Ohio State University

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Traumatic brain injury (TBI) is one of the foremost causes of death and disability in the United States. Most brain- injured individuals (~70%) develop neuropsychiatric or neuropathological complications, including depression, cognitive decline, epilepsy, or neurodegenerative disease, that negatively affect health and lifespan. Microglia are the resident innate immune cells of the brain and respond to insults, like TBI, that cause cell damage. While an early inflammatory response is often beneficial, chronic inflammation is detrimental and prevents return to brain homeostasis. Microglia reactivity is evident long after injury, and microglia are chronically hyper-reactive, or “primed,” to respond to secondary challenges. Secondary challenges include infections, which are common in the general population. In experimental studies, hyper-reactivity of microglia after TBI is associated with exacerbation of depressive-like behaviors, cognitive decline, and development of epilepsy. Though TBI is highly prevalent and associated with chronic disability, there are no current FDA-approved treatments for improving long-term outcomes. Furthermore, the link between inflammation after TBI, microglia priming, and poor long- term recovery is not understood. In this proposal, I will explore the role of NFkB, a prominent mediator of inflammatory gene expression, in propagating chronic microglia primed profiles and hyper-reactivity to secondary challenges. In Aim1, I will determine the therapeutic potential of an NFkB inhibitor to prevent chronic microglia activation and neuropathology (Aim1a), as well as microglia hyper-reactivity to secondary immune challenge associated with exacerbated sickness and depressive-like behaviors (Aim1b). In Aim2, I will focus on mechanism by using transgenic mice to determine if microglia-specific NFkB activation drives inflammation after TBI (Aim2a) and if microglia-NFkB activation contributes to epigenetic modifications in microglia that underlie enhanced reactivity (Aim2b). To complete these aims, I will have the support of 2 sponsors, as well as consultation with my other 3 committee members and bioinformatics experts at OSU. I am accomplished in several techniques that will be used throughout this proposal (midline fluid percussion injury, nCounter NanoString for gene expression analyses, immunofluorescent labeling, imaging, and quantification of gliosis) but will additionally add techniques to my skillset, including bulk RNA-sequencing, multi-ome single-nuclei RNA- and ATAC-sequencing, depressive behavioral assays, and neuropathology assessments. With the support of multiple OSU Core Facilities and Shared Resources (10X Genomics Platform, Flow Cytometry Core, and the OSU Comprehensive Cancer Center Genomics Shared Resources) and experts in these areas, I anticipate full completion of these aims, which will support at least one first-author publication. Attaining an F31 NRSA fellowship and completing these aims will make me a competitive postdoc applicant and position me to obtain future funding as I continue my career development into an independent academic researcher.

NIH Research Projects · FY 2025 · 2025-08

Project Summary In 2023, approximately 40 million people globally, including 1.2 million Americans, were living with HIV- 1, which causes acquired immunodeficiency syndrome (AIDS). The current standard care involves daily small-molecule antiviral drugs, which reduce viral load and the probability of transmission but do not cure the infection. Adherence to treatment is challenging due to side effects and complex regimens, leading to drug resistance and treatment failure. One way to combat the emergence of drug resistance is to develop novel anti-HIV-1 agents against alternative targets. Since small-molecule anti-HIV-1 drugs are generally limited to targeting viral enzymes that possess hydrophobic binding pockets, we propose to target critical, non-enzymatic HIV-1 proteins with nanobodies. In this project, we aim to develop protein-based proteolysis targeting chimeras (bioPROTACs) to degrade HIV-1 Rev protein, which is critical for the HIV-1 lifecycle but does not contain any hydrophobic pocket for small molecules to bind. This approach is enabled by the recent development of a powerful intracellular protein delivery platform, membrane translocation domains (MTDs), in one of our laboratories. Specific Aim 1 is to generate and biochemically characterize a small family of Rev-degrading bioPROTACs by recombinantly fusing MTD4 (one of the most active MTDs), a previously reported Rev-binding nanobody (Nb190), and several commonly used E3 ubiquitin ligases. Specific Aim 2 is to test and validate the bioPROTACs from Aim 1 for the targeted degradation of HIV-1 Rev in live cells. The development of a bioPROTAC strategy targeting Rev or other essential viral proteins for HIV-1 therapy presents several compelling advantages in the fight against HIV. This approach opens a novel pathway for targeting viral proteins that are difficult to inhibit using traditional small molecules. By leveraging PROTACs, which harness the cell’s own machinery to degrade the target protein, the likelihood of resistance arising from viral escape mutants—common in conventional inhibition-based therapies—is significantly reduced. PROTACs can also be designed for high specificity, minimizing off-target effects and toxicities often associated with small-molecule drugs. Furthermore, combining PROTACs with traditional antiretroviral therapy could create a multifaceted strategy, enhancing long-term viral suppression.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Approximately 60% of clients who enter substance use disorder (SUD) treatment have had at least one lifetime exposure to traumatic brain injury (TBI). TBI of any severity can result in chronic cognitive and behavioral impairments that, if unaddressed, can undermine the effectiveness of SUD treatment and lead to early treatment termination. The Ohio State University TBI Identification Method is a well-established, validated method for identifying clients with TBI, and neurocognitive accommodations can be used to overcome impairments and optimize client treatment success. However, our preliminary research demonstrates that neither TBI screening nor neurocognitive accommodations have been adopted in outpatient SUD treatment settings due to inadequate provider knowledge and skills to implement these interventions, as well as poor implementation readiness and support. External facilitation is an implementation strategy that can address these barriers to increase the adoption, reach, implementation, and sustainment of these interventions, but few studies have evaluated facilitation on intervention uptake in outpatient SUD treatment. Guided by Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) and Exploration, Preparation, Implementation, and Sustainment (EPIS) frameworks, I will conduct an embedded mixed methods hybrid type 2 effectiveness-implementation feasibility trial to: [Aim 1] Evaluate facilitation as a strategy for increasing the adoption, reach, implementation, and maintenance of the TBI-RECOVER intervention model (i.e., OSU TBI-ID, symptom screen, and neurocognitive accommodation) in outpatient SUD treatment; [Aim 2] Examine the feasibility and preliminary effectiveness of the TBI-RECOVER intervention model compared to treatment as usual on clients’ treatment self-efficacy, substance use severity, and treatment retention; and [Aim 3] Assess client satisfaction and provider acceptability of TBI-RECOVER, and utility of the facilitation strategy for implementation of TBI-RECOVER. The following training objectives will support these research aims and my career goals: (1) Gain advanced training in dissemination and implementation science, specifically in hybrid effectiveness-implementation trials, and implementation strategy development and evaluation; (2) Acquire training in substance use treatment research for adults with comorbid SUDs and TBI; and (3) Advance my career independence through conceptualizing and leading implementation trial research, R01 grant writing, and leading research teams. This proposal is directly aligned with NIDA’s 2022 – 2026 strategic plan to investigate novel treatment interventions and enhance optimal implementation outcomes in real-world treatment contexts. This NIDA K01 will provide me with the necessary resources to advance and maximize my skills to launch an independent, NIH-funded career and situate me as a leader in implementation science, TBI, and substance use treatment research. The results and training gained through this K01 will inform a fully powered hybrid effectiveness-implementation trial to scale-out TBI-RECOVER using facilitation.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Cornea is a transparent tissue without any vasculature. Diseases and injuries that compromise the optical clarity of the cornea are the third most common cause of blindness worldwide. A common sequela of these corneal diseases and injuries is the growth of pathological vessels, a process known as corneal neovascularization (CNV). To date, there is no specific therapy for CNV, underscoring the need to identify effective treatments for this disease. Tissue factor (TF) is a well-known factor for blood coagulation after blood vessel injury. Under physiological condition, TF is strictly expressed in cells underneath the endothelial cells, such as pericytes. Preliminary study revealed that TF level was low in uninjured mouse corneas and was upregulated after alkali injury. In the proposed work, TF as a potential biomarker for CNV and an immuno-conjugate that targets TF as a potential therapy to treat CNV will be investigated.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY There has been a dire need for developing a rapid biodosimetry tool for triaging victims in the aftermath of any radiological/nuclear mass casualty incident(s). Rapid triage is critical for timely administration of medical countermeasures and proper allocation of resources, thus saving lives. Currently, there are no US Food and Drug Administration (FDA) approved tests or assays that allow early exposure categorization of victims for effective medical countermeasures. The current gold standard for radiation biodosimetry is the dicentric chromosome assay (DCA) but its application to mass casualty incidents is severely restricted as it requires 48- 72 hours for dose estimation. To provide a rapid absorbed dose estimation within a few hours, we have developed a highly sensitive test tracking two-microRNAs found in blood samples collected by a simple finger prick. The miRAD assay enables accurate does estimation in less than four hours, covering dose ranges and time points critical for medical intervention in victims. In the miRAD assay, radiation dose dependent changes in evolutionarily and functionally conserved miR150-5p in the blood is internally calibrated with miR23a-3p which is non-responsive to radiation as it is not expressed at a significant level in blood cells, yet abundant in blood and passively released into circulation from non-blood cells. Our assay, tested so far in blood samples from irradiated mice, non-human primates and human radiotherapy patients and has shown a great potential for development as an effective triage tool. Robustness of the baseline expression of both the responder and normalizer using blood samples collected by a finger prick has been validated in volunteers, including individuals afflicted with common chronic medical conditions. The kinetic response of the miRAD assay will favorably allow integration with other clinical signs (clinical symptoms, time of emesis) and help prioritize treatment in the “life savable” group. As further development and refinement of the assay for triage applications is needed, the current proposal is designed to test the accuracy of dose prediction by miRAD with the gold standard DCA by using an in vivo total body irradiated mouse model system. Since alteration in miR150-5p in blood after radiation exposure appears to be an intrinsic in vivo phenomenon, we will systematically compare the miRAD assay with DCA for absorbed dose validation in pediatric and geriatric population mimicking a heterogeneous human population. The assay has potential utility at different stages in radiological/nuclear disaster management, including early triage, precision dosimetry, follow-up and evaluation of countermeasures. Beyond its utility in radiation disaster preparedness and management, the assay will have utility in evaluation of bone marrow ablation and reconstitution kinetics in radiotherapy patients.

