Virginia Commonwealth University

NSF Awards · FY 2026 · 2026-09

Enzymes can catalyze reactions that produce chemicals, fuels, and pharmaceuticals. Such reactions tend to occur at mild temperatures and without the use of hazardous solvents. This reduces energy and product purification costs. Enzyme activity is usually controlled by molecular interactions. These are hard to regulate in a reactor. This CAREER project will investigate a strategy to make the enzymes sensitive to different wavelengths of light. This approach will enable rapid control over enzyme-driven reactions in manufacturing processes. Biotech workforce development is also planned. It will be accomplished through engagement with community college students and faculty in a week-long protein engineering workshop. Light-activated domains will be incorporated into regions of the protein that affect enzyme activity. The ability of these domains to modulate enzymatic activity will be evaluated. The intent will be to create domains that reversibly couple two distinct yet complementary proteins, and that modulate protein sequestration on a surface. Expanding the range of light-activated proteins to include green, red, and near infrared light will be another major thrust of the project. To accomplish this, a variety of photoswitches will be covalently attached to de novo protein structures. The approach will be validated using biomineralization. Enhancing the performance of optoelectronic nanomaterial synthesis could improve the quality and functional performance of quantum dots, nanowires, and other inorganic nanostructures. 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 · 2026-06

PROJECT SUMMARY The Virginia Commonwealth University (VCU) and Massey Comprehensive Cancer Center (Massey) Lipidomics and Metabolomics Core (VLMC) is an established core for mass spectrometry for small molecules. While this facility was initially established to support a group of investigators conducting groundbreaking lipid research, the need for polar metabolite analysis has evolved and now contributes to novel research projects by other investigators. VCU and Massey have a growing mass of investigators working to understand how changes in bioactive lipids influence metabolism and the signaling pathways that regulate normal and pathological human cellular functions. In 2019, the VLMC procured a high mass accuracy instrument for exploratory/untargeted lipidomics and metabolomics, and these exploratory projects led to high demand for targeted analysis of polar molecules, including metabolic intermediates in the TCA cycle, glycolysis/gluconeogenesis, amino acid metabolism, redox metabolism, pentose phosphate pathway, nucleotides, energy equivalents including ATP and NADH, NADPH, FAD, FADH, and others. Current VLMC instrumentation includes a Sciex 6500, which, while useful, lacks sufficient sensitivity given our expanded range of quantifiable analytes. Furthermore, as one of a handful of centers of bioactive sphingolipid research, our sphingolipid-focused users are now probing alternative pathways of sphingolipid biosynthesis, sphingolipid-protein interactions, and subcellular compartmentation of sphingolipids. These applications require increased sensitivity due to low abundance of some metabolites and/or very small amounts of sample material. Therefore, funds are requested for a SCIEX Triple Quad 7500 System - QTRAP Activated mass spectrometer. This exceptionally flexible instrument combines the unique capabilities of the most sensitive triple quadrupole mass spectrometer available with the highest capacity ion trap to provide mass resolution, sensitivity, and dynamic response needed for structural characterization and quantitation of the diverse molecules, both polar and non-polar, that comprise the metabolome. Fourteen funded scientists and clinicians from seven different departments have specific needs for this instrumentation. The 7500 QTRAP will be operated as a shared research resource in our established VLMC, which has existing, appropriate site preparations for instrument installation, established billing and usage logistics, and generous institutional support. There is no mass spectrometer with the required capabilities on the Medical Center or VCU campus. The instrument will be administered as a VCU Massey core resource under the direction of Dr. L. Ashley Cowart and Dr. Jeremy Allegood, who have extensive experience in lipid analysis and administration of core resources. An Advisory Committee will oversee the equitable use of the instrument for the benefit of funded investigators and the university research environment. This mass spectrometer is essential for continuing the development and realization of lipidomic and metabolomic research toward a better understanding of normal and aberrant cellular function including cancer, cellular respiration disorders, and other metabolic diseases.

NIH Research Projects · FY 2026 · 2026-05

Title: Functional and structural characterization of phospholipase A2 in Porphyromonas gingivalis Phospholipases (PLAs) are a group of enzymes that hydrolyze phospholipids producing fatty acids and lipophilic substances. PLAs are ubiquitous, diverse, and play important roles in maintenance of cell membrane integrity, lipid signaling, and regulation of energy homeostasis. PLAs and their metabolites are also implicated in numerous human illnesses, such as autoimmune disease, atherosclerosis, Alzheimer’s disease, and cancer. Interestingly, growing evidence also suggests that there is a positive correlation between PLA activity and periodontitis, e.g., elevated PLA activity is detected in patients’ gingival crevicular fluid (GCF) and recovers to normal levels after treatments; however, little is known about its underpinning pathogenic mechanism. Specifically, the factors that elevate the activity of PLAs in GCF remain unknown. Is this effect caused by particular periodontal pathogens and/or by host responses to the infection? To answer this question, we interrogated the genomes of Porphyromonas gingivalis, a keystone pathogen of periodontitis, and identified a putative PLA in all sequenced isolates, such as PG1879 in W83 strain and PGN1806 in 33277 strain. We carried out biochemical and loss-of-function studies and our preliminary results reveal that PG1879 has PLA2 activity, lyses sheep red blood cells, and is required for P. gingivalis growth in a chemically defined medium (CDM). Building upon these results, we hypothesize that PG1879 is a PLA2 with a unique biochemical and structural feature and contributes to the pathophysiology of P. gingivalis. To test this hypothesis, the following two specific aims are proposed: (1) Delineate the biochemical and structural feature of PG1879 as a PLA2; and (2) Determine the role of PG1879 in the pathophysiology of P. gingivalis. To the best of our knowledge, PLA2 has not been functionally characterized in any oral pathogens and their role in the pathogenesis of periodontitis remains unknown. Completion of this project will elucidate the biochemical and structural feature of PG1879 as a PLA2 and its role in the pathophysiology of P. gingivalis and pave a way to investigate PLA2 in other oral pathogens. In addition, this project will provide me with a comprehensive training on bacterial genetics, biochemistry, cell biology, and structural biology.

