Virginia Commonwealth University

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Idiopathic Pulmonary Fibrosis (IPF) is a progressive scarring disease with limited therapeutic options. Fibrotic lung diseases are characterized by an accumulation of excess extracellular matrix (ECM), contributing to the destruction of lung architecture, inability to perform gas exchange, and even death. My mentor published pioneering work that IPF patients have abnormally high levels of lactate in their lungs. Lactate in turn decreases the local pH, which activates latent TGFβ, resulting in a pro-fibrotic feed-forward loop that drives fibrosis and dysregulated metabolism. We and others have demonstrated that increased tissue stiffness in lung fibrosis also drives fibroblast differentiation, expression of matrix proteins, and cross-linking, resulting in further increases in tissue stiffness. While tissue stiffness and altered lactate metabolism are independently recognized as pathogenic pathways and potential therapeutic targets, I have now identified the mechanoreceptor Piezo2 as a potential link between altered tissue mechanics and aberrant metabolism. In this revised project application, I will use patient-derived non-fibrotic and IPF lung fibroblasts to characterize the mechanism by which Piezo2 drives metabolic adaptations in response to increased matrix stiffness, and how these metabolic adaptations contribute to a feed-forward loop that drives fibrosis. I will also use well-characterized pre-clinical mouse models of pulmonary fibrosis to investigate the role of Piezo2 in vivo using genetic knockdown and pharmaceutical inhibition approaches. To further support the clinical relevance of my results, the metabolic adaptations identified in the cell culture and mouse models will be compared with my new evidence of metabolic disruptions in the lungs of IPF patients obtained by metabolomics analysis of exhaled breath condensate. This project will support my career goal to transition to a tenure-track faculty position as an independent investigator. To complete my technical training needs for this project, I will work with my co-mentor Dr. L. Ashley Cowart to participate in extensive hands-on training in metabolomics data analysis, as well as attend training courses at the highly regarded West Coast Metabolomics Center at UC Davis. My co-mentor Dr. Patricia Sime will guide me in my professional development as an independent scientist by providing additional training opportunities in translational research, grant writing and scientific communication, lab management and administration, teaching, and mentoring others. I have established a strong mentor committee and strong relationships with internal and external collaborators. Virginia Commonwealth University is a highly productive scientific environment and is very supportive of my development as an independent scientist. My training and research experience under this career development award will yield novel insights into the pathogenic mechanisms of pulmonary fibrosis, giving me foundational skills and my own research project to carry me into independence.