NIH Research Projects · FY 2025 · 2025-08

PROJECT ABSTRACT Menthol enhances the appeal of cigarettes and promotes nicotine dependence, leading the US FDA to propose a rule prohibiting menthol as a characterizing flavor in cigarettes. However, following restrictions on the sale of menthol cigarettes in California and Massachusetts, synthetic coolants have been added to cigarettes, potentially nullifying the public health benefit of the menthol restriction. This novel study aims to provide critical knowledge to understand the abuse liability and substitutability of synthetic coolants for menthol in cigarettes, employing both laboratory and naturalistic experiments. A total of 40 adults who smoke menthol cigarettes will complete a 3-phase, 3-week study. In phase 1, participants will smoke their usual brand menthol cigarette (UBMC) during a lab session and report daily usage for a week. Phase 2 will use a double-blinded, randomized crossover design, where each participant will complete three intensive lab sessions to smoke three, lab-prepared study products varying only in the absence or presence of menthol and synthetic coolants: menthol cigarette (MC), non-menthol cigarette with synthetic coolants (NMC+SC), and non-menthol cigarette control (NMC). Data on participants’ puffing behavior and the subjective effects of the products will be collected for each session. In Phase 3, participants will be instructed to replace their UBMC with their preferred study product from Phase 2 and report daily usage and perceptions for a week to assess substitution and perceived subjective effects. This Tobacco Regulatory K01 project will yield much-needed evidence on the abuse liability and substitutability of synthetic coolants for menthol in cigarettes, while providing valuable training to a promising new investigator with guidance from leading experts in the field of tobacco regulatory science.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Cortical inhibition provided by GABAergic interneurons (INs) plays a key role in both normal brain function and pathogenesis of several brain disorders such as schizophrenia, autism, epilepsy as well as injury-induced brain dysfunction such as chronic pain. Cortical INs (cINs) comprise a variety of subtypes that differ in morphology, electrophysiological properties, connectivity, gene expression, and circuit/behavior functions. Diverse modes of inhibitory regulations mediated by different cIN subtypes are necessary for the integrity of the cortical inhibitory function. Therefore, elucidating the genetic mechanisms underlying cIN diversification is imperative for not only understanding the origin of cIN functional diversity but also developing cell type specific treatments using drugs and stem cells. However, the transcriptional basis for cIN subtype specification remains poorly understood. The objective of our proposal is to characterize the expression of candidate cell type preferential TFs and determine their essential role in the synaptic organization of the cIN subtype during postmitotic terminal differentiation by in vivo functional screening. To achieve this goal, we will perform a series of experiments using the chandelier cell (ChC), which exclusively innervates axon initial segments of pyramidal neurons (PNs) and thus powerfully controls spike generation in PNs. The stereotypy of the axonal/synaptic organization makes ChCs ideal for studying development of cIN subtypes. Our published and preliminary studies identified TFs and CAMs that are predominantly expressed in postmitotic ChC precursors and showed that some of these CAMs critically control ChC synaptic development and specificity. Based on these results, we propose to test the hypothesis that ChC preferential TFs postmitotically control the synaptic organization characteristic of ChCs. We will pursue the following specific aims to achieve the above objective. To ensure feasibility for the proposed experiments, we developed in vivo genetic strategies that allow us to reliably manipulate murine young postmitotic ChCs as well as a single cell genotyping approach that links genotypes to phenotypes in ChCs subjected to genome editing. In Aim 1, we will characterize the expression of the ChC preferential genes identified by bulk RNA-seq, at single cell levels during postnatal development. In Aim 2, we will identify TFs that postmitotically control the ChC synaptic organization. Our study will unravel the transcriptional basis for the cell type specific cIN synaptic organization and provide an entry point into understanding the transcriptional principle of postmitotic cIN terminal differentiation. The genetic insight into cell type specific cIN terminal differentiation obtained from this study will ultimately serve as a foundation for differentiating human pluripotent stem cells into specific cIN subtypes, which will benefit a cell transplantation-based therapy and drug discovery.