NIH Research Projects · FY 2026 · 2026-05

Project Summary. Project Summary. Ovarian cancer (OC) is usually diagnosed at advanced stages, and platinum-based chemotherapy with surgical debulking remains the most effective first line treatment for all OC subtypes. Although the initial response rate is high, most patients develop drug-resistant terminal cancer relapse within 5 years. Overcoming the mechanisms contributing to platinum resistance is urgently needed for improvingbthe treatment outcomes. Sulfated glycosaminoglycans (GAG), such as heparan sulfate (HS) and chondroitinbsulfate (CS), are linear polymers of repeated disaccharide units that are modified by addition of sulfate groups. High levels of GAG and high expression of proteoglycans (proteins with attached GAG) at the cell surface and within the extracellular matrix can promote cancer progression and chemoresistance, thus positioning GAG as emerging relevant factor in the treatment of OC. Previously, we discovered that GAG mediate the tumor uptake of Triplatin, a positively charged trinuclear platinum (Pt) agent of a structurally distinct class from the mononuclear Pt drugs. The efficacy of Pt drugs depends on the tumor uptake, and drug tumor accumulation is essential for increasing the potency and diminishing toxic side effects. A central HYPOTHESIS of our Translational Exploratory/Developmental study is that high expression of C4S contributes to platinum resistance in OC, which can be overcome by GAG-targeted drugs, such as Triplatin. Clear cell ovarian carcinoma tumors are known to portend a worse prognosis than high grade serous or endometrioid OC, in part due to inherent resistance to platinum-based chemotherapy and lack of novel therapies for these high-risk histologic subtypes. The overarching goal of this study is the elimination of mortality associated with Pt-resistant OC by improving drug tumor penetration, accumulation, and selectivity. This study can benefit the patient by using the GAG profiling to predict the response to the conventional or novel platinum drugs such as Triplatin. The proposal will be the first to use a mechanism-based approach for precision medicine of platinum anticancer agents. This study aims to refine and validate this approach for the future clinical translation. To validate our hypothesis and to advance the use of Triplatin against platinum-resistant OC subtypes, this study will use in vivo murine tumor models because they enable assessment of antitumor efficacy, intra-tumor and organ drug accumulation, as well as the platinum drug interaction with stromal, vascular, and immune context that cannot be recapitulated in vitro. Project will be deemed a success when 1) the role of GAGs in platinum resistance is established, 2) Triplatin shows significant improvement over the available therapies in treatment of Pt-resistant primary and recurrent OC and 3) a candidate diagnostic companion marker is characterized to identify what patients will benefit most. Success of this study would have a significant positive impact on survival outcomes for OC patients, their families and community.

NIH Research Projects · FY 2026 · 2026-05

SUMMARY Converting the host cell into a supportive niche is essential for intracellular pathogen survival and replication. Orientia tsutsugamushi is a genetically intractable obligate intracellular bacterium that causes scrub typhus, a globally emerging infection with a high fatality rate. Disease progression depends on bacterial-driven modulation of host antimicrobial responses that affords Orientia the ability to replicate to high loads in endothelial cells. The bacterial mechanisms responsible are largely unknown, highlighting a gap in our knowledge of host-pathogen interactions that influence scrub typhus outcome. Circadian rhythm and the hypoxic response are universal and essential pathways that influence innate immunity (e.g., ROS, DNA damage responses, and apoptosis) through gene expression regulation. We discovered that O. tsutsugamushi promotes the hypoxic response. In infected cells, HIF2⍺, a transcription factor that stimulates hypoxic response-regulated gene expression, is stabilized and nuclear. Moreover, the circadian rhythm-related transcription factor pair, BMAL1-CLOCK, is also nuclear and stimulates robust expression of circadian rhythm genes. Remarkably, Orientia uniquely promotes HIF2⍺ interaction with BMAL1-CLOCK indicating that it encourages interplay between circadian rhythm and the hypoxic response likely to combat host innate immune defenses. We surmised that O. tsutsugamushi executes this strategy, at least in part, using its effector, Ank13, which is a nucleomodulin that pronouncedly alters host cell gene expression. The abilities of Ank13 to modulate host gene expression, prevent host cell genotoxicity, and DNA damage-dependent apoptosis are nucleotropism-dependent. The Ank13 mechanisms of action are undetermined. Conspicuously, the circadian rhythm genes, PER1 and CRY1, are upregulated and BMAL1 expression is decreased in uninfected cells ectopically expressing Ank13 indicating that circadian rhythm-related transcription is active and that Ank13 alone recapitulates these Orientia infection associated phenomena. Yeast two-hybrid screening and co-immunoprecipitation both identified host HIF2⍺ and FIH (negative regulator of HIF2⍺) as Ank13 binding partners. Together, these data establish the model where O. tsutsugamushi uses Ank13 to orchestrate the interplay between circadian rhythm and hypoxic responses as a promicrobial strategy. Aim 1 will test the hypothesis that O. tsutsugamushi promotes interaction between the hypoxic response and circadian rhythm to counter innate immune defenses. Aim 2 will validate the ability of Ank13 to bind FIH and, in turn, stabilize HIF2⍺ allowing it to regulate BMAL1-CLOCK activity to manipulate host cell transcription and combat ROS production, DNA damage, and apoptosis. Achieving these aims will have a powerful impact by advancing fundamental understanding of O. tsutsugamushi pathobiology, dissecting a new microbial strategy for modulating host immunity, and revealing host-directed therapeutic targets for treating scrub typhus.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY The Massey/VCU McCaskill-Stevens K12 for Community Oncology and Prevention Research will mentor promising, multidisciplinary, early-stage clinical investigators in the conception, development, and implementation of innovative cancer prevention and control studies designed to optimize participation by cancer survivors and individuals most at risk for cancer throughout Virginia. The Massey Comprehensive Cancer Center (Massey) at Virginia Commonwealth University (VCU), a 50-year National Cancer Institute (NCI)-designated Center, is the ideal training environment for this McCaskill-Stevens K12 program as it is part of a safety-net health system, which provides cancer care to all. As a participating institution in the NCI Community Oncology Research Program since 1990, Massey has also built a state-wide network to provide access to cutting-edge clinical and community-based research studies in the areas of symptom management, cancer prevention, health-related quality of life, and cancer care delivery. The experienced Massey investigators leading and providing mentoring for this McCaskill-Stevens K12 program are engaged in and committed to cancer prevention and control research and have strong track records of mentoring clinical residents, fellows, and early-career faculty to develop and lead investigator-initiated and national studies as part of the NCI Clinical Trials Network and other NCORP research bases. During the five-year project period, six K12 Scholars will participate in a variety of courses and career development experiences, and they will be guided by a mentoring triad that will include at least one well-funded cancer prevention and control investigator, an experienced clinical trialist, and a Community Champion who together will promote bi- directional perspectives as interventions are designed, implemented, analyzed, and disseminated. Over their two-year, grant-funded tenure in this program, each K12 Scholar will be afforded the time, effort, and resources to conduct cancer prevention and control-related pilot research, write and implement an investigator-initiated interventional study, seek extramural funding to support their future investigations and/or further career development, and submit manuscripts based on their research. These K12 Scholars will continue to receive two further years of salary support from Massey beyond the initial K12-funded period to realize their maximum potential as independent investigators. The McCaskill-Stevens K12 program leaders will continually evaluate the success of the K12 Scholars, mentors, and program activities based on both short- and long-term outcomes, reassessing and modifying the program to provide each new cohort with an optimal career development experience. This McCaskill-Stevens K12 program will ensure that the next generation of oncologists and cancer-focused healthcare providers have the ability to design community-centric cancer prevention and control research that meets the needs necessary to eliminate the cancer burden for all Virginians.