NSF Awards · FY 2025 · 2025-09

This project examines how exposure to scholarly forecasts about artificial intelligence's (AI's) impact on labor markets shapes perceptions, decision preferences, and intended behaviors among U.S. workers, business managers, and decision makers. Research into how AI will affect the workforce is important for public debate and individual and business decisions, but it is unclear how such research influences the beliefs and decisions of key stakeholders. The findings of this study clarify how such research informs—or complicates—critical decision-making by these groups. To support broad understanding and practical use of the findings, the project includes development of a public-facing online portal with plain-language summaries of major AI forecasting studies and interactive tools, allowing users to compare labor forecasts across industries, occupations, and demographic groups. The project contributes to national priorities related to AI leadership, the future of work, and science communication, while mentoring students. The research draws on insights from labor economics, science of science, and public administration to design a set of multi-sample online survey experiments targeting three distinct stakeholder groups: workers in non-managerial roles, business managers responsible for organizational decisions, and regulatory decision makers. Participants first answer questions assessing their knowledge, beliefs, and attitudes about AI. They are then randomly exposed to brief informational vignettes based on real-world academic forecasts about AI's labor impacts. Treatments vary by predicted level of disruption, groups identified as most affected, framing of AI’s role, and whether the predictions presented are consistent or conflicting. Participants subsequently answer follow-up questions on AI-related beliefs, regulatory preferences, and stakeholder-specific outcomes. The project advances U.S. leadership in responsibly navigating AI innovation. 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 Urinary urgency is the defining symptom in Overactive Bladder (OAB) which affects nearly 25% of the US population and proportionately more women than men. Current treatments for OAB are lacking with the majority of patients quickly withdrawing from drug treatments due to poor efficacy or side effects. When initial treatments fail, appropriate patients may be offered sacral neuromodulation (SNM) which involves implantation of a neurostimulator at the S3 nerve root. The majority of these devices require reprogramming (remotely manipulating the amplitude or lead stimulation pattern) to restore efficacy, thus preventing discontinuation or removal of the expensive device. There are no objective tools to optimize reprogramming, individualize treatments, or predict long-term outcomes with SNM. Currently, pelvic and perineum sensation is the only guiding feature for reprogramming and articulating the location and sensation details to providers in this anatomic area can be difficult. SNM is thought to work by generating signals to interrupt abnormal afferent (toward the brain) neural signals relaying sensations of bladder urgency. Components of this abnormal neurologic response to increases in urinary urgency can be measured in the prefrontal cortex (PFC) of the brain. Functional near-infrared spectroscopy (fNIRS) is a non-invasive tool capable of detecting brain signal changes during increased urgency and SNM programming in the PFC. Therefore, establishment of non-invasive methods with fNIRS to detect real-time neural responses to acute reprogramming, which are then correlated with long- term treatment success, have the potential to transform OAB treatment in terms of efficacy, quality-of-life, and cost-effectiveness. Furthermore, incorporating improved tools for mapping the pelvic and perineal sensation changes during reprogramming can better quantify these sensations and allow for prediction modeling. The proposed research has three aims: (1) To develop novel fNIRS analytics to identify PFC patterns associated with acute SNM adjustments and correlate these patterns with treatment responses (2) To develop an instrument for correlating perineal and pelvic sensation to acute SNM programming and treatment response, (3) To develop a model to predict acute SNM programming responses using clinical, fNIRS, and sensory analytic data. The tools developed in this innovative study will have applications for optimizing treatments in other forms of urgency and voiding dysfunction. The PI, Dr. Burkett, is an Early-Career Investigator and Urogynecologist physician. This career development award will fill gaps in her training necessary for her transition to independence in neuroexcitation research related to bladder and voiding dysfunction. Specifically, Dr. Burkett will seek further structured training and mentorship in fNIRS analysis and application, instrument design and implementation, predictive model computation, professional development, and responsible conduct of research. She will work closely with her multidisciplinary mentorship team to complete her training goals and research aims.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT The current opioid crisis in the United States is primarily fueled by synthetic opioids such as fentanyl, its analogs, and non-fentanyl novel synthetic opioids (NSOs). These substances are highly potent mu opioid receptor (MOR) agonists, often labeled as super agonists, and are linked to side effects including euphoria, tolerance, constipation, and respiratory depression leading to opioid use disorders (OUD). Standard treatments, like naloxone (NLX), frequently prove insufficient, highlighting the pressing need for new and more effective treatments for OUD. However, a significant gap in knowledge remains regarding the behavioral pharmacology and activation mechanisms contributing to the extreme potency of these synthetic opioids. For the Avenir Award, I propose to develop MOR selective bitopic ligands that bind to both orthosteric and allosteric sites of the MOR. These ligands will serve as novel pharmacological probes and tools, potentially offering improved therapeutic outcomes. Our focus is on the 2-benzylbenzimidazole scaffold, also known as nitazene, whose derivatives were initially developed in the 1950s as potent analgesics but later abandoned due to their high addictive potential. Applying computational chemistry and molecular modeling, we demonstrated that nitazene agonists may bind to a novel positive allosteric site in addition to the orthosteric site in the active MOR, explaining their ultra-high potency at the MOR. We have designed, synthesized and characterized a series of nitazene analogs and identified novel chemical entities capable of antagonizing morphine, fentanyl, and the nitazene agonist etonitazene. Computational studies of these antagonists revealed that they may bind to a novel negative allosteric site as well as the orthosteric site in the inactive MOR. These interactions differ from the binding mode observed with NLX and explain at least in part NLX’s sub-optimal efficacy in counteracting the ultra-high potency synthetic opioids. Thus, our pilot studies have established the proof-of-concept that the 2-benzylbenzimidazole (nitazene) scaffold can be adapted to modulate the MOR function. This project aims to comprehensively investigate the nitazene scaffold by integrating computational modeling, synthetic chemistry, and cellular and behavioral pharmacology. The study will focus on understanding the structure-activity relationships (SAR) that govern the binding and function of nitazenes. This research represents a pioneering effort to study bitopic ligands as a strategic molecular approach. The outcomes of this project will establish the nitazene pharmacophore as a foundation for refining MOR function and deliver transformative insights and knowledge to the field. The project aligns well with the Avenir Award's goal of fostering forward-looking research, as it seeks to address urgent needs, including enhancing our understanding of novel mechanisms of receptor activation and inhibition, supporting the development of novel therapeutics for OUD, safer analgesics and proactive harm reduction strategies. Furthermore, the research holds the potential for broad applicability of bitopic ligand development across other class A G-protein coupled receptors (GPCRs).