NSF Awards · FY 2025 · 2025-08

Drug development is a critical yet notoriously resource-intensive and time-consuming process, typically taking 10-15 years and costing between $1 to $1.6 billion to bring a successful drug to market. To expedite the process and enhance cost efficiency, significant research has focused on developing computational methods as alternatives/in parallel to conventional experiment-based approaches. Although promising, these methods rely heavily on trial and error within limited chemical subspaces (e.g., molecular libraries), resulting in suboptimal precision and outcomes dependent on the expertise of the researchers. This reliance also limits the scalability and automation of rapid drug design for new protein targets. To address these challenges, this project seeks to develop comprehensive generative AI methodologies and computational tools that expedite drug discovery, enhance cost efficiency, and improve success rates. By creating a holistic generative artificial intelligence (AI) framework capable of generating high-quality drug candidates with multiple desired properties, the project has the potential to transform pharmaceutical research. This initiative promotes advancements in healthcare by reducing the time and costs associated with drug development, ultimately benefiting public health. It also supports education and diversity by involving students from varied backgrounds, integrating AI into coursework, and conducting outreach to K-12 students, fostering broader societal engagement with STEM fields. Generating structured data, such as molecules, with multiple properties is technically challenging. This project will develop a conditional diffusion model for 3D molecule generation to enable both ligand-based drug design and structure-based drug design. The diffusion model employs an SE(3)-equivariant denoising component conditioned on given ligands, binding pockets, or both, and a classifier-free guidance mechanism to ensure that generated molecules closely align with specified conditions. Additionally, the project introduces the Direct Multi-Property Optimization framework, which optimizes drug-specific properties without requiring expensive model retraining. This framework leverages advanced optimization techniques, such as bi-level and multi-objective methods, to enhance the quality and adaptability of generated molecules. Research activities include three thrusts: (1) developing the conditional diffusion model for conditional 3D molecule generation, (2) creating the Direct Multi-Property Optimization framework for multi-property molecule generation, and (3) conducting rigorous evaluations and validations in silico and on other applications. These innovations aim to significantly reduce the time, cost, and resources required for drug discovery while increasing its success rates. 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 · 2025-08

The research conducted in this project will produce new and broadly applicable experimental methods, protocols, and analysis software for the more accurate and realistic characterization of proteins at the atomic level in their native environment for the fundamental understanding of their function in terms structure, dynamics, and interactions with binding partners. The tools developed through this project will make nuclear magnetic resonance (NMR) more widely accessible to both experts and non-experts through standardized workflows and free, easy-to-use software for automation, enhanced by AI/ML, for optimal reproducibility and quantitation. The project provides interdisciplinary training and research opportunities for STEM undergraduate students, graduate students, and postdoctoral fellows at Ohio State. The new NSF-funded National Gateway Ultrahigh Field NMR Center will help introduce a broader public to the discoveries and benefits of basic and applied molecular and materials research to society, including high school students to perform and analyze NMR experiments of common molecular compounds. The realistic representation of protein structure and dynamics at atomic detail is essential for understanding protein function. Protein dynamics can occur on a wide range of timescales covering pico- to milliseconds and beyond. Nanoparticle-assisted nuclear spin relaxation (NASR) provides unique opportunities to observe nano- to microsecond events at atomic resolution under near-physiological conditions that are hard to detect by other experimental methods. New types of NASR experiments utilizing different types of spin relaxation mechanisms will be developed and applied to protein systems to gain insights into their structural dynamics in relationship to their function. This includes backbone and side-chain dynamics studies of immunity protein and small GTPases with their interaction partners. The new data will also be used as benchmarks for extended molecular dynamics (MD) computer simulations assisted by AlphaFold for the generation of physically realistic conformational ensembles for the better understanding of the driving forces underlying protein-protein and protein-ligand interactions and allosteric signaling. Enhanced machine-learning based NMR spectral tools will be developed and incorporated into the new open source COLMARvista software for the autonomous processing and quantitative analysis of biomolecular NMR spectra. This includes multidimensional NMR experiments for the rapid and routine measurements of structural and dynamics protein parameters. These tools will help elucidate the intricate relationship between structural dynamics and function of proteins and their interaction partners. 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 · 2025-08