NSF Awards · FY 2026 · 2026-04

This project broadens undergraduate and graduate student participation from U.S. universities at the Digital Forensic Research Conference (DFRWS), a premier international venue advancing digital forensics research and practice across academia, industry, and government. The project provides competitive travel support for undergraduate and graduate students across U.S. institutions to ensure student access to cutting-edge security science and professional research communities. 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 · 2026-01

PROJECT SUMMARY / ABSTRACT Alzheimer's disease (AD) is a neurodegenerative condition that progressively destroys memory and cognition, exacting devastating personal and public health costs. Recent evidence indicates that soluble oligomeric Aβ42 (oAβ42) begins accumulating in the human brain one to two decades before clinical symptoms of AD emerge. Multiple studies suggest that elevated levels of soluble oAβ42, rather than insoluble Aβ plaques, drive the selective degeneration of vulnerable neurons and serve as the strongest predictors of cognitive decline in AD. Basal forebrain cholinergic neurons (BFCNs) are particularly vulnerable to functional modulation by oAβ42, and their dysfunction has been implicated in memory loss and cognitive impairment. In septo-hippocampal pathways, α7-containing nicotinic acetylcholine receptors mediate synaptic transmission and neuronal intrinsic excitability. Most α7-nAChR contain only α7 subunits. However, α7β2-containing nAChRs, are predominantly expressed on BFCNs. Our published research has demonstrated (i) α7β2-nAChRs are selectively sensitive to functional modulation by oAβ42, (ii) oAβ42/α7β2-nAChRs interactions lead to BFCN dysfunction by altering neuronal intrinsic excitability, and (iii) genetic deletion of the β2 nAChR subunit improves memory deficits observed in the APP/PS1 mouse model of AD. In this proposal, we provide direct evidence that oAβ42/α7β2- nAChRs interactions enhance BFCN excitability by altering large-conductance (BK-type), small-conductance (SK-type), and KCNQ/Kv7 (M-type) K+ channel subtypes on BFCNs. We will expand our published work to demonstrate how oAβ42/α7β2-nAChR interactions drive BFCN dysfunction by altering BK-, SK-, and M-type K+ activity in distinct forebrain cholinergic sub-regions. In Specific Aim 1, we will use whole-cell patch-clamp recordings to determine how α7β2-nAChRs contribute to oAβ42-induced alterations in BK-, SK-, and M-type K+ channel function and BFCN hyperexcitability by using our newly-developed α7β2-nAChR-selective antagonist, conotoxin α-CtxPnIC[L10Y]. Using next-generation RNA sequencing (RNAseq), we will investigate specific gene ontologies and associated signaling pathways implicated in (i) K+ channel functional regulation, (ii) neuronal intrinsic excitability, and (iii) AD-related neuronal dysfunction. In Specific Aim 2, we will use two experimentally- tractable mouse models of AD to determine whether knockdown of α7β2-nAChRs ameliorates AD-related spatial-reference and working memory deficits. Long-term AAV-mediated delivery of small inhibitory RNAs (siRNAs), targeting α7- and/or β2-nAChR subunit genes will be delivered in both young and mature adult male and female mice to capture disease progression and sex-dependent effects. We will perform ex vivo patch clamp recordings from the same animals to correlate the behavioral outcomes with BK-, SK-, and M-type K+ channel activity and BFCN intrinsic excitability. By integrating multidisciplinary approaches, we aim to identify novel drug targets for developing effective, long-term pharmacotherapies to prevent BFCN dysfunction and memory loss in AD, either by disrupting oAβ42/α7β2-nAChR interactions or by modulating the function of specific K+ channels.

NSF Awards · FY 2026 · 2026-01

The LLMDaL project leverages generative Artificial Intelligence (AI) along with data from the AmLight international research and education (R&E) network to provide an essential and previously unavailable building block necessary for automated network defense. The growing complexity and sophistication of modern networks are driving the need for automated cybersecurity and management. Operators of critical infrastructure must increasingly rely on AI to cope with the sheer scale of information and the growing use of AI by adversaries. However, effective AI defenses depend on both the quantity and quality of data for training. The lack of high-quality, labeled datasets from production environments presents a significant barrier. Without access to such datasets, advanced models often remain untested in real-world scenarios, limiting their effectiveness, as they fail to learn the complexity and uncertainty of production environments. Without labeled packet-level data from production networks, the AI models essential for critical infrastructure defense will fail. The LLMDaL project utilizes Large Language Models (LLMs) to automatically label packet-level data collected from AmLight maintained at Florida International University. Technical, financial and privacy challenges of providing such data remain substantial. To accurately and quickly label this real-world data, open-source LLMs are fine-tuned using data gathered from AmLight, along with known threat signatures, and expert-annotated cybersecurity events. Validation is performed through a Retrieval-Augmented Self-Refinement process, cross-checking with an ensemble of LLMs, and verification through a human-in-the-loop approach. LLMDaL fills a critical gap in automating dataset labeling, enabling effective testing of AI models for real-world environments. LLMDaL will release datasets from AmLight in batches to reflect the evolving threat landscape. 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 · 2025-12

Project Summary Congenital myotonic dystrophy (CDM), the most severe form of myotonic dystrophy, causes muscle weakness, breathing problems, and feeding difficulties at birth. During childhood affected individuals experience intellectual impairment and gastrointestinal issues while, in contrast, muscle strength and weakness improve. Muscle symptoms experienced by adults with myotonic dystrophy, including myotonia and fatigue, are not observed until individuals reach adolescence. Individuals with CDM and myotonic dystrophy type 1 (DM1) both exhibit widespread alternative splicing dysregulation due to the sequestration of muscleblind-like (MBNL) proteins by expanded CUG-repeat DMPK RNA. Our Center previously performed RNA sequencing on 43 congenital myotonic dystrophy muscle biopsies from individuals 2 weeks to 16 years of age. We found that the severity of RNA mis- splicing mirrored the triphasic course of muscle symptoms captured clinically; children in early childhood showed improvement in RNA splicing dysregulation that regressed in adolescence. Preliminary data also indicates varying DMPK expression in CDM patients, suggesting DMPK’s potential role in CDM pathophysiology, particularly in infancy. While these observations correlate with the clinical course of CDM, the mechanisms responsible for these dynamic shifts remain unknown. This proposal is designed to further clarify and define the molecular mechanisms responsible for the clinical and molecular progression of CDM. This study will characterize the epigenetic landscape around the DMPK locus in skeletal muscle across CDM development and elucidate how DMPK methylation contributes to CDM. We hypothesize that epigenetic modifiers play a significant role in the unique clinical/molecular pattern we observe in individuals with CDM across development, most specifically in infancy, by serving as a protective mechanism to modulate toxic DMPK expression via changes in methylation. Aim 1 will characterize methylation patterns in matched skeletal muscle and blood samples from CDM children, adult DM1 patients, and controls, analyzing changes across development and disease progression. Aim 2 will assess the role of DMPK methylation using iPSCs and CRISPR-based systems to modulate methylation and MBNL expression, examining the molecular effects in myogenic cells. At the completion of this project, we will have mapped the epigenomic course of CDM disease progression across pediatric development and performed experiments vital to understanding the unique mechanisms that contribute to CDM. This research will enhance understanding of CDM's clinical and molecular progression, identify potential biomarkers for therapeutic trials, and provide insights into targeting DMPK methylation in CDM.

