaxel, one of the most widely used antineoplastic drugs, is highly effective in treating a variety of solid tumors, including breast and non-small cell lung cancer (NSCLC). However, the clinical use of paclitaxel is limited by the development of dose-limiting paclitaxel-induced peripheral neuropathy (PIPN) by most cancer patients who receive paclitaxel. Unfortunately, current strategies to prevent or treat PIPN are ineffective, and our understanding of the molecular mechanisms underlying PIPN remains incomplete. In addition to directly damaging neurons within the dorsal root ganglia (DRG), the site of injury for PIPN, paclitaxel also induces neuroinflammation and the recruitment of immune cells to the DRG, which has recently emerged as a key driver of PIPN; however, druggable targets within this cascade have remained elusive. In pursuit of our long-term goal to decrease adverse events associated with paclitaxel, we have identified S100A9, an inflammatory damage- associated molecular pattern (DAMP) with readily available pharmacologic inhibitors, as a candidate target to reduce PIPN and neuroinflammation. In preliminary studies, we found that mice treated with paclitaxel developed a PIPN-like phenotype and had upregulated S100A9 in their DRG. Functional validation studies in S100A9- deficient and matched wild-type (WT) mice demonstrated that S100A9 deficiency protected mice from neuropathy in both acute and chronic models of PIPN. Next, to elucidate whether the protection conferred by deficiency of S100A9 is related to neuroinflammation involving immune cells recruited from the bone marrow, we performed allogeneic transplant experiments and found that only mice with S100A9-deficient bone marrow were protected from PIPN. To provide proof-of-principle and demonstrate the translational relevance of this target, we found that multiple pharmacological inhibitors of S100A9 also protected against PIPN without affecting paclitaxel’s plasma levels or its cytotoxic potential against multiple breast cancer cell lines. Based on these preliminary findings, we now outline three sets of related studies that will further test and refine the validity of our central hypothesis that targeted inhibition of S100A9 can reduce paclitaxel’s toxicity and downstream neuroinflammatory cascade without negatively influencing its plasma pharmacokinetic profile or antitumor properties: (i) characterize the mechanism underlying S100A9-induced PIPN, with an emphasis on neuro- immune interactions; (ii) determine an optimal regimen to pharmacologically inhibit S100A9 and prevent PIPN utilizing PK-PD modeling; (iii) safety, toxicokinetic, and efficacy analyses of an optimized combinatorial regimen of paclitaxel and a pharmacologic S100A9 inhibitor with simultaneous assessment of protection from PIPN and antitumor properties in established experimental models of breast cancer and NSCLC. It is expected that these studies will shed new light on the etiology of PIPN and provide a rationale for the future implementation of a novel targeted intervention strategy to prevent this debilitating side effect.

NIH Research Projects · FY 2026 · 2025-04

SUMMARY Oxidative stress is a principal driver in the development and progression of various debilitating ocular diseases including the age-related macular degeneration (AMD). Because of its intense exposure to light combined with its high oxygen consumption and the presence of its photosensitizing endogenous chromophores, retinal tissue is uniquely susceptible to oxidative stress. Recent findings, both from our research and others, have unveiled that oxidative stress—a crucial pathogenic factor in AMD—triggers the release of nuclear and mitochondrial DNA (self-DNA) into the cytosol, culminating in the activation of cellular innate immune pathway called cGAS-STING. Remarkably, our preliminary data indicate that this pathway is activated not only in acute but also in chronic mouse models of oxidative retinal damage. This conserved response positions cGAS-STING pathway as a promising therapeutic target for halting the characteristic slow and progressive deterioration of retinal structure and function in AMD. Therefore, a comprehensive understanding of the mechanism by which self-DNA translocates to the cytosol, as well as the details of the cGAS-STING-initiated effector mechanisms activated during oxidative retinal damage is critical. To bridge this knowledge gap, we propose a multifaceted investigation utilizing both chronic and acute mouse models of oxidative retinal degeneration. In Aim 1, we will investigate the molecular mechanisms governing the escape of self-DNA into cytosolic compartment. Aim 2 will focus on defining the activation of the full range of cGAS-driven effector pathways in mouse retinal and RPE tissue enduring acute and chronic oxidative stress. Aim 3 will evaluate the potential protective benefits of inhibiting cGAS signaling in chronic RPE degeneration in Sod2fox/floxVMD2-Cre mouse model as well define how cGAS- STING signaling modulates gene expression and function in specific retinal cell types employing single cell RNAseq analysis. Collectively, our proposed studies aim to reveal intricate mechanisms of cGAS-STING involvement in AMD-related RPE and retinal deterioration hence hold significant promise for the development of innovative therapeutic strategies

NSF Awards · FY 2025 · 2025-03

This award supports participation in the conference "Arithmetic, K-theory and Algebraic Cycles" to take place May 26-31, 2025 at the Ohio State University. In recent years, there have been several major advances in the field of Arithmetic Geometry, Algebraic K-theory and Algebraic Cycles. Arithmetic Geometry is the study of spaces from the point of view of number theory and is largely concerned with the solutions of polynomial equations, especially over the integers. Algebraic K-Theory and Algebraic Cycles are certain special techniques that can understand the geometric nature of a problem, one that is again defined in terms of polynomial equations. In recent years there have been a number of important developments in this area and the purpose of the week-long workshop and conference is to bring together established experts in these areas along with early-career researchers with the goal of stimulating further progress. In more detail, in recent years there have been major developments in Arithmetic Geometry, Algebraic K-theory and Algebraic Cycles, leading up to the solution of the Milnor, Bloch-Kato and Lichtenbaum-Quillen conjectures, as well as the conjectures of Thomason and Morel concerned with equivariant phenomena for actions of linear algebraic groups. The powerful techniques introduced for the solution of the above conjectures have stimulated work on several outstanding remaining problems in the area, which are often arithmetic in nature, but use sophisticated tools from Algebraic K-theory and Algebraic cycles. The goal of the program is to focus on several of the outstanding problems in the area, surveying the progress made and planning strategies for further advancement. The conference website is https://people.math.osu.edu/joshua.1/AKC_conf_2025.html. 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 · 2025-03