RNA has recently gained widespread interest in the therapeutic field and is now actively being involved in research is now realized as the third milestone in therapeutics, following chemical and protein drugs; with a recent major increase in interest for gene therapy, vaccine development, and novel immuno-stimulations across many disease models. The goal of this R13 application is to request partial funding support for the upcoming 5th Biennial Conference on Biomotors, Virus Assembly, and RNA Nanobiotechnology, scheduled to be held December, 2025 in Rosemead, CA and expand this conference to focus on RNA therapeutics/mRNA vaccines. This meeting will be chaired by Peixuan Guo, who pioneered the field of RNA Nanotechnology. The conference will be co-chaired by Kirill Afonin, Sarah Woodson, Eric Westhof, and Karin Musier-Forsyth, all having extensive expertise in RNA structure, RNA biology, and RNA therapeutics. The conference will build upon its foundation of the previous four iterations and conferences founded by PI Guo dating back to 2010 to expand crossdisciplinary approaches heavily involved in RNA research at the fundamental and application level. Close interaction of attendees across multiple disciplines will be promoted to advance RNA therapeutic research. This conference is geared towards hosting multidisciplinary approaches to discuss the applications of mRNA, novel RNA molecules as therapeutics, and RNA nanoparticles for early disease diagnosis, non-invasive imaging to monitor the progression of diseases, and targeting and treatment of a wide range of diseases from cancer, bacterial, to viral infections. The specific aim of this conference is to provide a forum for advancing these rapidly growing fields grouped together as RNA therapeutics from discovery to clinical evaluations. Accordingly, researchers from public and private sectors will be invited to: (1) share existing knowledge and set future research initiatives in the field; (2) foster collaborations between physical/engineering scientists with life sciences researchers, and basic science with clinical investigators; and (3) promote the participation of early career scientists for close interaction with advanced career scientists. The meeting will cover a range of topics, including biophysical and single molecule approaches for characterization of RNA nanostructures; structural and functional studies on RNA nanoparticles by chemical or biochemical approaches; computation, prediction, modeling, and understanding dynamics and motion of RNA structures; RNA processing and regulation; design and advances of mRNA therapeutics, mRNA viral vaccines, and mRNA cancer vaccines; application of RNA nanoparticles in therapeutics for the treatment of diseases; and RNA involved in viral assembly and biomotors. The invited speakers and discussion leaders for this conference will include a mix of world-renowned researchers in the field as well as exceptional junior-level investigators from around the world. The meeting will be advertised to a diverse audience ranging from world-renowned experts to early career (trainees and postdocs) in a highly integrated format to facilitate interactions.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus which causes a highly aggressive CD4+ T-cell malignancy called adult T-cell leukemia/lymphoma (ATLL), the neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and other inflammatory disorders. Treatment of HTLV-1- associated diseases remain inadequate. Viral transmission occurs by sexual intercourse, infected blood products, and mother-to-child through breastfeeding. Proliferation of viral infection is first through viral replication and infectious transmission, followed by subsequent mitotic expansion of infected clones with periodic viral replication. Our group has shown that clinically approved human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and integrase (IN) inhibitors also effectively block HTLV-1 transmission in cells. Pre-exposure prophylaxis (PrEP) is the use of antiretrovirals for the prevention of HIV-1 in those people who have not yet been exposed to the virus. The effectiveness of PrEP for HIV-1 is through early inhibition of viral replication, before infection is established. Unlike HIV-1, antiviral therapies to treat existing HTLV-1 infections is lacking, placing a higher emphasis on transmission prevention. We hypothesize clinically approved PrEP antiretrovirals will effectively block HTLV-1 transmission in vivo. Currently, people on PrEP are either prescribed a combination of RT inhibitors (e.g. Truvada), or a long-acting injectable IN strand transfer inhibitor, cabotegravir (CAB-LA). HTLV- 1 RT has higher fidelity than HIV-1 RT. Together with the difference in replication dynamics, we hypothesize HTLV-1 will be less likely to develop resistance to antiretrovirals. To date however, this has not been tested. In this proposal, we will determine the efficacy of PrEP in blocking HTLV-1 transmission in vivo and investigate whether HTLV-1 will develop resistance upon prolonged exposure to antiretrovirals. The efficacy of PrEP will be examined in our well-established preclinical rabbit model. HTLV-1 infection of rabbits mimics early infection in humans and is used to study early viral infection events, persistence, and immune responses in vivo. Rabbits pre-treated with antiretrovirals (CAB-LA or Truvada) will be intravenously challenged with HTLV-1. Viral load and immune response against the virus will be measured at weekly time points. Rabbits with breakthrough infection will be identified and the integrated virus will be sequenced for mutations. The stimulated HTLV-1 immune response will also be examined. Resistance mutations will be identified and characterized in vitro using chimeric virus technology and IC50s for the indicated drugs will be determined. Finally, residues critical for drug resistance will be incorporated into an HTLV-1 molecular clone and subsequent viral fitness and EC50 for CAB-LA and Truvada will be determined by infectious virus release. The wide usage of PrEP has critical implications for HTLV-1 transmission. Data concerning the effect of antiretroviral activity against HTLV-1 transmission is severely lacking. Our study will be the first to test antiretroviral drugs in animal models with HTLV-1 transmission. This study will inform the efficacy of these clinically approved drugs and the types of resistance that may arise.

NSF Awards · FY 2025 · 2025-08

Faculty beginning their independent careers often find the process of writing their first grant proposals to be challenging. Community faculty leaders Davita Watkins of the Ohio State University and Sarah Tasker of Franklin & Marshall College are organizing a workshop that seeks to provide new chemistry faculty insight into the proposal writing and reviewing process so that they can identify and develop strong research, education, and outreach activities. Participants will have the opportunity to network with each other as well as successful grant recipients and federal program officers from a variety of agencies. The participants will engage in mock panels, research presentations, and other activities designed to provide them with a better understanding of how to put together a research plan that is ambitious, yet realistic and compelling. Broader impact criteria are also discussed in terms of educational activities, outreach, and technical applications to societal problems. The 2026 Chemistry Early Career Investigator Workshop, supported by the Division of Chemistry is planned for Spring 2026 in Alexandria, Virginia. This workshop will bring together up to 100 junior faculty from a broad range of institutions and scientific backgrounds to discuss steps in strategically crafting research ideas, planning educational and outreach activities, and assessing and evaluating project aims. 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 · 2025-07