NSF Awards · FY 2025 · 2025-10

Digital forensics revolves around the definition of forensics as a science serving the law. The technical skills in this area are in high demand in industry and government. Considering the evolving landscape of computing infrastructure (e.g., cyber-physical systems, cloud, and cryptocurrency), digital forensics necessitates ongoing research efforts to address emerging and significant challenges in this field. This REU site aims to provide undergraduate students with early research experience in the field of digital forensics within the context of computer science. It will help the students identify their interest in digital forensics, realize their research potential, and encourage them to pursue graduate studies. The REU site will have a strong focus on research experience and provide a comfortable and inspiring environment for students to learn about the process of academic research. It provides a pathway for undergraduate students to pursue graduate studies after completing this research program. Several sectors, including the military, civil law enforcement, corporate, and private sector communities, all benefit from the highly skilled and much-desired digital forensics workforce. In this REU site, the students will pursue their research projects under the supervision of faculty members. The projects will develop new forensic capabilities to help law enforcement agencies solve cyber-crimes, including new forensic data acquisition and analysis for emerging computing environments such as cyber-physical systems and the cloud. The students will experience a comprehensive research cycle, encompassing a literature review to justify the novelty of their research projects, as well as design, implementation, evaluation, and dissemination of research outcomes. Their projects will primarily focus on automated data acquisition and analysis of digital artifacts in computing infrastructure, including cloud computing and system virtualization. The students will develop new forensic techniques and tools in emerging research areas of digital forensics, including memory forensics, industrial control systems, blockchain forensics, and forensic analysis of IoT devices. The outcome of the REU projects will contribute to the health, safety, and economic well-being of our society by enhancing state-of-the-art digital forensics tools and techniques in emerging computing environments, thereby fighting cyber-crimes more effectively. 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 · 2025-09

Project Summary Cisplatin (CDDP) is a widely used chemotherapeutic used to treat various cancers, including testicular, lung, head and neck, and ovarian. CDDP use is associated with long-term cardiovascular morbidity and mortality risk, including acute coronary syndrome (ACS). Patients treated with CDDP-based therapies have demonstrated a higher prevalence of cardiovascular risk factors that contribute to the development of ACS. The induction of oxidative stress and pro-inflammatory signaling are known contributing factors in other pathologies of CDDP- induced toxicity. During atherosclerosis progression, pro-inflammatory activation promotes macrophage foam cell death; expansion of the necrotic core, and deterioration of the fibrous cap, resulting in plaque destabilization and coronary artery thrombosis. Hydrogen sulfide (H2S), a gasotransmitter, has gained therapeutic interest due to its known ability to reduce oxidative stress and inflammation. However, H2S has not been studied for its potential to treat CDDP-induced ACS, thus we will assess its protective effects against CDDP-induced plaque instability in a model of atherosclerosis. Based on my preliminary results, I hypothesize that CDDP-induced ROS and inflammation promote macrophage foam cell necroptosis, which may be attenuated by H2S. Our preliminary data support that CDDP induces macrophage foam cell death, which is attenuated by Nec-1, a necroptosis inhibitor, and GYY4137, an H2S donor. We will first assess the activation of necroptosis in CDDP-treated macrophage foam cells by western blot, ELISA, and siRNA knockdown of necroptotic mediators. Furthermore, we will evaluate the ability of H2S to attenuate CDDP-induced cell death. Second, we hypothesize that CDDP administration increases plaque vulnerability in vivo, which may be attenuated with an orally administered H2S donor, SG1002. To test our hypothesis, we will use Ldlr knockout mice placed on a high-fat diet as a model of atherosclerosis. A repeated low-dose model of CDDP toxicity will be used (weekly i.p. injections, for 4 weeks). We will perform aortic dissections to conduct histological and immunocytochemical analysis to assess plaque burden, necrotic core area, fibrous cap thickness, and macrophage-to-smooth muscle ratio. We will then determine the impact of SG1002 administration on the effects of CDDP on plaque vulnerability using the parameters mentioned previously. Identifying the molecular mechanisms contributing to CDDP-induced foam cell death and plaque instability will provide crucial insights into the link between CDDP-based regimens and ACS in cancer survivors. Furthermore, this proposal will present a novel therapeutic approach to circumvent CDDP-induced ACS, which can result in the clinical presentations of myocardial infarction in cancer survivors.