PROJECT SUMMARY / ABSTRACT The bacteria that colonize the oral cavity, forming biofilms on surfaces such as the hard tissues of teeth, participate in complex exchanges with other microbes inhabiting the same niche. One such example is the relationship between Streptococcus mutans, one of the primary drivers of dental caries development, and other oral commensal streptococci species. Organic acids produced by S. mutans, an end product from the fermentation of dietary carbohydrates, accumulate and are concentrated within microcolony-like biofilm structures that are the sites of enamel demineralization. Encasing the microcolonies are oral commensal streptococci – thus, understanding how these structures form, the interactions that occur between S. mutans and other oral streptococci that enclose them, and development of new strategies/targets to disrupt these structures is of critical significance to the field of oral health. Our group has begun to address these needs through characterization of S. mutans gene expression when it is cocultured with other oral bacteria and have made several crucial observations such as alterations to the S. mutans transcriptome through a specific, characterized pattern only in the presence of oral commensal streptococci, and not with other disease- associated streptococci or oral non-streptococci. One such change is in the expression of phosphotransferase systems (PTS) for specific carbohydrate uptake and utilization. During growth in coculture, both S. mutans and oral commensal streptococci gene expression stratifies into different carbohydrate utilization preferences, suggesting that each species partitions into a different nutritional niche during the interaction. However, these conclusions are only based on transcriptomic datasets and require further experimentation to validate. Our central hypothesis is that during active competition, health- and disease-associated oral streptococci modify carbohydrate utilization preferences via gene expression changes as to not compete for the same carbohydrate source. Our objective is to validate this hypothesis though using functionalized carbohydrates for click chemistry that will allow for single cell analysis of carbohydrate utilization during super-resolution microscopy imaging of mixed-species biofilms, as well as to validate/confirm our findings through genetically engineered mutants in both S. mutans and oral streptococci. Our long-term goal is to be able to manipulate these interactions through either prebiotic/probiotic strategies and/or therapeutic interventions to target pathways that selectively remove S. mutans from oral biofilms while leaving health-associated, commensal species intact. Included in our approach are research objectives that: i) explicate nutritional niches between health- and disease-associated oral bacteria, ii) exploit nutritional niches to alter microbial ecology through oral streptococci interactions, and iii) elucidate partitioning of the oral microbiome by specific carbohydrate utilization preferences. Together, this proposal will strengthen our understanding of the interconnectedness of the oral microbiome while working to answer new and relevant questions in understanding how intermicrobial interactions can drive dysbiosis of a healthy microbial community, eventually leading to disease (caries) formation.

NIH Research Projects · FY 2024 · 2025-03

Epidermal Growth Factor Receptor (EGFR) mutant (mt) non-small cell lung cancer (NSCLC), initially has a high response rate to EGFR tyrosine kinase inhibitors (TKIs), however, resistance is inevitable. HGF-MET pathway activation and an epithelial-mesenchymal transition (EMT) transcription factor (TF) induced mesenchymal phenotype are commonly observed mechanisms of EGFR TKI resistance. We have identified the hepatocyte growth factor (HGF)-MET-TWIST1 axis as a novel targetable signaling axis that may account for both de novo and acquired resistance to EGFR TKIs including osimertinib. Our published data showed that the EMT-TF, TWIST1 is required for EGFR mt tumorigenesis and can mediated EGFR TKI resistance in vitro and in vivo through suppression of apoptosis. Targeting TWIST1, genetically or pharmacologically with our first-in-class TWIST1 inhibitor, harmine resensitized EGFR mt NSCLC to EGFR TKIs. Our preliminary data demonstrate that HGF increases TWIST1 expression and that TWIST inhibition can reverse HGF-MET mediated EGFR TKI resistance in vitro. Therefore, TWIST1 maybe the critical targetable node that connects these pathways. Central hypothesis: HGF-MET mediated induction of TWIST1 leads to the suppression of apoptosis and EGFR TKI resistance in EGFR mt NSCLC, which can be overcome with TWIST1 inhibition. We will test this hypothesis in the following Specific Aims: Aim 1: Determine the mechanism and clinical significance of HGF-dependent TWIST1 induction in EGFR mutant NSCLC. Hypothesis: HGF leads to increased TWIST1 expression and activity through phosphorylation by ERK and/or AKT (Aim 1a). We further hypothesize that HGF-MET activation correlates with increased TWIST1 expression and poor response to EGFR TKIs in the EGFR TKI de novo and acquired resistance setting in patients (Aim 1b) Aim 2: Elucidate the mechanism of HGF-TWIST1-mediated EGFR TKI resistance. Hypothesis: TWIST1 mediates HGF-MET dependent EGFR TKI resistance in both de novo and acquired resistance through suppression of apoptosis in vitro (aim 2a) and in vivo (aim 2b-c). Aim 3: Evaluate the efficacy of the TWIST1 inhibitor, harmine to overcome HGF-MET induced EGFR TKI resistance. Hypothesis: Targeting TWIST1 with harmine in combination with osimertinib will overcome HGF- induced resistance as well as MET driven resistance in the acquired resistance setting in vitro and in vivo. Translational Impact: There are no FDA approved targeted therapies after progression on osimertinib. We are uniquely positioned to identify TWIST1 as a mediator of HGF-MET-dependent EGFR TKI resistance and a novel therapeutic target for the treatment of EGFR TKI resistance.