Project Summary/Abstract Chronic ultraviolet (UV) radiation induces not only genetic mutations but also aberrant epigenetic modifications that affect the expression of transcription factors, oncogenes, and tumor suppressors, leading to the development of cutaneous squamous cell carcinoma (cSCC), the second most common cancer in the United States. A better understanding of the mechanisms underlying UV-associated epigenetic abnormalities will provide novel approaches to inhibit skin malignancies. Strikingly, chronic UV exposure induces DNA hypermethylation at the promoter of CDKN2A gene, which encodes tumor suppressors p16INK4A and p14ARF. This epigenetic alteration silences CDKN2A, promoting tumor growth and metastasis. However, it remains unclear whether the reversal of this epigenetic aberration can reactivate CDKN2A and inhibit malignant phenotypes of cSCC. In Aim 1, we will use our CRISPR-Cas9-based epigenome editing tools to specifically demethylate the CDKN2A promoter and investigate the effect of targeted DNA demethylation on cancer phenotypes. UV radiation increases the expression of Myc, which is an oncogenic transcription factor. Myc activation is a cancer hallmark, and the Myc oncogene family is deregulated in many human cancers. When overexpressed, Myc binds to noncanonical (low-affinity) motifs, invading enhancers, and potentially activates super-enhancers (noncoding genomic regions defined by unusually high levels of H3K27 acetylation). Cancer-specific super- enhancers strongly upregulate oncogenes, driving malignancies. However, it remains elusive how aberrant super-enhancers are formed in cSCC. We hypothesize that overexpressed Myc binds to low-affinity Myc binding sites, recruits histone acetyltransferase p300, and generates aberrant super-enhancers that drive malignancy. In Aim 2, we will determine the role of overexpressed Myc in super-enhancer formation in cSCC. A subset of cSCC displays poor differentiation, which correlates with poor patient survival. However, it remains unclear what confers the aggressiveness of poorly differentiated cSCC. We hypothesize that small-molecule inhibitors of DNA methylation and/or Myc suppress poorly differentiated cSCC in vivo by reactivating CDKN2A and/or inhibiting Myc-associated super-enhancers. In Aim 3, we will use poorly differentiated cSCC patient- derived xenografts as preclinical models to assess the effects of these inhibitors on tumor growth and metastasis. Innovative technologies will be used for epigenetic analyses: “PIXUL-ChIP” (high-throughput chromatin shearing for robust ChIP signals) and “EVA” (epigenetic visualization assay that detects specific DNA methylation at the single-cell level). With our epigenome editing tools, the proposed study will elucidate the contribution of epigenetic abnormalities to cSCC aggressiveness and reveal therapeutic potential of modulating epigenetic marks to suppress cSCC.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT Dr. Julia Coleman is establishing herself as an early-career, translational surgeon-scientist with expertise in trauma-induced coagulopathy (TIC), sex dimorphisms in platelet function, and their mechanistic underpinnings to improve the care of injured patients. This K08 award will provide her with the support necessary to accomplish the following goals: (1) become an expert surgeon-scientist in sex dimorphisms in platelet function as it relates to TIC; (2) study the mechanisms underlying estradiol’s pro-platelet effect in vitro in donor platelets intended for transfusion in bleeding trauma patients; and (3) develop the tools necessary to have an independent translational research career. Dr. Coleman is supported by a multidisciplinary scientific advisory committee: primary mentor Dr. Richard Gumina (Professor in Internal Medicine with expertise in purinergic biology and functional platelet assays critical to this proposal); content co-mentors Dr. Thomas Hund (biochemist with expertise in calcium signaling) and Dr. Bryce Kerlin (hematologist with expertise in thrombosis and hemostasis); scientific advisors Dr. Kristy Townsend (neuroscientist with expertise in the effect of sex and estrogen on disease processes) and Drs. Mitchell Cohen and Matthew Neal (translational surgeon-scientists with expertise in TIC and platelet dysfunction). Trauma-induced coagulopathy, characterized by platelet dysfunction, is a leading cause of preventable death despite decades of resuscitation practice optimization. An opportunity for advancement in TIC treatment stems from an awareness that coagulation demonstrates a strong sex-dependent effect. Compared to males, females have increased platelet reactivity, and in the setting of TIC, this results in decreased morbidity and mortality. Platelets demonstrate sex-specific reactivity to P2Y receptor stimulation, which signals through Src kinase. In addition to P2Y receptors, platelets also express estradiol-β receptors, and 17β-estradiol is known to exert nongenomic effects on intracellular signaling pathways including Src kinase. As such, the objective of this proposal is to test the central hypothesis that estrogen receptor-β stimulation on platelets primes Src kinase signaling pathways to potentiate aggregation through nongenomic effects on P2Y receptors (Aim 1) and the platelet proteome (Aim 2). To address these aims, we will perform a variety of platelet function assays in native and estrogen-treated platelets in human apheresis platelets. Understanding these mechanisms at a basic level is critical to advance translational studies to improve TIC-related morbidity and mortality for both sexes, as it may impact donor sex-specific transfusion and support the use of estrogen-treated platelets in the resuscitation of bleeding trauma patients. This proposal addresses a major gap in our understanding of the effect of biological sex and estrogen on donor platelet biology. This will also generate data for an R01 application that translates concepts from this platelet donor-focused project to platelet dysfunction in TIC to examine the role of recipient sex and estrogen treatment in the blood of trauma patients.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY Human papillomaviruses (HPVs) cause a range of anogenital malignancies and are the major drivers of a current head and neck cancer (HNC) epidemic, which is expected to exceed 30,000 annual US cases by 2030. The dependence of HPV+ HNC on the continuous dysregulation of the tumor suppressors p53 and Rb by the viral oncoproteins E6 and E7, respectively, renders these viral proteins ideal therapeutic targets. Of note, the targeting of E6 and E7 oncoprotein expression and/or function has been demonstrated to yield substantial anti-cancer effects. However, clinical therapeutics targeting these indispensable viral proteins are lacking, highlighting the need to evaluate novel approaches to target HPV oncoproteins. Recently, the targeting of mutated oncoproteins with dimeric immunoglobulin A (IgA) molecules was reported to result in mutated oncoprotein expulsion and subsequent growth retardation of epithelial cancers. The anti-tumor effect of oncoprotein-targeting IgA requires the transcytosis of dimeric IgA through the target cell, a process that is initiated by binding to pIGR on the cell surface. Our preliminary data show that the vast majority HPV+ HNC express PIGR, suggesting that IgA-based targeting of viral oncoproteins might be an attractive and innovative treatment avenue for this malignancy. Importantly, we recently pioneered the generation of HPV-specific human monoclonal antibodies (hmAbs) from intratumoral B cells of patients with HPV+ HNC, yielding a unique set of recombinant hmAbs specific for the viral oncoprotein E6. Overall, this puts us in the unique position to generate HPV oncoprotein-targeting dimeric IgA antibodies and assess their anti-cancer activity in HPV+ HNC. Our central hypothesis is that that dimeric IgA molecules targeting the oncoproteins E6 and E7 will efficiently inhibit the growth of HPV+ HNC. Our main objectives in this proposal are (i) to generate HPV E6- and E7-targeting dimeric IgA therapeutics using our recombinant hmAb platform, (ii) to define their anti-tumor activity against various HPV+ HNC cell lines, (iii) to measure the expression of pIGR, the receptor initiating IgA transcytosis, at the protein level in primary HPV+ HNC to determine whether IgA-based treatment approaches could be broadly applicable for the treatment of HPV+ HNC, and (iv) to identify proinflammatory signals that can upregulate pIGR in HPV+ HNC and thus sensitize cancer cells for dimeric IgA therapies. Together, these aims will address whether IgA-based therapeutics can be leveraged to target viral oncoproteins in HPV+ HNC, and will provide the necessary preliminary data for a subsequent R01 application. Overall, our study has thus the potential to guide the development of a new class of HPV-specific therapeutics that would allow for improved and gentler therapies for patients with HPV+ HNC.