NIH Research Projects · FY 2025 · 2025-09

Pediatric asthma remains a significant public health challenge, affecting 8.1% of U.S. children. Disparities are particularly evident, with asthma prevalence ranging between 10.5% and 19.5% in communities experiencing health disparities. Effective pediatric asthma control involves individual, caregiver, community, and healthcare factors. The role of these factors in asthma management is well-documented, but gaps remain in understanding how their influence changes from childhood to adolescence. Poor sleep is also prevalent among adolescents with asthma, in part due to nocturnal symptoms. Sleep research in adolescents with asthma often overlooks caregiver factors, such as attitudes and beliefs about youth sleep hygiene, and knowledge of youth’s sleep environment. Caregivers often have inaccurate perceptions of their adolescent’s sleep practices, indicating a lack of congruence. Given the importance of sleep in adolescent development, examining its impact on asthma control and the alignment between adolescent and caregiver sleep perceptions is crucial for effective asthma management. This project uses data from RVA Breathes, a study that included 250 families of children with asthma, many of whom are from populations experiencing health disparities (U01HL138682, PI: Everhart). In Aim 1, we will use extant data from 250 5-11-year-olds from the RVA Breathes study to examine childhood asthma control trajectories and to identify predictors of poor asthma control using latent growth curve modeling (LGCM). We hypothesize that higher child quality of life, less caregiver stress, fewer caregiver depressive symptoms, and less neighborhood deprivation will be associated with better child asthma control trajectories over time. In Aim 2, we will conduct a six-month study with 100 adolescents aged 12-15 recruited from the same community as RVA Breathes to evaluate whether asthma control predictors from Aim 1 remain significant in this age group; we will also examine new factors relevant to adolescence (e.g., peer influence, asthma responsibility, and sleep quality). We hypothesize that childhood predictors from Aim 1 will continue to influence asthma control in adolescence and that less peer influence, greater asthma responsibility, and better sleep quality will more strongly influence positive asthma control trajectories in adolescence. In Aim 3, we will use data from the adolescent cohort to explore the association between sleep behaviors and asthma control, and examine how congruence between caregiver and adolescent sleep beliefs influences this link. We hypothesize that greater sleep quality (Model 1) and sleep efficiency (Model 2) will predict better asthma control and that higher congruence will strengthen this association. Findings from this study will lay the foundation for developing interventions that optimize asthma control trajectories during the transition from childhood to adolescence. The research and training plan will equip the applicant with the skills to become an independent researcher specializing in pediatric health disparities through training in advanced statistics, adolescent health management, and sleep research methodologies.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative condition that results in rapidly progressive muscle weakness and, ultimately, death from respiratory failure within 2-5 years of symptoms onset. The VCU Department of Neurology runs the largest ALS clinic in the region and, over the past 4 years, began witnessing an uptick in incident ALS cases. In partnership with the ALS Association, we analyzed the spatial distribution of ALS in Virginia. We identified apparent spatial ALS clustering with the highest relative risk of 3.75 for developing ALS in these “hotspots.” It should be mentioned that ALS has a global incidence of 2 per 100,000. There is mounting evidence that ALS stems from a combination of genetic susceptibility, age-related cellular damage, and environmental exposure. We, therefore, investigated whether local environmental factors contributed to increased ALS risk in these “hotspots.” Analysis of drinking water samples from households of ALS patients from this cluster identified elevated levels of a plasticizer dtBHQ (2,5-ditert-butylhydroquinone). At this point, it is unknown how dtBHQ appears in drinking water in these regions, but a reported application of dtBHQ is in the coatings of water pipes. Nonetheless, the presence of dtBHQ is intriguing, given some reports that at high doses, dtBHQ can cause muscle weakness and damage motor endplates in rats. Next, we investigated whether low-level exposure to dtBHQ could cause motor impairment in laboratory animals. Using a Zebrafish model system, we found that dtBHQ at nanomolar concentrations decreased touch-evoked response and caused shortening of primary motor axons and reduced branching indicative of motor circuit dysfunction. These preliminary results led us to propose a central hypothesis that the presence of a plasticizer dtBHQ in the environment of ALS clusters activates molecular mechanisms that cause motor neuron toxicity, contributing to the elevated risk of ALS in these hotspots. We are applying under Funding Option B and our proposal meets both of the RFA-TS-25-036 funding objectives by identifying a potential environmental risk factor for ALS and investigating how this risk factor contributes to the pathophysiology of ALS. Thus, for this investigation, in Aim 1, we will investigate the environmental and occupational risk factors in our ALS clusters through deep qualitative interviews. We will also compare this data with the National ALS Registry Epidemiological data of registrants from Central Virginia and the National cohort. In Aim 2, we will collect water specimens from households in ALS clusters and analyze them for dtBHQ levels and the presence of other toxicants. In Aim 3, we will investigate whether sustained, low-level exposure to dtBHQ activates neurotoxic pathways that cause motor neuron toxicity and lead to the expression of ALS-like phenotype using zebrafish and mice as model systems. This study will provide new data on the presence of a novel environmental toxicant and its role in elevating the risk of ALS in humans.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Substantial resources have been devoted to developing effective youth violence prevention (YVP) programs over the past 30+ years. However, firearm-specific risk factors were largely overlooked in the development of these programs due to previous barriers to studying firearm violence. This is concerning as firearms are a leading cause of injury and mortality among youth. There is a dire need to develop effective prevention strategies for intentional firearm injuries, particularly strategies that address cross-cutting risk factors for firearm-related violence and suicide. Rather than re-inventing the wheel, it is logical and feasible to enhance existing YVP programs to address firearm-specific risk factors for intentional injury. This project will use youth participatory action research to develop and test the preliminary effectiveness of SAFE Futures, a single-session intervention that will address cross-cutting risk factors for intentional firearm injuries from violence and suicide. A randomized controlled trial will be conducted to determine whether adding SAFE Futures to an existing YVP program for high-risk youth, Emerging Leaders, reduces firearm violence and suicide above and beyond Emerging Leaders alone. Importantly, this project will also examine the economic efficiency of SAFE Futures. SAFE Futures has great potential to be a cost-effective, resource-efficient tool to enhance YVP programs’ effectiveness in preventing intentional firearm injuries among youth. This project is closely aligned with CDC’s research priorities for interpersonal violence and cross-cutting prevention. The findings will inform an R01 proposal to conduct a larger RCT of SAFE Futures that builds on the proposed work. Importantly, this award will enable Dr. O’Connor, a promising early-stage investigator, to acquire skills and knowledge in community-engaged and qualitative research methods, clinical trials research, economic analysis, and cross-cutting risk factors for firearm injuries. Virginia Commonwealth University and its Level 1 Trauma Center provide a rich context for Dr. O’Connor’s career development, which is bolstered by a multidisciplinary team of expert mentors with substantial expertise relevant to her research and career goals and a successful track record of mentoring junior faculty into independent investigators. Ultimately, this K01 award will equip Dr. O’Connor with the training and protected time necessary to initiate a high-impact program of research on strategies to prevent intentional firearm injuries among youth.

NIH Research Projects · FY 2025 · 2025-09

Myotonic Dystrophy Type 1 (DM1) is a progressive, multisystemic disorder caused by a toxic CUG repeat expansion in the 3’UTR of the DMPK gene that leads to dysregulated RNA splicing. Therapies targeting knockdown of the DMPK transcript have gained traction with multiple Phase I/II studies releasing positive results. Related approaches that interfere with the interaction between toxic repeat and RNA splicing proteins have entered clinical trials. Notably, all of these trials currently include a fairly homogenous population of adults with DM1. This leaves clear gaps in the ability for the entire community to access these promising therapies. The Center is designed to bring these therapies to the entire community. We have identified a sparsity of natural history and biomarker data in children with DM1 as one clear gaps in trial readiness. We also have identified that genetic modifiers of disease severity and therapeutic efficacy may also be a gap in the investigation of these therapies. The projects will benefit from the significant ongoing and prior efforts by the Center Investigators, the Myotonic Dystrophy Clinical Research Network (DMCRN) and the international community to achieve successful completion. Project 1 will enroll 150 children with congenital myotonic dystrophy or childhood onset into a two-year observational study. Participants will be followed with measures of motor function, cognition, and quality of life. In a subset of children with childhood myotonic dystrophy we will expand prior efforts to validate a composite measure of RNA splicing, the Splice Index, into this population. In Project 2, we will leverage six prior or nearly completed studies to perform a genome wide association study (GWAS) with over 1600 DM1 participants. We will identify genetic variants that contribute to variation from the predicted relationship between selected phenotypes and the repeat length. In parallel we will identify genetic variants that influence the efficacy of therapeutics currently in clinical trials. We will confirm identified variants in animal models of DM1. The combined projects, including prior efforts within the Center will be deposited into a biorepository that will be disseminated through the resource core along with supportive phenotypic and genomic data. The resource core will also provide access to the Splice Index, the biomarker of choice for ongoing therapeutic trials. The training core will focus on developing a pipeline of myotonic dystrophy scientists through summer didactic courses in bioinformatics and clinical trial design and will support a 1-year clinical research fellowship in myotonic dystrophy. The administrative core will provide the website that will serve as the portal into the Center, provide resources to execute these multinational projects, and will use virtual platforms to link the investigator teams. Combined, these cores and projects are linked synergistically to achieve the shared goal to prepare the entire DM community for these advancing therapies, including populations that currently have access to disease modifying therapeutic trials. Given the absence of available therapies and high unmet need in myotonic dystrophy, there is urgency to move these objectives forward.