NSF Awards · FY 2025 · 2025-03

Most computers generate random-looking numbers without using any randomness at all; instead, the numbers are generated by a mathematical sequence that appears random. This might not be random enough for every application. Pseudorandomness, a key idea in theoretical computer science, involves constructing mathematical objects that exhibit random-like behavior while being created in a predictable way. These objects are essential for solving problems where true randomness is computationally costly or impractical to generate. The project addresses challenges such as developing efficient algorithms to determine whether complex mathematical expressions simplify to zero, a critical question in areas like algorithm design and circuit complexity. It also explores connections to error-correcting codes, which ensure reliable communication and data storage by correcting transmission errors. By advancing knowledge in these areas, the project contributes to foundational methods in computation and communication systems while supporting the national interest through fundamental research. The project also includes educational initiatives to create resources and courses that inspire the next generation of scholars in mathematics and computer science. The work spans computational complexity and coding theory, unified under the theme of algebraic pseudorandomness. In complexity theory, the project focuses on deterministic methods for polynomial identity testing in special classes of arithmetic circuits, addressing a central problem in derandomization. It also applies algebraic geometry to study structural properties of algebraic varieties that arise in computational problems, offering new perspectives in complexity theory. On the coding theory side, the research examines the combinatorial and algebraic properties of error-correcting codes, particularly list-decodable and list-recoverable codes, with the goal of developing more efficient constructions and improving their theoretical guarantees. By tackling these challenges, the project advances fundamental questions in pseudorandomness and contributes novel insights to the fields of complexity theory and coding theory. 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 · 2025-03

This award supports the creation of the Research Experience for Undergraduates (REU) site in the Department of Physics at The Ohio State University. The program provides eight undergraduate students each summer with a ten-week immersive experience in cutting-edge research spanning astrophysics, atomic, molecular, and optical physics, biophysics, condensed matter physics, nuclear physics, particle physics, and physics education research. Through this initiative, students gain hands-on experience in scientific inquiry, bolstered by field trips and professional development activities designed to equip them with the tools and insights needed to achieve their academic and career aspirations. This program aligns with NSF’s mission by advancing the progress of science across multiple disciplines, fostering educational growth, and broadening participation in STEM fields by engaging students who may have limited access to research opportunities. The REU site seeks to provide students with meaningful research experiences through a structured program of mentorship, professional development, and research training. Students will engage with expert faculty mentors—including APS Fellows and NSF CAREER award winners—who offer a dynamic, collegial environment and innovative research opportunities. Mentorship will be enhanced by the inclusion of graduate student "near-peer" mentors and integration with the OSU Polaris program, fostering collaboration and community. 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 · 2025-03

Abstract A significant percent of individuals with optic nerve (ON) injuries, secondary to trauma or glaucoma, suffer permanent visual loss. The adult mammalian visual system has a limited capacity for self-repair, making it vulnerable to damage and degenerative processes. Mature retinal ganglion cells (RGCs, the projection neurons of the eye) do not replicate, and severed ON axons have a limited capacity to regrow, increasing the likelihood of poor visual outcomes. Various strategies, such as genetic reprogramming of RGC, blockade of endogenous axon growth inhibitors, and biomaterial transplantation, have been attempted in animal studies to promote axon regeneration, but none have been curative. Successful outcomes in the clinical setting will likely require personalized, multimodal approaches using synergistic therapeutic agents. A promising strategy for restoring the integrity of injured tissue is to deploy natural immune driven healing pathways. Immune-drive healing has been convincingly demonstrated in animal models of cutaneous wounds and myocardial ischemia. There is an increasing recognition of the potential for immune responses to drive repair in the eye as well. However, the specific immune cell populations involved, and their mechanisms of action, are poorly understood. In preliminary experiments, we showed that immature bone marrow neutrophils (BMN), harvested from naïve mice, express markers of alternative activation and acquire neuroprotective pro-regenerative properties following short term polarization with interleukin (IL)-4 and granulocyte-colony stimulating factor (G-CSF). These novel cells promote RGC survival and drive RGC axon regrowth, both in vitro and in animal models of optic neuropathy, at least partially through the secretion of soluble factors. Similarly, IL-4/G-CSF polarized human BM myeloid cells, as well as their conditioned media, promoted neurite outgrowth of human iPSC derived RGCs. A major goal of the current proposal is to elucidate the factors secreted by the IL-4/G-CSF polarized murine BMN that contribute to their reparative effects. Additionally, we will investigate how these BMN modulate glial cells in the eye to promote a neuroprotective phenotype. Lastly, we will characterize pro- regenerative human BM myeloid cells in depth, explore their mechanisms of action, and develop protocols to expand them in vitro, in a manner that preserves their reparative properties. We are hopeful that, collectively, the results of these experiments will inform the development of the first autologous myeloid cell therapies that promote visual recovery in individuals with optic neuropathy. Furthermore, this line of research could lead to the development of therapeutic cocktails of pharmaceutical agents, nanoparticle-based therapies, and/ or gene therapies, that mimic the mechanism of action of the IL-4/G-CSF polarized myeloid cells.

NIH Research Projects · FY 2025 · 2025-03

Proportional growth ensures overall size is coordinated with organ and limb size to generate the correct animal body form. In all animals, body size is determined by a plastic response to environmental factors such as nutrition. The TOR pathway senses amino acids and, together with the insulin pathway and hormones, regulates growth to produce an overall size best suited for the conditions, such as a small organism if food is limiting. Local growth of organs and limbs is more autonomous and robust so that the final structure is correctly patterned while scaled for overall body size. For example, fly wings of different sizes have the same stereotypical pattern of veins, intervein regions, and sense organs needed to produce a functional wing. The long-term goal of this project is to understand how systemic signaling and local growth are coordinated in the gene regulatory network (GRN) for Drosophila wing development. The goal for this proposal is to investigate the first circuit in the GRN when it is hypothesized that a systemic signal activates local growth pathways to induce the first cell divisions in the nascent wing disc. The fly wing is a flagship model for analyzing signaling and appendage growth and patterning; however, there is a gap in knowledge about the earliest stage of wing disc development. This stage is poorly understood because the tiny disc is comprised of only approximately 30 cells. Expertise in handling the small samples, exemplified in preliminary data, show size is not a barrier to gaining mechanistic insights into the nature of the systemic signal and determining which local growth pathways are sensitive to it. In Aim 1, experiments will test the hypothesis that insulin signaling is the systemic input that stimulates wing cell growth and activates a morphogenetic pathway(s) to initiate the cell cycle. Genetic manipulation, antibody staining, and imaging will be used to determine if modulation of insulin signaling regulates cell cycle dynamics in the wing disc. In Aim 2, the target pathway(s) of the systemic signal will be identified. The pathways under investigation are the major growth and morphogenetic pathways; Dpp, Wingless, Egfr, Hedgehog, and Notch, which are required for correct patterning and growth of the wing disc. Pathway markers and targets will be used to monitor activity in starved and fed larvae. Pathways that are sensitive to nutrition for activation are candidates for response to the systemic signal. The role of these pathways in cell cycle initiation will be determined by using genetics to activate or repress a given pathway followed by assaying the cell cycle. Preliminary data show that Egfr activity is sensitive to nutrition and required for cell cycle progression. The results strongly support feasibility of the approach but leave open the question of how direct the link is between the Egfr pathway and the systemic signal. In the last part of Aim 2, the interrelationships of the morphogenetic pathway to each other and to the systemic signal will be analyzed. As well as being a fundamental question in development, proportional growth also has health and wellness implications. Altered body forms can lead to stigmatization, influence susceptibility to disease, and in the case of limb abnormalities, occur in 1/1900 births.