NIH Research Projects · FY 2026 · 2025-07

PROJECT SUMMARY Lung transplantation is the only definitive and successful therapy for end-stage lung disease. However, while the waiting list of patients eligible for lung transplant grows, the number of suitable donor lungs falls far short of the demand, and people are dying while waiting for acceptable lungs. To attempt to address this shortfall, there has been an aggressive expansion of organ quality criteria for transplantation to meet this critical need. An evolving strategy to meet the critical unmet demand for viable lungs suitable for transplantation is donation after circulatory death (DCD) donation. Unfortunately, ischemia-reperfusion injury (IRI), which happens universally in transplantation, is especially pronounced in these DCD allografts and highly variable. Therefore, resulting in the use of marginal or extended criteria donor organs where there exists the increased potential for early allograft dysfunction or failure after transplantation. Normothermic ex-vivo lung perfusion (EVLP) is a technology that enables the assessment and, with sufficient metabolic support on the perfusion circuit, potential resuscitation of DCD donor lungs significant metabolic debt. In current clinical practice, EVLP uses either an acellular perfusion solution or perfusion solution containing red blood cells (RBCs), which are both unable to support the donor organ for extended duration perfusions. There are no commercially available or viable blood alternatives that are able to be used for EVLP. For RBC-based perfusates, there are limitations with respect to erythrocyte degradation, hemolysis, and antigen exposure over time while on the EVLP circuit. We have demonstrated that engineered hemoglobin-based oxygen carriers (HBOCs) can be tailored to mimic RBC oxygen delivery by mixing tense and relaxed quaternary state polymerized hemoglobin molecules. These molecules are stable at normothermia and can be the basis of an organ support solution or oxygen-carrying perfusate used to resuscitate donor lungs prior to transplantation. An engineered and tailored oxygen affinity HBOC that can effectively deliver oxygen over a broad range of physiologic conditions would be favorable, ensuring optimal lung viability. A novel, innovative HBOC-based perfusate with a prescriptive O2 affinity tailored to effectively deliver O2 over a broad range of physiologic conditions would favorably ensure lung viability, especially for lungs that have amassed different metabolic debts. This supports the rationale that a tailored HBOC-based perfusate with tunable O2 affinity can effectively support DCD lungs by meeting the enormous and variable metabolic O2 debt incurred during ischemia and can sustain organ viability through EVLP leading to successful transplantation. We will engineer a tailored oxygen affinity HBOC perfusate mixtures and define their biocompatibility and stability (Aim 1) and we will demonstrate the ability of the novel, tunable HBOC formulation to resuscitate DCD lungs during EVLP by meeting the metabolic demands of the lung to restore function and ensure successful transplantation (Aim 2).

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT Homologous recombination (HR) is the primary mechanism for repair of DNA double strand breaks (DSBs) arising during DNA replication. Chromosomes can break when the replication machinery collides with the transcription machinery, navigates repetitive DNA sequences, or runs into other impediments. These types of DSBs are called endogenous because they are caused by normal cellular transactions. They are district from exogenous breaks which are caused by chemicals or radiation. Central to HR are the breast cancer susceptibility genes, BRCA1 and BRCA2 which load the RAD51 recombinase onto the broken end to engage homology search and repair. Mutations in BRCA1 or BRCA2 severely cripple HR and cause chromosomal re-arrangements. RAD52 is an accessory gene that can substitute for the BRCA1&2, but it is not as proficient and can cause chromosomal instability. Importantly, most cancers harbor mutations in these four genes underscoring the HR machinery role in maintaining genome stability. Chromatin remodeling also plays a major role in HR repair. Accurate removal or reposition of histones is essential to access the broken ends and initiate strand invasion. The KAT5 histone acetyltransferase is one enzyme that is required for both activation of the DNA damage checkpoint and recruitment of HR machinery at the break. We have identified previously unreported physical and genetic interactions between KAT5 and RAD52 in the yeast model system. We also published data showing that KAT5 recruits RAD52 to the break and that KAT5 mutations affect DSB end resection and repair pathway choice. KAT5 is a subunit of the TIP60-complex which also functions in transcription dependent chromatin remodeling. However, the role of the other TIP60 subunits in DSB repair is less understood. In this grant we want to place all TIP60 complex subunits with the DNA damage response epistatic group. We hypothesize that KAT5 and members of the TIP60-complex promote error-free DSB repair by modulating the role of RAD52. In Aim 1 we propose to test combinations of mutations between the HR repair machinery components and the TIP60-complex subunits. We will use in vivo recombination assays to directly delineate their role within the several HR sub pathways. In Aim 2 we will use in silico protein structure techniques to model the HAT module of TIP60, which is currently unknown. We will then model the overall TIP60 complex including the HAT module. Additionally, we will query cancer genomes to identify high frequency and driver mutations in TIP60-complex components and investigate how they affect interaction with other members of the complex and HR repair.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY Influenza A viruses (IAV) pose significant global health threats, causing annual epidemics with substantial morbidity and mortality. The prevailing resistance of the majority of H1N1 and H3N2 strains to antiviral drugs, coupled with the emergence of the highly pathogenic avian H5N1 IAV that has breached species barriers to infect humans, underscores the urgent need for a paradigm shift towards identifying drugs effective across a spectrum of viral strains. The airway epithelium is the primary site for IAV replication. Our prior investigations have highlighted the host cellular protein BIK as a pivotal player in IAV replication within airway epithelial cells (AECs), influencing disease severity in humans. BIK deficiency impedes, while its overexpression exacerbates viral replication, virus-induced lung inflammation, and mortality. Additionally, we have identified a single nucleotide polymorphism in the BIK gene associated with influenza severity. IAVs facilitate their replication in AECs by stabilizing BIK protein through inhibiting proteasomal BIK degradation. Our mass spectrometry analysis has unveiled a novel BIK-interacting E3 ligase, Ariadne RBR E3 ubiquitin protein ligase 2 (ARIH2), which is inhibited by IAV to stabilize BIK. ARIH2 depletion enhances BIK levels and viral replication, while its expression reduces both, identifying ARIH2 as a novel IAV restriction factor exploited by the virus. Our proposal aims to elucidate how IAV manipulates ARIH2 to inhibit proteasome-mediated degradation of BIK, thereby promoting viral replication. We will test the central hypothesis that IAV nucleoprotein (NP) inhibits ARIH2 to block the ubiquitin-dependent degradation of BIK, thereby promoting viral replication. Conversely, ARIH2 mitigates viral burden in AECs by directing BIK towards proteasome-mediated degradation. To test this hypothesis, we proposed three Specific Aims. Aim 1 investigates how IAVs exploit ARIH2 to Inhibit BIK degradation and promote viral replication in the AECs. This Aim focuses on identifying crucial ARIH2 domains and BIK lysine residues for ubiquitination, exploring the impact of ARIH2-mediated BIK degradation on viral replication and inflammatory responses. Aim 2 explores ARIH2's role in mitigating influenza disease progression in vivo. Aim 3 evaluates ARIH2’s therapeutic potential in mitigating viral load and lung inflammation in normal human bronchial epithelial cells and human Precision-Cut Lung Slices. The proposed studies may uncover ARIH2 as a universal and novel target for treating influenza infections, offering therapeutic promise due to its enzymatic nature and potential selectivity towards BIK. These studies will have profound translational implications and hold the potential to enhance prevention and treatment strategies for emerging and reemerging influenza strains.