NIH Research Projects · FY 2025 · 2025-09

Summary/Abstract The limb girdle muscular dystrophies (LGMD) are a group of over 30 genetic muscle diseases which share a pattern of weakness affecting proximal muscles of the shoulders and hips. LGMD type R1 (LGMDR1) is the most common LGMD and is caused by mutation of the calpain 3 gene. There is no FDA approved treatment for LGMDR1, and patients experience progressive weakness and muscle wasting which can lead to loss of the ability to walk or maintain a job. Excitingly, recent advances in other muscle diseases give hope that LGMDR1 patients can be treated with gene therapies that replace the calpain 3 gene to restore its function to muscle. Five research groups already have calpain 3 gene replacement therapies in pre-clinical development. Additionally, non-specific therapies targeting muscle mass or function are in development for related diseases which may also prove beneficial for LGMDR1. Unfortunately, despite this excitement, the pace of therapeutic development has outpaced our ability to prepare for and evaluate efficacy in clinical trials. Towards this, there is a great need to develop muscle-based molecular and imaging biomarkers that can facilitate LGMDR1 clinical trials. Our goal in this Ancillary Project is to leverage the large LGMD natural history study of our Parent Project into reasonably validated molecular and imaging biomarkers with prognostic, predictive and pharmacodynamic value for LGMDR1. To accomplish this, we urgently need to add muscle biopsy, serum discovery assays, and MRI-based imaging protocols into that study. Doing so will allow us to benchmark molecular and imaging-based readouts against Clinical Outcome Assessments as well as Patient Reported Outcomes taken at the same time. Specifically, we plan to 1) assay properties of calpain 3 in muscle, 2) discover proteins and miRNAs that are disrupted by disease, and 3) assay quantitative MRI biomarkers in relation to upper limb function as well as muscle inflammation. All patients are followed longitudinally over a period of one year in order to correlate change in serum and MR biomarkers to change in clinical outcomes, with a focus on the North Star Assessment for LGMD as a functional measure. We are uniquely positioned to accomplish this project through our parent project “TREATing LGMDR1” and our LGMD Research Network (GRASP-LGMD), which is made up of 12 sites with standardized evaluator training. We hypothesize that calpain 3, molecular pathways, and MRI-based measurements will provide sensitive monitoring biomarkers that reflect disease progression and response to treatment. Our rationale is that by benchmarking biomarkers against clinical outcome assessments we can identify reasonably likely surrogate endpoints to facilitate therapeutic development.

NSF Awards · FY 2025 · 2025-09

This Developing and Testing Innovations project will continue the development of a nonvisual interface for the Scratch educational programming environment. Drag-and-drop programming environments like Scratch have done much to lower the barrier to learning and increase engagement for a variety of students. Such resources support K-12 students' exploration and preparation for careers in computer science, and in many other science, technology, engineering and mathematics fields that require programming skills. This project will continue the development of a tangible, nonvisual programming interface to allow blind and visually impaired (BVI) students to fully and independently participate in the same Scratch learning opportunities as their sighted peers. A key component of the approach is to translate visual aspects of Scratch into the haptic domain, focusing specifically on elements known to increase engagement and lower hurdles to learning programming and taking into account the differences in how the haptic and visual sensory systems process information. In addition, resources will be developed for teachers who may have students using the nonvisual interface alongside those using the visual interface for Scratch, including provision of some best practices. The goals of the project are threefold. First, the project will continue to develop the nonvisual interface for Scratch through a) using user feedback and observations of a two-day programming camp for BVI middle school students held at the end of the previous project term to improve the system design, b) automate components of the interface previously implemented using Wizard of Oz methods, and c) add components designed to increase engagement of a wide variety of learners, in a similar manner to visual Scratch. Second, the project will develop teaching resources, including curricula, support materials and training videos for K-12 teachers; these resources will incorporate how to integrate instruction for nonvisual and visual interfaces, and best practices for paired programming with the nonvisual interface. Third, the project will develop mentoring and educational guidance resources for students using the nonvisual interface. All of these components will be developed through the use of universal and participatory design techniques, as well as evidence-based design. Multiple five-day camps for mixed groups of BVI and sighted students will be held at collaborating science centers to provide an objective measurement of the effectiveness of the interface and teaching materials developed, and provide insight into the requirements for widespread deployment. This project is funded by the Innovative Technology Experiences for Students and Teachers (ITEST) program, which supports projects that build understandings of practices, program elements, contexts and processes contributing to increasing students' knowledge and interest in science, technology, engineering, and mathematics (STEM) and information and communication technology (ICT) careers. 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 · 2025-09

PROJECT SUMMARY We aim to develop a novel fenofibrate-loaded microemulsion (Feno-ME) eyedrop as a new, non-steroid treatment for nitrogen mustard (NM)-induced corneal injury. NM is in the list of the Chemicals of Concern (CoC) in NIH CounterACT. Ocular exposure to NM causes a range of complications including corneal ulceration, corneal neovascularization (NV), corneal opacity, chronic inflammation, and eventually blindness. Effective interventions to treat vesicants-induced ocular injury have not been developed yet, which highlights the need to establish effective treatment options. Our previous studies reported that PPARα agonist fenofibrate confers anti- inflammatory, anti-angiogenic effects and promotes corneal wound healing. We demonstrate that PPARα levels are decreased in the cornea with NM-induced wound and fenofibrate alleviates corneal neovascularization and opacity in rats with NM-induced corneal injury. These observations suggest that PPARα has an important therapeutic function in the cornea and is a promising drug target for NM-induced corneal injury. Here we have developed a novel fenofibrate microemulsion (Feno-ME) with high drug loading and excellent stability. We hypothesize that Feno-ME eyedrops are effective on corneal ulceration, corneal NV, corneal opacity, and suppressing inflammatory and angiogenic biomarkers in the cornea exposed to NM. In Aim 1 (UG3), we plan to validate PPARα signaling as a drug target for NM-induced corneal injury and optimize the Feno-ME eyedrop formulations. In Aim 2 (UG3), we will investigate Feno-ME eyedrops for the treatment of NM-induced corneal injury in rabbit model and identify a lead Feno-ME and optimize the regimen of administration. To facilitate the translation to human use, Aim 3 (UH3) targets the development and characterization of an NM-induced corneal wound model in minipigs, and verify the efficacy the lead Feno-ME identified in UG3 in a minipig model. Lastly, in Aim 4 (UH3), we intend to determine the pharmacokinetic profile and toxicity of the lead Feno-ME eye drop in minipigs. These studies will identify a new drug target for the treatment of NM-induced corneal injury and promote repurposing fenofibrate for the treatment of mustard-induced corneal injury.