NIH Research Projects · FY 2026 · 2025-03

Colon cancer (CC) is one of the leading causes of cancer-related death in the world. Hepatic or liver metastasis (LM) is the primary cause of death in colon cancer patients. Unfortunately, many CC patients develop LM despite surgery with lymph node removal, and many die. Therefore, identifying novel therapeutic approaches is necessary to prevent LM in these patients. COAD (GDC TCGA CRC) and our preliminary data show that VEGF-C/FLT4 (VEGF-C and VEGF-A are different cytokines with distinct functions) axis might be a major driver of LM in many CC patients. As we further showed that dopamine D4 receptors (DRD4) could regulate this axis, we hypothesized that DRD4-mediated therapy alone or in combination with the currently used anti-cancer chemotherapeutic drugs might prevent LM in colon cancer. There are three aims in this proposal. The first aim will determine the therapeutic efficacy of selective DRD4 agonists, either alone or in combination with the anti-cancer drugs, to prevent or significantly lower the incidence of liver metastasis in preclinical animal models simulating human cancer patients. The second aim will elucidate the molecular mechanisms by which DRD4 acts. The third aim will elucidate the molecular mechanisms by which DRD4 inhibits VEGF-C expression in the cells producing VEGF-C in the liver premetastatic niche.

NIH Research Projects · FY 2026 · 2025-02

Project Abstract The plasma membrane (PM) forms a biophysical barrier that protects the cell from its extracellular environment and regulates its functions. Mammalian cells are regularly exposed to stressors that can damage their PM. Therefore, conserved molecular mechanisms repair the PM to maintain cell viability. Dysregulation of PM repair mechanisms is involved in chronic or acute pathologies such as muscular dystrophy, ischemia-reperfusion, heart failure, chronic inflammation, and neurodegenerative diseases. PM repair mechanisms can be exploited by intracellular pathogens to successfully infect their host mammalian cells. The bacterial pathogen Listeria monocytogenes produces the pore-forming toxin listeriolysin O (LLO) that perforates the cytoplasmic and endocytic membranes to invade multiple cell types including epithelial cells, endothelial cells, cardiomyocytes, macrophages, and neurons. The PM repair mechanism(s) of LLO-perforated cells are poorly understood. In a preliminary screen, we identified the cytoskeletal protein, septin 7, as a protein required for the PM repair of cells damaged by LLO. The septins are a family of highly conserved cytoskeletal proteins that act as scaffolds for protein recruitment and vesicular trafficking. Septins are known to interact with the PM and the actin and microtubule cytoskeletons to regulate numerous cellular functions. During PM repair of LLO-treated cells we found that the septin filaments redistribute into subplasmalemmal loop structures that contain F-actin and annexin A2 in a Ca2+-dependent manner. Until recently there was no known role of the septins in plasma membrane repair. We plan to dissect the mechanisms used by the septins to repair the plasma membrane. We will test the central hypothesis that septins play a general role in PM repair by controlling the spatiotemporal organization of PM repair domains. Using our expertise in quantitative fluorescence microscopy and the development of inducible cell lines, electron microscopy, and proteomics, we will elucidate the role of septins in PM repair. We expect to determine how the septins regulate PM repair and what molecules septin 7 interacts with during this mechanism. Together, these studies will provide novel insights into septin biology and plasma membrane repair and provide new targets for diseases involving plasma membrane repair.

NIH Research Projects · FY 2026 · 2025-02

Abstract Post-transcriptional RNA modifications are widespread and regulates numerous biological processes including RNA metabolism, protein translation, gene expression, and disease. Among the more than 180 types of RNA modifications, N6-methyladenosine (m6A) and pseudouridine (Ψ) are the two most prevalent. The m6A modification is catalyzed by the host RNA methyltransferase complex of METTL3 and METTL14. The Ψ modification is converted from the nucleoside uridine (U) by the host pseudouridine synthases (PUSs). Despite being discovered in the 1950s, the biological functions of the m6A and Ψ modifications in the context of virus infection remain poorly understood. This project is built upon our recent development of high throughput sequencing techniques that have enabled mapping of m6A and ψ sites at a single base resolution. Using these techniques, we discovered that SARS-CoV-2 RNA isolated from well-differentiated primary human bronchial epithelial (HBE) cultures that include their in vivo target cells is heavily modified with m6A and ψ. In addition, we have found that depletion of several m6A and ψ writer proteins decreases SARS-CoV-2 replication in HBE culture. These findings led to our hypothesis that SARS-CoV-2 acquires m6A and Ψ modifications in its RNA to maximize virus replication. Thus, the goal of this project is to determine the mechanisms by which RNA m6A and ψ modifications modulate SARS-CoV-2 replication, gene expression, innate and adaptive immunity, and pathogenesis. In Aim 1, we will use a CRISP-Cas 9 technique to knock out host RNA m6A methyltransferases and PUSs in HBE cultures to determine the role(s) of m6A and Ψ modifications in the SARS-CoV-2 life cycle. We will also use knockout mice to examine the role(s) of m6A and Ψ modification in SARS-CoV-2 replication in vivo. We will also identify the specific PUS enzyme(s) that catalyze pseudouridylation on SARS-CoV-2 RNA. In Aim 2, we will mutate the m6A and/or ψ sites in the SARS-CoV-2 genomic RNA and use the reverse genetics system to generate recombinant SARS-CoV-2 lacking m6A and/or ψ modification sites and use them to determine the roles of m6A and ψ modifications on viral RNA metabolism, encapsidation, RNA replication, viral protein translation, and innate immunity. In Aim 3, we will determine whether m6A and ψ modifications modulate mucosal and adaptive immune responses of SARS-CoV-2 live attenuated vaccines (LAVs) and determine whether LAVs lacking m6A and/or ψ are more immunogenic in golden Syrian hamsters. Upon completion of this project, we expect to have unravelled the mechanisms by which m6A and Ψ modifications modulate the SARS- CoV-2 replication cycle, leading to the development of novel and improved LAVs and therapies for COVID-19 that target these RNA modifications.