NIH Research Projects · FY 2025 · 2025-07

Project Summary Adeno-associated virus (AAV) is the leading gene delivery vector for treating different human diseases. Some AAV therapies have been approved for use in the clinic and constitute an essential step toward personalized gene therapy. However, despite its promise to treat many genetic diseases, AAV gene therapy still face many safety challenges that lead to several adverse events, including death. In most cases, these adverse events were related to the use of AAVs with high vector genome (vg) titers (>1E14 vg/kg). Despite following a multi-step purification process, these AAV preparations are often contaminated with non-therapeutic AAV particles, such as empty or partial AAV capsids (lacking or containing truncated vg) and cross-packaged DNA. These contaminants can contribute to adverse events at high AAV vg titers even when present in lower ratios. Accordingly, the success of AAV therapies relies on the use of high-quality AAV capsids (qualified to package a high majority of full therapeutic AAV vg and minimal levels of contaminants) and on the precise quantification of AAV titers to ensure optimal dosage, efficacy and safety. The current analytical methods used to ensure the production of high-quality AAV are not comprehensive and thus lack the precision needed for the accurate and reproducible quantification of AAV vg, capsid and contaminant titers. These limitations result in a misestimation of the empty/partial/full AAV capsid ratio, leading to the administration of either low AAV vg titers with sub-optimal therapeutic efficacy or high AAV vg titers with toxic levels of contaminants, potentially causing severe adverse events or death in treated patients. Therefore, there is an unmet need for developing analytical methods that provide an efficient, cost-effective, and easy implementation for the comprehensive, accurate, and reliable quantification of AAV capsid and genomic titers and AAV integrity. In this proposal, we are set to develop a unique and groundbreaking QC platform that we named “AAVBiochip.” It will be an essential in situ single particle analytical tool to determine capsid and vg titers and the ratio of empty/partial/full AAV capsids in a single assay. We will immobilize AAVs on the platform surface by electrostatic interactions for rapid imaging and analysis. In Aim 1, we will demonstrate the feasibility of our technology by using well-characterized AAV titers for which the capsid proteins, conformational epitope (3D structure) of assembled capsids, and ITR genomic regions will be targeted using specific antibodies and sensitive molecular beacons. We will also compare our measurements with standard methods for quantifying AAV titers, ensuring the accuracy and reliability of our results. In Aim 2, We will conduct a comprehensive benchmarking comparison using different AAV serotypes approved by the FDA for gene therapies. AAVs will be engineered to carry the green fluorescence protein (GFP) payload. For the analytical characterization of these AAV capsids, a combination of standard analytical methods and the AAVBiochip will be used. Overall, our work will enable a comprehensive, ultrasensitive and accurate AAV characterization technology that will offer significant advantages as a QC tool for any AAV-based gene therapy.

NIH Research Projects · FY 2025 · 2025-07

Alveolar type II (ATII) cells are the primary site for influenza A virus (IAV) replication in the distal lung and central players in the pathogenesis of IAV-induced ARDS. ATII cells also regulate alveolar lining fluid depth by alveolar fluid clearance (AFC). Prior studies show infection with H1N1 IAV A/WSN/33 (WSN) causes ARDS in wild-type (WT) C57BL/6J mice by 2 days post-inoculation (dpi). WSN-induced ARDS in WT mice is accompanied by a significant reduction in AFC rate, decreased ATII cell mitochondrial (mt) oxidative phosphorylation (OXPHOS), and a switch to aerobic glycolysis as a primary means of ATP synthesis. Post-infection treatment with the liponucleotide cytidine 5’-diphosphocholine (CDP-choline) improves gas exchange, restores normal AFC, and reduces pulmonary inflammation, without altering WSN replication or improving surfactant function. CDP-choline also prevents WSN-induced ATII cell mt depolarization and restores OXPHOS but does not prevent the glycolytic shift. Pilot studies using inducible, ATII cell-specific Transcription Factor A, Mitochondrial (TFAM)-KO mice show that the beneficial effects of CDP-choline treatment on WSN-induced hypoxemia and AFC impairment are ATII cell mt-dependent, but its anti-inflammatory effects are not. This implies that induction of hypoxemia by WSN is directly related to its effects on ATII cell OXPHOS and results from impaired AFC rather than pulmonary inflammation or surfactant dysfunction. In addition, infection of mice with H1N1 IAV strains that lack functional PB1-F2 had no detrimental effects on oxygenation in vivo or ATII cell OXPHOS ex vivo, showing WSN effects on both are PB1-F2-dependent. Hence, it is hypothesized that the PB1-F2 protein of IAV interacts with MAVS to depolarize mt which inhibits ATII cell OXPHOS, thereby reducing mt ATP generation. This causes an energy crisis in ATII cells, which impairs AFC and results in hypoxemia that promotes progression to ARDS. This hypothesis will be tested in 2 independent but complementary Specific Aims. In Aim 1, WT mice will be infected with PB1-F2-expressing and PB1-F2-negative H1N1 IAV strains to define their effects on oxygenation, AFC rate, lung mechanics, pulmonary edema, and pulmonary inflammation in vivo, and on ATII cell mt function ex vivo. MAVS-KO and WT/MAVS-KO chimeric mice will then be infected with WSN to show IAV effects on the above parameters are non-myeloid MAVS-dependent. Proximity ligation assays will be used to confirm the interaction between MAVS and PB1-F2 in ATII cells. Aim 2 will use human precision-cut lung slices to validate mouse data and to define the effects of IAV and its PB1-F2 protein on the human ATII cell secretome, energetics, gene expression, and ultrastructure. Proposed studies will use innovative experimental tools to provide additional evidence (and a potential mechanism) for the finding that PB1-F2 is an important virulence determinant of IAVs and may show that new IAV strains should be assessed for their ability to inhibit OXPHOS. They will also demonstrate a causal link between AFC impairment (secondary to PB1-F2/MAVS-mediated ATII cell mt dysfunction) and development of hypoxemia in influenza, which has broader relevance to other forms of ARDS.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY Rising prevalence rates of Alzheimer’s disease (AD), paired with limited treatment options to alter the disease course, have prompted substantial scientific investigation into delineating and prolonging preclinical stages of AD. Presence of subjective cognitive decline (SCD) is the earliest detectable preclinical stage of AD, reflected by self-reported cognitive decline in the absence of objective cognitive impairment on standardized neuropsychological testing. People with SCD are at elevated risk of developing AD, report more variable cognitive functioning in daily life not yet detectable on lab-based neuropsychological testing, and exhibit less stable brain dynamics that mirror changes commonly observed in AD—making them ideal candidates for prevention-based behavioral interventions. Thus, there is an urgent need to identify promising preventative interventions to mitigate cognitive and neural risks associated with the development of AD for adults with SCD. Mindfulness training is one such intervention shown to improve multiple aspects of functioning relevant to AD, including cognitive functioning, brain structural integrity, and brain functional integrity. Building upon this prior work, the current proposal will leverage my sponsor’s ongoing pilot feasibility trial—the Internet-based Mind- Body Training study (iMBT; 1R61AG081982-01)—to investigate whether mindfulness training reduces everyday cognitive variability and enhances intrinsic brain dynamics among adults with SCD. Here, I will investigate whether an internet-delivered Mindfulness-Based Stress Reduction (iMBSR) program compared to a Lifestyle Education (iLE) program reduces cognitive variability in daily life, as indexed by two ecological momentary assessment cognitive tests. I will also examine the preliminary effects of iMBSR versus iLE programs on dynamic, whole-brain states—measured using resting-state dynamic functional connectivity and k-means clustering analysis. By using innovative methodologies, findings from this proposal will enable us to delineate cognitive variability in everyday contexts and neural dynamics among individuals with SCD. Critically, the proposed research will yield novel insights into the utility of mindfulness training for promoting cognitive and neural stability in adults at-risk for AD.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY The etiology of neurodevelopmental psychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia remains elusive, hindering the innovation of novel treatments. These disorders are thought to have an overlap in their pathophysiology due to a shared association with in utero exposure to maternal infection, stress, and cytokine levels. These hypothesized immune programming mechanisms have begun to be investigated by using mouse models of prenatal stress and maternal immune activation which cause a similar offspring behavioral phenotype as these disorders. Our lab has established prenatal stress to increase fetal microglia inflammatory cytokine expression, which continues into adulthood in the cortex, suggesting their function is dysregulated throughout life. Further, preliminary data from our lab has shown prenatal stress to reduce the presence of maternal macrophages relative to fetal-derived macrophages in the placenta with an overall decrease in immune cells. This imbalance is paralleled by a diminished interferon response and a stressed-induced suppression in the maternal plasma cytokine response to exposure of the viral mimetic poly(I:C). Given this preliminary data, we hypothesize that prenatal stress impairs the placental immune response to maternal viral stimulation with a subsequent potentiation of the effects of maternal immune activation on fetal neuroimmune and behavioral development. To delineate the specific effects on maternal and fetal placental immune cells we will apply our established prenatal stress and poly(I:C) exposure model to a transgenic mouse line that specifically expresses TdTomato in fetal macrophages. In Aim 1, we will investigate changes in the placental immune response using flow cytometry, immunohistochemistry, and RNA-sequencing of FACS sorted maternal and fetal macrophages. In Aim 2, we will assess the changes in fetal microglia using RNA-sequencing and evaluate their long-term programming by isolating microglia from adult wild type offspring to evaluate their reactivity in vitro. Further, we will characterize changes to offspring communicative output, social behavior, anxiety-like behavior, and repetitive behaviors to determine whether the interaction between prenatal stress and maternal viral stimulation potentiate the deleterious behavioral consequences on the offspring. Our approach is innovative and significant, as it will be the first project to define the maternal and fetal specific effects on placental immune function in both prenatal stress and poly(I:C) stimulation and how these common maternal environmental disruptions interact to impact offspring neuroimmune and behavioral development. The outlined aims are coupled with a rigorous training plan integrating advanced technical skill development in in vivo analyses, high-parameter flow cytometry, and bioinformatics with essential non-technical skill development in scientific communication, mentorship, and scientific writing. This comprehensive training plan will provide the unique and necessary skills to develop into an independent physician-scientist innovating novel therapies for neurodevelopmental disorders.