NIH Research Projects · FY 2025 · 2025-09

Opioid overdose deaths continue to be a major public health problem in the US requiring improvements in treatments for opioid use disorder (OUD). Despite current medication for addiction treatment (MAT), treatment dropout and substance use recurrence rates remain high. Thus, novel therapeutics to augment MAT to improve treatment outcomes and reduce opioid overdose deaths are needed. Prior research suggests that 5-HT2A and mGluR5 receptor antagonists could be useful in reducing impulsive responses to drug cues, improving negative emotionality, and reducing the overall rewarding value of reinforcing stimuli, and through these mechanisms improve treatment retention and reduce relapse in patients with OUD. Vivozon Inc, has developed VVZ-2417- a new chemical entity, which has a high selectivity for 5-HT2A and mGluR5 antagonism. In preclinical studies, VVZ-2471 reduces morphine self-administration, drug-induced reinstatement of morphine self-administration after forced abstinence, and morphine withdrawal symptoms precipitated by naloxone. In human studies, single and multiple ascending dose studies showed VVZ-2471 to be safe in healthy controls with the most common adverse events being dizziness and gastrointestinal symptoms, with no serious adverse events. Taken together, preclinical, and early clinical safety data all support further research on VVZ-2471 as a potential treatment for OUD. This project, which is a collaboration between Vivozon Inc and Virginia Commonwealth University, will establish preliminary safety and early efficacy data to support VVZ-2471 phase II clinical trials for a future NDA with the indication as an adjunctive treatment with buprenorphine for OUD. UG3: Specific Aim 1. Establish the preclinical safety of VVZ-2471 when administered in combination with opioids. Milestone 1. Completion of safety and drug-drug interaction (DDI) study in rodents for VVZ-2471 when administered in combination with buprenorphine and separately with fentanyl. Specific Aim 2. Complete human data collection and protocol development for IND submission for human phase Ib studies. Milestone 2. Completion of a 30-day chronic dosing safety study in controls with no study drug related SAEs or unanticipated problems affecting the UH3 IND. Milestone 3. Opening the IND without clinical hold for Phase 1b UH3 studies. UH3: Specific Aim 3. Assess VVZ-2471 as an adjunctive treatment with buprenorphine in OUD participants in a double-blind, randomized, placebo-controlled, double-blind phase 1b acute inpatient study assessing effects of adjunctive VVZ-2471 (vs. placebo) on the PK and PD properties related to safety in OUD patients stabilized on buprenorphine. Specific Aim 4. Complete a 14-day double-blind, randomized, placebo-controlled outpatient extension of the trial of participants in Aim 3, assessing chronic safety as the primary outcome with secondary outcomes of impulsivity, negative emotionality, and opioid cue-related attentional bias, and exploratory outcomes of opioid craving, subjective reward, withdrawal symptoms, non-prescribed substance use.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Primary sclerosing cholangitis (PSC) and primary biliary cholangitis are characterized by biliary fibrosis, which involves activated cholangiocyte signaling with immune cells. Insufficient understanding of the transcriptomic and lipidomic changes in activated cholangiocytes that orchestrate signaling with the immune cells is a major barrier for developing effective therapies for biliary fibrosis. Transforming growth factor-β (TGFβ), a key mediator of fibrosis, activates cholangiocytes to produce fibroinflammatory signals. Our preliminary data show that Runt- related transcription factor 1 (RUNX1) expression is increased in models of biliary fibrosis and PSC livers. RUNX1 inhibition reduces the upregulation of fibroinflammatory signals in TGFβ-activated and PSC-derived cholangiocytes. RUNX1 inhibition in a mouse model of biliary fibrosis reduces the hepatic peri-portal infiltration of immune cells and markers of hepatic injury. The effects of RUNX1 may be further facilitated by its upregulation of stearoyl-CoA desaturase-1 (SCD1) and lipid signaling. Treatment with an SCD1 inhibitor, Aramchol – an agent with a well-established safety profile in clinical trials – results in reduced fibroinflammatory markers in mouse models of biliary fibrosis. Therefore, we hypothesize that RUNX1 plays a crucial role in the activation of cholangiocytes by coordinating an interdependent transcriptomic and lipidomic program that stimulates immune cells. To test this novel hypothesis, we propose two specific aims. In aim 1, we will investigate RUNX1 co-regulators of gene expression and the full spectrum of RUNX1-dependent fibroinflammatory pathways in TGFβ-activated cholangiocytes. Using a biliary epithelial-specific Cre, we have generated cholangiocyte- selective Runx1 genetic deletion to study immune cell recruitment and activation, and fibrosis in mouse models of biliary fibrosis. We will also determine the direct effects of cholangiocyte RUNX1-induced signals on macrophage activation and Th17 cell differentiation using in vitro co-culturing of primary cells and spatial transcriptomic and single cell RNA-seq analyses of PSC and mouse model livers. In aim 2, we will determine if TGFβ-RUNX1 signaling directly regulates SCD1 expression and function, and effects on cholangiocyte fibroinflammatory lipidomics. The effects of SCD1 on cholangiocyte lipidomics and fibroinflammatory signals will be investigated in mouse models of biliary fibrosis using Aramchol and Scd1 genetic deletion. TGFβ-induced transcriptomic and lipidomic changes in cholangiocytes will be integrated to better define the roles of RUNX1 and SCD1. Further elucidation of these transcriptomic and lipidomic regulatory mechanisms will advance our grasp of biliary fibrosis and support the development of effective therapies. Therefore, our proposal is consistent with the objectives of NIDDK in understanding and developing therapeutic avenues for hepatobiliary diseases. Additionally, this proposal will allow a promising physician-scientist to gain expertise in the epithelial immunology, lipidomics, and transcriptomics of biliary fibrosis under the expert guidance of highly dedicated mentors to successfully transition to an independently funded physician-scientist with a unique research program.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY / ABSTRACT More than 38 million American adults are diagnosed with Type 2 Diabetes (T2DM), and about 98 million have prediabetes. One factor for poor outcomes may be social determinants of health, such as food insecurity, associated with suboptimal diet quality and elevated glucose levels. T2DM prevention program focusing on self-management education and lifestyle behavior changes is the cornerstone to achieving glycemic control ─ assessed by glycosylated hemoglobin (HbA1C), which reflects the average blood glucose level over the previous three months. However, evidence suggests that T2DM prevention programs are heterogeneous in design and implementation and provide inconsistent effectiveness in improving glycemic control. Our team's research indicates that many adults experience improved dietary habits, enhanced food security, and reduced blood glucose levels after participating in a 6 to 12-week Prescription Produce Program (PPP). This community-based nutrition intervention provides health education, wellness and goal setting, and fresh fruits and vegetables to low-income adults with chronic diseases. We aim to fill the gaps in existing literature regarding the effectiveness of integrating a PPP into a diabetes prevention program to enhance glycemic control for individuals with prediabetes. We are expanding on our team's initial work on the PPP to incorporate this nutrition intervention into the Diabetes Prevention Program. This evidence-based diabetes prevention program has been implemented at over 1500 sites nationwide. Building on our team’s multi-disciplinary expertise and experience serving low-income adults from minoritized racial/ethnic groups, we propose a feasibility and pilot mixed methods using a randomized controlled trial and two focus groups. The study aims to evaluate the feasibility, acceptability, and preliminary effectiveness of a DPP that integrates a PPP (DPP+PPP) compared to a DPP only control group. Aims 1 and 2 focus on the feasibility, acceptability, and preliminary effectiveness among N=100 Adults with prediabetes. Aim 1 examines the feasibility and acceptability of DPP+PPP compared to a DPP only on recruitment, enrollment, attendance, retention rates, and treatment fidelity markers. Aim 1 also uses a qualitative methodology with n=20 participants to understand barriers/ facilitators of engaging in the study. Aim 2 examines the preliminary effects of the DPP+PPP versus DPP only blood glucose and weight changes. This study is important because DPP+PPP's innovative delivery method could potentially be more effective and acceptable for wider implementation. Diabetes prevention strategies such as this, addressing social determinants of health, may empower individuals to engage in early symptom self-management. This pragmatic study aims to test a diabetes prevention intervention among adults with pre-diabetes, with the potential for translation to a larger-scale community-based intervention.