NIH Research Projects · FY 2026 · 2025-02

Abstract Acute inflammatory diseases are life-threatening health conditions that are most often caused by bacterial or viral infection such as Pseudomonas aeruginosa- or SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) and sepsis. ARDS and sepsis-related mortality remains at unexpectedly high levels due to lack of effective pharmacotherapies. Hence, a new therapeutic strategy for ARDS and sepsis is needed. Microvascular inflammation and barrier disruption play critical roles in the pathogenesis of acute inflammatory diseases. A mitochondrial de-ubiquitinating enzyme, USP30, plays a vital role in regulation of mitochondrial outer membrane protein homeostasis. USP30 has been considered as a potential target for treating Parkinson’s disease and cancers; however, the role of USP30 in microvascular endothelial cells (ECs) and acute inflammatory diseases has not been reported. In our preliminary data, we discovered that inhibiting USP30 diminished EC dysfunction and reduced the severity of experimental lung injury. Mechanistically, we discovered a non-canonical pathway of USP30 that links MAT2A stability, the S- adenosylmethionine (SAM) cycle, DNA methylation, miRNA-30a-5p synthesis. Based on our comprehensive preliminary data, we hypothesize that inhibiting USP30 preserves EC function by modulating intracellular signaling cascades implicated in MAT2A stability, SAM production, DNA methylation, and miR-30a-5p expression. We propose testing the hypothesis with the following Specific Aims: Aim 1 is to determine if USP30 in the endothelium is a potential target for treatment of acute lung injury. We will determine if inhibiting EC USP30 diminishes leukocyte cell adhesion to EC and transendothelial migration and preserves EC barrier integrity. Further, we will determine if depletion of USP30 in endothelial cells reduces severity of pseudomonas aeruginosa- or sepsis-induced experimental lung injury. Aim 2 is to determine the molecular mechanisms by which inhibiting USP30 destabilizes MAT2A, decreases the SAM production, and increases miR-30a-5p. We will determine if inhibiting USP30- induced miR-30a-5p occurs through modulation of MAT2A stability in the SAM cycle, reduction of SAM production and pri-miR-30 promoter methylation. Further, we will determine if miR-30a-5p regulates USP30 inhibition-mediated MDM2, MLC, and NFAT5 downregulation. Aim 3 is to determine if the protective effect of USP30 inhibition occurs through modulating miR-30a-5p expression. We will determine if USP30 inhibition preserves EC function by modulating miR-30a-5p expression in HLMVECs. Further, we will determine if EC USP30 depletion reduces severity of experimental lung injury through modulating miR- 30a-5p expression by using a cutting-edge RNA nanoparticle technology. Comprehensive understanding of mitochondrial de-ubiquitinating enzyme inhibition-induced changes of cell metabolisms and EC function is important for development of new therapeutic targets for treatment of acute inflammatory diseases.

NIH Research Projects · FY 2026 · 2025-02

Project Summary: Relative hypoxia in the expanded alveolar interstitum in fibrotic lung disease can drive altered fibroblast metabolism characterized by decreased mitochondrial respiration and increased lactate generation. Fibrotic lung fibroblasts demonstrate aberrant phenotypes including persistent differentiation, increased matrix production, apoptosis-resistance, and senescence, which are critical to the pathobiology of progressive fibrotic lung disease. However, our understanding of the mechanistic links between hypoxia, lactate, fibroblast phenotypes and lung fibrosis, is limited. Lungs from patients with IPF (a common and severe form of progressive lung fibrosis) and from mice with experimental lung fibrosis have increased lactate levels. Inhibition of lactate generation, either by preventing pyruvate formation from glucose or by blocking the conversion of pyruvate to lactate, diminishes experimental lung fibrosis in murine models. But the mechanisms by which lactate directly contributes to lung fibrosis remain unclear. We have shown that hypoxia differentially affects the lactate production in normal and IPF fibroblasts through downregulation of the “B” isoform of lactate dehydrogenase-B (LDHB, which decreases lactate by catalyzing conversion back to pyruvate) in IPF, but not normal, fibroblasts. Combined with an increase in the LDHA isoform, this suppression of LDHB amplifies lactate generation by IPF cells under hypoxic conditions. Our preliminary data now show that IPF fibroblasts in hypoxic conditions also have an increase in the lactate export protein MCT4, which promotes lactate transfer to the extracellular space. We have shown that lactate signals through its cognate receptor, GPR-81, to induce normal fibroblast differentiation under hypoxic conditions. We now show that this direct effect of lactate is mediated by a reduction in intracellular cAMP. Our in vivo data show that MCT4 and GPR-81 are increased in the lungs of mice following bleomycin-induced lung injury. MCT4 and GPR-81 are strongly expressed in the fibrotic interstitium and fibroblastic foci in IPF lungs, whereas LDHB is identified in normal, but not IPF lung tissue. Finally, we show that GPR-81 inhibition can diminish bleomycin-induced lung fibrosis in mice. In this proposal, we will examine 1) how hypoxia induces changes in LDHB, MCT4 and GPR-81 expression to regulate lactate generation, shuttling, and signaling; 2) how lactate directly drives pro-fibrotic fibroblast phenotypes (differentiation, proliferation, matrix synthesis, survival, mitochondrial function and senescence) via GPR-81 dependent signaling in a hypoxic microenvironment, and 3) how systemic inhibition or mesenchymal- cell specific deletion of MCT4 and GPR-81 (alone and in combination) impacts the resolution of lung injury and fibrosis. These novel studies will enhance our understanding of how hypoxia-mediated aberrant lactate production, shuttling and signaling directly contributes to lung fibrosis while interrogating the potential to target lactate-mediated signaling as a therapeutic approach to fibrotic lung diseases including IPF.