NSF Awards · FY 2025 · 2025-07

Hydrogen can be used as a fuel or chemical feedstock to generate energy. However, hydrogen is difficult to store and transport. Ammonia has the chemical formula NH3, and is more convenient to store and transport. Accordingly there is great interest in temporarily converting hydrogen into ammonia, and then decomposing ammonia to recover hydrogen as a fuel. This project develops a membrane-based process for recovering hydrogen from ammonia. It combines the ammonia decomposition reaction, and the subsequent separation of hydrogen from ammonia and nitrogen, into a single operation. The process does not use expensive rare metals as catalysts. It is expected to be more energy-efficient compared with existing processes. The project benefits society by diversifying energy sources. Additional benefits to national interests come from training students in energy technology, outreach programs to engage pre-college students in STEM fields, and strengthening partnerships with industry. This project uses a mixed ionic-electronic conducting (MIEC) membrane with catalyst to convert ammonia and steam at the two sides of the membrane. The overall reaction is the redox-driven decomposition of ammonia. Oxygen permeability and long term durability of the membrane are critical for this technology. The overall research objective is to tune the kinetics and stability of the oxygen-permeable membrane-catalyst system. This will enable ammonia conversion to exceed its single-step decomposition limit and prevent formation of nitrogen oxides (NOx compounds). The project elucidates the coupled mass transport, charge transfer, and chemical kinetics occurring at membrane surface and interfaces. First, kinetic parameters of NH3 conversion and oxygen permeation will be analyzed to elucidate the reaction kinetics model for the proposed membrane-catalyst system. Next, the fundamental mechanisms influencing bulk and surface properties of the membrane-catalyst system will be investigated. For bulk properties, grain boundary chemistry, cation site distribution, and microstructural uniformity and defects will be characterized to discover their relationship with membrane bulk diffusion and stability. For surface properties, chemical bonding, redox state, and secondary phase(s) of catalyst and membrane will be correlated with surface kinetics and stability. Finally, the materials and system knowledge will be combined to construct a model that achieves ammonia conversion above the single-step NH3 decomposition limit and avoids NOx formation. Furthermore, the findings will extend beyond ammonia decomposition to inform other membrane-catalyst systems such as hydrocarbon reforming. Education and outreach activities in the project will include hands-on experiments, field visits, course development, and fireside chats to increase student and public interest in energy technologies and STEM careers, and to facilitate exchange between the students and industrial employers about career opportunities in energy fields. 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 · 2025-07

The Message Passing Interface (MPI) standard has been the de-facto communication approach for scaling large scientific problems on large High-Performance Computing (HPC) clusters. Recently, MPI libraries are also being used for scaling Deep Learning (DL) and Machine Learning (ML) applications on HPC clusters. The performance and scaling of an MPI library for HPC and AI applications are heavily dependent on the optimization of the underlying point-to-point protocols and collective communication algorithms. These optimizations, on the other hand, are heavily dependent on the characteristics of the underlying cluster architecture involving CPU, GPU, memory, and interconnects. The current approach used by the MPI library developers is to carry out such optimizations in an offline, static, and manual manner. This makes the task very time-consuming. This project develops a novel AI4MPI approach where AI techniques can be developed and used for optimizing point-to-point protocols and collective algorithms for current and next-generation HPC clusters with diverse characteristics. The proposed approach will enable MPI library developers to optimize their MPI libraries with significantly reduced effort for a range of clusters with varying characteristics, and deliver higher performance for a range of HPC and AI applications. The project will provide valuable guidelines for designing and deploying next-generation HPC and AI systems, benefiting users in academia and industry. The research outcomes will also contribute to curriculum advancements, supporting education and research in HPC, AI, and Data Analytics. Additionally, the dissemination of results to collaborating organizations will positively impact their HPC and AI libraries and software applications, benefiting society at large. 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 · 2025-07

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.