NIH Research Projects · FY 2025 · 2025-09

TITLE: C18-Ceramide as an essential factor in iron dependent cell death Abstract Ferroptosis is a novel form of regulated cell death in which labile iron-dependent accumulation of phospholipid peroxides in membranes is lethal. Despite its involvement in many physiological and pathological processes, there is serious deficiency in understanding the molecular mechanisms, especially controlled by bioactive lipids, that regulate ferroptotic cell death. The long-term goal of this project is to discover the fundamental biochemical mechanisms by which the bioactive sphingolipid ceramide controls iron metabolism and ferroptosis. In preliminary studies, we found that CerS1, which specifically generates C18-ceramide, is required for ferroptosis. In addition, our preliminary results suggest that ceramide can interact with NCOA4, the adaptor protein for selective ferritin degradation in lysosomes (ferritinophagy) for labile iron generation, a key step in ferroptosis. Based on our preliminary data, we generated the novel hypothesis that CerS1-generated C18- ceramide is a crucial regulator of ferritinophagy and subsequent ferroptosis through its interaction with NCOA4, and that targeting CerS1 can mitigate ferroptosis. To test this hypothesis, we propose the following Specific Aims: Aim 1: Establish C18-ceramide as an essential factor for ferroptosis and identify the subcellular localization of the C18-ceramide pool responsible for this activity. Aim 2: Define the role of C18-ceramide–NCOA4 interaction in regulating ferritinophagy and elucidate the molecular mechanisms underlying this interaction. Aim 3: Determine the molecular mechanisms activating CerS1 in ferroptosis. Overall, these studies will establish CerS1 and C18- ceramide as key factors controlling ferroptosis via a novel lipid-protein interaction and define the biochemical basis of this control mechanism. In addition, the knowledge generated from this study will be essential for designing mechanism-based novel therapies centered around modifying ferroptosis through targeting CerS1 in diseases where ferroptosis is a central factor for pathological adverse conditions.

NIH Research Projects · FY 2025 · 2025-09

Project summary/ Abstract The overarching goal of this K99/R00 proposal is to explore aggregate genetic liability and neurocognitive mechanisms in the co-occurrence of alcohol use/problems and suicidal thoughts and behaviors (STB). Excessive alcohol use is prevalent worldwide and represents a significant burden to human health; it is associated with medical and psychopathological problems such as STB. STB are a critical public health concern, with a continuing increase in suicide attempts and deaths every year in the US. The prevalence of STB is particularly high among individuals with alcohol problems and studies have tackled this question from different perspectives. Research indicates that alcohol problems could causally impact risk of STB; there is also empirical support for a shared genetic liability between alcohol use/problems and STB. This shared genetic liability underscores the existence of possible common mechanisms that would be involved in both alcohol use/problems and STB. Decision-making (DM) has been observed in relation with adolescent drinking behavior and alcohol use disorder, while both have been associated with STB. In STB research, DM difficulties have been described and may be characteristic of impulsive suicide attempts, but current findings largely rely on self-reports and lack objective evaluations. Additional knowledge could be gained by relying on a theoretical conceptualization of DM, a systematic evaluation of its underlying neurocognitive mechanisms, and a consideration of the role of genetic factors. Capitalizing on genetics and neuropsychology, we will explore which DM mechanisms play a role in alcohol use/problems and STB co-occurrence, how genetic liability is involved in this association, and whether environmental factors may influence the development of DM and its relation with alcohol use/problems and STB. An improved understanding of these processes will contribute to prevention and intervention efforts by advancing our ability to target potentially modifiable mechanisms according to the influence of genes and environment. This proposal delineates a series of training aims to advance our understanding of the co-occurrence between alcohol use/problems and STB: 1) the candidate will establish expertise in the assessment of aggregate genetic risks and other genetic models, and in advanced statistical methods that will lay the foundation of her independent career; 2) different suicide phenotypes will be used and distinguished according to their association with alcohol use, neurocognitive, and genetic characteristics; 3) the K99/R00 proposal gathers experts in the disciplines of genetics and neuropsychology that will support the development of the scientific project and the pathway to independence. The environment at the Virginia Institute for Psychiatric and Behavioral Genetics is ideal for the candidate’s goal of developing a comprehensive program in genetics, alcohol, and STB research, and the proposed project represents an important contribution toward advancing the understanding of alcohol use/problems and STB through a combination of genetics and neuropsychological methods, consistent with NIAAA’s missions.

NSF Awards · FY 2025 · 2025-09

In the “Beyond Moore’s Law” era with increasing edge intelligence, domain-specific computers in heterogeneous fabrics will rule the roost. Algorithms accelerating NP-hard (i.e., provably complex) applications or pre-compute processes that do not demand exact precision will run on tailored hardware. The hardware performance, rather than the algorithmic or software efficiency, may dictate solution speed, energy cost, footprint, and cyber-resilience. Clever hardware innovations for application-specific integrated circuits (ASICs) are no longer a rarity, but they all employ conventional material platforms like silicon, insulators, and compound semiconductors. This proposal will explore a new prospect – the use of quantum materials with exotic properties – to elicit computational activity with unprecedented size, weight, and power (SWaP). Additionally, innovative technologies and methods to train students in lab procedures through virtual platforms (e.g. GoPro video sessions, kid-friendly Minecraft and Roblox design challenges) will be developed and posted on YouTube and Vimeo for the public. Students selected through online exercises will be evaluated using rubrics developed by learning centers at the universities and sent to the Army Research Laboratory (ARL) and the National Institute of Standards and Technology (NIST). For the hardware needs of modern computing and artificial intelligence to be “self-contained”, all the data and resources needed to execute a computing task should be available in situ and not have to be fetched from a remote server or “cloud” which may be unreliable or unavailable. One powerful paradigm that satisfies many or all of these requirements is “processor-in-memory (PiM)”, where compute happens right at the memory site. The project plans to design, simulate, fabricate, characterize, and experimentally demonstrate a processor-in-memory architecture implemented by heterogeneously integrating a topological insulator (TI) (a quantum material) with nanomagnets and a piezoelectric material. The nanomagnet enables storage and the piezoelectric enables gating, while the TI brings in both high spin-selectivity and voltage tunable bandgap. The device is projected to perform logic operations and image processing with ultralow footprint and energy cost. A new and powerful PiM-based on a novel genre of materials with unusual quantum mechanical properties will be developed, which can be leveraged to outperform other PiMs in energy consumption, footprint and speed. This PiM will be built, characterized and its superior performance demonstrated. New light will be shed on the physical properties of these quantum materials to stimulate further research to benefit computing hardware. 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.