NSF Awards · FY 2025 · 2025-02

Examining Servingness: The Experiences of Latino Engineering Graduate Students in Hispanic- Serving Institutions Latinos are projected to soon become the largest demographic group in the U.S. Our representation in engineering higher education is critical for the country’s competitiveness and will broaden our engagement in the field. To that effect, Hispanic Serving Institutions (HSIs) play a crucial role in serving the Latino community— yet the concept of “serving” in doctoral education at HSIs remains largely unclear. Federal designation requires only that an institution’s enrollment consists of ≥ 25% Latino full-time students, so—as Latino population demographics increase—more institutions will become HSIs. HSIs’ high graduation rates of Latinos with engineering doctorates indicate a degree of success in how these institutions support their Latino students. However, how HSIs promote doctoral students’ success in achieving degree completion has not been studied. Therefore, to better understand the role of HSIs on Latino Ph.D. success, understanding how “serving”—that is, how to support Latino graduate students beyond enrollment—is crucial. This CAREER project will lay the foundation for HSIs to effectively empower Latino students to lead research and innovation through their doctoral engineering programs. Specifically, this project will explore how Engineering HSIs directly impact the experiences of Latino graduate students in engineering. This project addresses the research question: How do HSIs’ servingness support Latino engineering doctoral students? To do so, this project will employ a multi-case study methodology using institutions as the unit of analysis to longitudinally study the experiences of Latino engineering doctoral students at two different types of engineering HSIs: the University of Puerto Rico at Mayagüez, a research-emerging engineering HSI, and Arizona State University, an R1 recently designated as an HSI. This project will leverage trusted site coordinators in each institution’s College of Engineering to recruit Latino engineering students in the first year of their engineering Ph.D. and follow them over a four-year period via monthly prompts to understand their Ph.D. experiences. This project will also involve graduate education stakeholders at these institutions via periodic interviews to understand the institutional factors that impact doctoral students’ experiences at their institutions. The collected data will be analyzed alongside institutional data and documents relating to the servingness efforts at each university to contextualize the participants’ perspectives. By triangulating these data sources, this work will uncover the connection between doctoral student experiences as a function of the structures for “serving.” The methods will be guided via two frameworks: (1) Garcia, Núñez, and Sansone’s framework for servingness and (2) the Graduate Student Socialization framework. Combining these two frameworks will address two vantage points in the analyses—one from the students’ development in HSIs and a second from the HSIs’ impact on students. The education plan focuses on doctoral education leaders from both institutions. Using a community of practice model, graduate associate deans, program leads, and staff will learn how institutions can serve Latino doctoral students in engineering through collaborative workshops showcasing research findings. Outcomes include a list characterizing high-impact practices articulating insights across both institutions and an established network of HSI practice-sharing. Finally, this project will develop a scoresheet to be used as a rubric by HSI leaders at other institutions to evaluate institutional structures for servingness and their impact on doctoral students. As a result, this work will help identify and disseminate best practices that HSIs and other institutions can implement to better serve Latino doctoral students. 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 · 2025-02

ABSTRACT Lysosomes are round-shaped acidic organelles full of hydrolases. They play multiple roles within the cell, including degradation, recycling, or signaling. Notably, lysosomal damage is a hallmark in various human diseases, including lysosomal storage disorders, neurodegeneration, and immune-related diseases. A prevalent outcome of lysosomal dysfunction is the rupture of the lysosomal membrane. During this process, protons and hydrolases escape into the cytosol, potentially triggering cell death if left unaddressed. Recently, new cellular responses to lysosomal membrane damage have been identified. Lysosomes activate various pathways to counteract membrane damage and prevent cell death, including lysosomal membrane repair and the clearance of damaged lysosomes through autophagy. Nevertheless, additional pathways likely exist and await identification. Through the integration of unbiased proteomics and advanced microscopy, we have uncovered a novel cellular process triggered by lysosomal membrane damage, which we named LYsosomal Tubulation and sorting driven by LRRK2 (LYTL). LYTL is orchestrated by Leucine-rich repeat kinase 2 (LRRK2), a large kinase typically located in the cytosol that becomes active upon recruitment to membranes. Mutations in LRRK2 are associated with neurological disorders such as Parkinson’s disease and Progressive supranuclear palsy, as well as immune-related disorders like Crohn's disease, Leprosy, and Tuberculosis. Once recruited to lysosomes, LRRK2 phosphorylates and recruits several RAB GTPases. Phosphorylated- RABs (pRABs) subsequently recruit two effectors, C-JNK-Interacting Protein 4 (JIP4) and RILP-like protein 1 (RILPL1). Both proteins bind to motor proteins upon membrane recruitment, regulating the elongation and retraction of LYTL tubules. Despite LYTL vesicles contacting healthy lysosomes, likely delivering undegraded cargo, the precise cellular role of LYTL in cellular homeostasis remains elusive. This proposal aims to unravel lysosomal membrane dynamics under stress conditions, providing a better mechanistic understanding of lysosomal quality control and potential therapeutic applications. In the first aim, we will elucidate the role of LYTL in cellular homeostasis by precisely tracking the destination of LYTL vesicles and identifying their cargo through unbiased proteomics and lipidomics. The second aim focuses on studying a novel response to lysosomal membrane damage driven by a subset of Annexin A proteins (ANXA4/5/6/7/11 or ANXA4-11). Lastly, we will address a crucial and unknown question in the field: How do disease-relevant cell types respond to lysosomal membrane damage? To answer this question, we will study the response to lysosomal membrane damage in human macrophages differentiated from induced pluripotent stem cells (iPSC).

NIH Research Projects · FY 2026 · 2025-01

Project Summary Chronic pancreatitis (CP) is a fibro-inflammatory syndrome of the pancreas that develops in individuals with genetic, environmental, and/or other risk factors who develop persistent pathological responses to parenchymal injury or stress. CP patients develop a number of metabolic and nutritional complications. To date, no treatment is available to reduce or reverse the inflammatory damage associated with CP, and management is limited to treating complications after they develop. Nutritional studies and strong epidemiological data provide rationale for dietary interventions to reduce inflammation and improve clinical outcomes in chronic diseases such as CP. Data from our group demonstrates a soy-enriched diet can reduce pro-inflammatory cytokines and suppressive immune populations in prostate cancer patients, and soy isoflavones can reduce immune cell activation in vitro. Carotenoids (lycopene) are suggested as the bioactive agents responsible for the health benefits of tomatoes and directly modulate inflammation. Preliminary Data: Our team has developed a novel soy-tomato juice for use in human studies, which has previously been evaluated in healthy individuals for compliance, bioavailability, and effect on blood lipids. Preliminary data in this proposal shows that administration of this soy-tomato juice to human participants (NCT03783013) is tolerable, safe, and it is feasible to analyze immune populations in the blood. Additional work from our group provides evidence this soy-tomato dietary intervention can reduce inflammation and the severity of CP in a pre- clinical animal model. We observed that a soy-tomato diet in mice with CP reduces acinar destruction and fibrosis, systemic inflammatory cytokines and immune populations, and improves physical activity levels. Impact: This pilot trial will generate evidence to demonstrate the safety, compliance, and efficacy of a soy- tomato juice to reduce inflammation, and ultimately improve clinical outcomes in participants with CP. Project Hypothesis: A novel soy-tomato dietary intervention will reduce inflammation and improve outcomes in individuals with CP. The goals of this small R01 pilot trial project are to: 1) conduct a pilot clinical trial to assess the safety and compliance of our soy-tomato dietary intervention in participants with CP, and 2) evaluate the effects of the diet on inflammation and patient-reported outcomes (PROs). We propose the following aims: Aim 1. Conduct a pilot clinical trial to demonstrate the tolerability and compliance of a soy-tomato dietary intervention in CP. Aim 2. Demonstrate the efficacy of a soy-tomato dietary intervention to reduce systemic inflammation in CP and assess preliminary data regarding improvement in patient reported outcomes. After completion of this small R01 clinical trial project, we believe the data will inform a larger clinical trial to investigate the efficacy of this soy-tomato dietary intervention to improve PROs in the CP patient population.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT Glioblastoma (GBM) is a highly aggressive brain tumor with a dismal prognosis, necessitating the urgent development of novel therapies. Recent studies indicate that GBM requires elevated lipid levels for rapid growth. Our research has revealed that GBM enhances the uptake of low-density lipoprotein (LDL) by upregulating the LDL receptor, utilizing lysosomal breakdown to access cholesterol and fatty acids (FAs) for growth. Additionally, GBM contains abundant lipid droplets (LDs), which are also hydrolyzed in lysosomes to release stored cholesterol and FAs, further promoting GBM growth. Given the reliance of GBM on lysosomal breakdown of LDL and LDs for essential lipid supply, inhibiting lysosome function to block cholesterol/FAs supply might be an effective approach to target GBM. Through drug screening, we identified pimozide, a brain- penetrant antipsychotic medication, as a potent agent that inhibits lysosomal function, effectively suppressing LDL and LD hydrolysis in GBM cells. Surprisingly, inhibition of lysosome function unexpectedly increased the expression of the glutamine transporter ASCT2, enhancing glutamine uptake/consumption. This was accompanied by upregulation of enzymes involved in cholesterol and FA synthesis. Promisingly, our initial in vivo tests showed that inhibiting glutamine uptake/consumption or lipogenesis, in combination with pimozide, effectively inhibited tumor growth in orthotopic GBM models without observed toxicities in mice. These findings support our hypothesis that, in response to reduced lipid supply from lysosomes, GBM enhances glutamine uptake and consumption to promote de novo lipid synthesis, ensuring survival. We further hypothesize that inhibition of the glutamine uptake/consumption-lipogenesis axis combined with lysosome inhibition is an effective approach to target GBM. Our proposed studies aim to elucidate the molecular mechanisms upregulating glutamine uptake/consumption and lipogenesis in GBM cells upon lysosome inhibition (Aim 1), and to validate the therapeutic efficacy of targeting these pathways in combination with lysosome suppression by pimozide in GBM in vitro and in vivo (Aim 2). Successful completion of this study will provide valuable insights into the intrinsic connection between lysosome function, glutamine metabolism, and lipid synthesis in GBM, potentially paving the way for new therapeutic approaches to target this deadly cancer.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Individuals clinical high risk for psychosis (CHR-P) are at increased risk for suicide with approximately 66% reporting suicidal ideation and up to 30% reporting suicidal behavior. Despite these high rates, very little is known about the mechanisms that contribute to suicidal thoughts in this population. The proposed study addresses this gap by examining emotion regulation as a mechanism for suicidal ideation using the Extended Process Model as a guiding framework. According to this model, emotion regulation is a dynamic process that involves 1) the identification of the need to regulate, 2) the selection of an emotion regulation strategy, 3) the implementation of that strategy, and 4) ongoing monitoring dynamics to determine whether to maintain, switch, or stop strategies. Our preliminary data using ecological momentary assessment (EMA) suggests that individuals with psychosis exhibit abnormalities across all of these stages. Additionally, we have found that identification, selection, and implementation stage abnormalities are associated with suicidal ideation in real time. More specifically, suicidal ideation is associated with a higher threshold for deciding to regulate, suggesting that this population may be regulating too late. This finding has critical implications, as regulating too late may subsequently influence strategy selection and effectiveness, resulting in emotional cascades that often precede suicidal ideation. This may be particularly relevant for individuals at CHR-P, given the established finding that they have difficulty identifying and recognizing their emotions—critical information that is needed to determine when to regulate. Thus, innovative time-sensitive approaches are needed to detect and assist individuals at CHR-P with identifying when to regulate. To address this gap, the current project will combine EMA, wearable sensors, and smartphone-based technology to study emotion regulation as a mechanism for suicidal ideation in CHR-P using the Extended Process Model as a guiding framework. We will recruit 40 individuals at CHR-P with suicidal ideation/behavior, 40 clinical controls with suicidal ideation/ behavior, and 40 non-clinical controls to complete two research visits (baseline and 1mo follow up) and 28 days of intensive ambulatory assessments (EMA, wearables, smartphone sensing). This data will be used to complete the following aims: 1) Estimate the effect sizes for unique and trans-diagnostic emotion regulation stages predicting time-lagged suicidal ideation in CHR-P; 2) Establish the validity of using wearable and smartphone sensors to objectively detect emotion regulation stages in real time. Findings from this study will inform future grants designed to develop/test prospective algorithms for predicting suicidal ideation and develop/test a just-in-time intervention for reducing suicide risk among individuals at CHR-P.

NSF Awards · FY 2025 · 2025-01

While rapid advances in digital technologies have revolutionized modern living, they have also increased the complexity and frequency of cyber threats. To address this ongoing challenge, the Buckeye SFS program at The Ohio State University will prepare a cohort of cybersecurity experts with advanced degrees to serve national security interests. By offering a comprehensive curriculum and hands-on learning opportunities, the project will train students to contribute to the federal cybersecurity workforce. The program will equip graduates with advanced knowledge and practical experience to secure critical systems, enable them to drive innovation, and lead the cybersecurity field. The project will recruit a wide range of students, including those from diverse backgrounds, to ensure a sustainable and robust cybersecurity workforce for the next generation. The Buckeye SFS program will emphasize advanced graduate training through the accelerated BS+MS, MS, and PhD programs. The program will offer an integrated curriculum encompassing both solid theories in cybersecurity and applied cybersecurity fields, such as network security, system security, cryptography, and secure autonomous vehicles. The project will provide extensive opportunities to engage students in a wide spectrum of cutting-edge cybersecurity research ranging from hardware to software, large cyber-physical systems to ubiquitous Internet of Things devices and large-scale networked distributed systems. It will also prepare doctoral graduates as researchers and educators in higher education, to build capacity for expanding the pipeline of scientific talent. Through outreach and community-service activities, the project will spotlight cybersecurity issues for the community, introduce educational opportunities, and stimulate public awareness with the long-term goal of changing people's security and privacy perceptions and improving their security behaviors in daily life. This project is supported by the CyberCorps® Scholarship for Service (SFS) program, which funds proposals establishing or continuing scholarship programs in cybersecurity and aligns with the U.S. National Cyber Strategy to develop a superior cybersecurity workforce. Following graduation, scholarship recipients are required to work in cybersecurity for a federal, state, local, or tribal Government organization for the same duration as their scholarship support.  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 · 2025-01

Despite the implementation of enhanced recovery protocols for gastrointestinal (GI) surgeries (ERAS), there is still significant postoperative ileus (POI) and postoperative gastrointestinal dysfunction (POGD) associated with prolonged hospitalizations, increased morbidity and health care costs into the billions. A better understanding of the pathogenic mechanism(s) of POI is required to develop better therapeutic strategies. General Hypothesis: Our recent work, strong pilot, feasibility and preliminary data (Figs 1-18) and publications support the novel hypothesis that the glial Piezo-1“mechanosensor” modulates motility, and the mechanical stress’’ on the bowel during GI surgery results in amplification in the Piezo-1/Cx43-ATP signaling pathway to cause disruption of motility, POI and POGD in the context of intestinal inflammation. Targeting a glial mechanosensor (Piezo-1) is a paradigm shift in our thinking about the pathogenesis of POI, and it seems reasonable, since gut physical manipulation (“mechanical stress”) is sufficient to cause POI. We assembled a dream team of investigators and plan to utilize an impressive array of novel innovative models and techniques for mouse or human studies on mechanogated channels. These include glial specific cKO mice for Piezo-1, Cx43 HCs and mitochondrial complex-1, RiboTag–gene reporter mice for glia or neurons, human models to study glia, isolated neural networks of ganglia and Early/Late human specimens to study impact of surgical stress on mechanogated channels, bulk-RNAseq in RiboTag, Ca2+wave studies, and a ‘first in man’ patch clamp technique for whole cell recordings. The “mechanotransduction hypothesis” is tested in 3 specific aims in mice and humans. Aim 1 will determine the role of Piezo-1 and Cx43 HCs in glial mechanotransduction and intestinal motility, using Ca2+reporter mice, pharmacologic agents or glial cKO mice for deletion of Piezo-1 and Cx43. Aim 2 will unravel the pathogenic role of Piezo 1 channels and Cx43 HCs in POI using a surgical model of “mechanical stress” induced POI. Studies will (1) Investigate the protective effect of deleting Piezo1 and Cx43 in glia on inflammation and GI dysmotility (hallmarks of the disorder) in mouse POI. (2) Bulk-RNAseq analysis in glial or neuronal RiboTag-Piezo1cKO or - Cx43cKO mice (and controls) will evaluate whether deletion of specific channels can protect against mechanical stress induced POI. (3) We will investigate Ca2+waves in glial conditional knockouts for Piezo-1 and Cx43 HCs. (4) Cell-stretch (FlexCELL) is used to test if “mechanical stress” can cause a reactive glial phenotype by activating Piezo-1 channels. (5) And we will evaluate mitochondrial dysregulation in enteric gliosis. AIM 3 will test whether findings from animals are translatable to humans on Piezo-1 and Cx43 – mechanotransduction and evaluate impact of “surgical stress” in Early/Late samples of ileum, from 65 right colectomy patients. OVERALL IMPACT: Studies will address a critical gap in knowledge, identify the “glial Piezo mechanosensor” operating in motility and the pathogenic mechanism of POI induced by mechanical stress during GI surgery, perhaps offering a possible new way to protect the gut.