NIH Research Projects · FY 2025 · 2025-08

Project Summary Stimulant use disorder (SUD), defined as the patterned use/abuse of psychostimulants such as cocaine, methamphetamine, or prescribed amphetamines, is an epidemic that directly affects around 2.5 million people in the United States. Currently, there are no FDA-approved pharmacotherapies for SUD. Signaling through the neurotransmitter dopamine (DA) in the mesolimbic circuit brain regions, the nucleus accumbens (NAc) and ventral tegmental area (VTA), is necessary for the maintenance of SUD. Muscarinic acetylcholine receptors (mAChRs) in the NAc have been shown to modulate the dopaminergic tone in the region and decrease cocaine preference in rats. Of the five subtypes of mAChR, the M1 and M4 receptors show promise as pharmacological targets for the treatment of SUD. These two receptors are located on the dendritic spines of medium spiny neurons (MSNs) within the NAc and are fed by inputs from cholinergic interneurons (CINs). MSNs are projection neurons containing either D1 or D2 DA receptors, which mediate the direct (reward) and indirect (aversion) reward pathways, respectively. Previously, the modulation of mAChR activity has been shown to reduce cocaine choice in rodents. The M1-preferring agonist xanomeline, for example, has been shown to lower preference for cocaine in rodents. However, not only does this produce undesirable peripheral side effects, the highly conserved orthosteric binding site makes subtype-selectivity difficult. Allosteric modulators of mAChRs effectively solve both problems and could prove valuable for the treatment of SUD through attenuation of cocaine-dependent increases in DA signaling in the NAc. Two mAChR PAMS, the M4- selective VU0152100 and VU0364572, have both been shown to reduce cocaine preference in a drug versus non-drug reinforcer assay and to reduce DA in the NAc using microdialysis. Here the following hypothesis is proposed: Administration of mAChR-selective compounds will reduce cocaine-dependent increases in reward signaling by modulating M1 and M4 mAChRs located on MSNs in the NAc. Aim 1 will determine the ability of these two compounds to reduce the cocaine-dependent alterations in DA levels and dynamics in the NAc using fiber photometry with the GRABDA fluorescent label for DA activity. Aim 2 will explore the differential role that mAChR modulation may have on Ca2+ signaling D1- and D2-containing MSNs using fiber photometry on D1- and D2-Cre rats.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The prognosis of patients with advanced head and neck squamous cell carcinoma (HNSCC), including oral cancer, remains poor. Radiation therapy (RT) is widely used for clinical management; however, recurrence occurs frequently in patients with advanced diseases. While the rich immune infiltrate often seen within these tumors designates them as prime candidates for immunotherapy such as immune checkpoint inhibitors (ICIs), the response rates in patients with recurrent, metastatic disease is low, indicating an unmet clinical need for developing novel approaches to improve outcomes. In this application, we propose to address these challenges using a novel immune PRIME agent (i.e., Flagrp170), in which a unique microbial pattern recognition sequence is built into a superior antigen-delivery platform, to immunologically program the tumor microenvironment to enhance HNSCC responsiveness to standard of care (i.e., RT, ICIs). This first-in-class multi-functional agent possesses distinct features for optimizing and sustaining immune activation (e.g., forcing cancer cells to produce and secrete a foreign molecule carrying tumor antigenic fingerprints, thereby revitalizing the function of antigen- presenting cells) while concurrently reversing tumor-induced immunosuppression. We will investigate a newly engineered human version of this agent therapeutically and mechanistically to support its bench-to-bedside translation. To accomplish our goal, we will evaluate the immunotherapeutic activity of hFlagrp170 administered intratumorally using multiple oral cancer models and investigate its mechanism of action in orchestrating innate and adaptive antitumor immunity. We will study the interplay between cancer cells and the immune system governed by this microbial chimeric molecule and a less studied microbial pattern recognition signaling pathway. To prevent the tumor recurrence that is often associated with advanced HNSCC following RT, we will leverage the unique property of hFlagrp170 to promote the immunogenicity of cancer cell death and transform the immune landscape of irradiated HNSCC to amplify the ‘abscopal’ response of RT. Additionally, we will use hFlagrp170 to potentiate HNSCC susceptibility to ICIs by increasing tumor-reactive T-cell repertoire and provide mechanistic insights into the hFlagrp170-induced T-cell ‘inflamed’ tumor phenotype. Since an RT and ICI combination regimen being tested extensively in the ongoing trials has yet to show clinical benefits, we will evaluate a tripartite anti-HNSCC approach by capitalizing on the superior immune programming activity of hFlagrp170 to achieve a robust and durable antitumor response. The successful completion of this project is anticipated to establish a scientific framework for rapid translation of this immune PRIME agent, which not only will expand the toolbox of Immuno-Oncology, but also can potentially revolutionize the current treatments of advanced HNSCC.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD, previously Non-Alcoholic Fatty Liver Disease or NAFLD) affects 30% of people globally. Among these, 1 in 4 have a more severe form of the disease, Metabolic dysfunction-Associated Steatohepatitis (MASH). MASLD and MASH strongly associate with high caloric intake and are highly comorbid with obesity, metabolic syndrome, and type II diabetes. The onset of MASLD is insidious, incurable and it affects a massive proportion of the global population. Persons with MASLD are at increased risk of osteoporosis and fracture. Given the high prevalence of MASLD and massive osteoporosis-related healthcare spending, MASLD-associated skeletal fragility exerts substantial socioeconomic impact. The mechanisms by which skeletal fragility arises in MASLD and MASH are not understood, owing largely to the lack of an appropriate preclinical model. Most mice do not develop MASLD from conditions mimicking the human disease. Uniquely, the Diet Induced Animal Model of NAFLD (DIAMOND) mouse, will develop MASLD and MASH on a high-fat Western diet alone, like humans. The DIAMOND mouse mimics the human phenotype of MASLD and MASH exceptionally well. Using these mice, we demonstrated significant deleterious changes in mechanical strength and geometries of bones from DIAMOND mice fed a high-fat Western diet. In this study, we aim to elaborate histologic bone changes and liver-bone crosstalk driving skeletal fragility in MASLD and MASH. Further, we will describe the role of estrogen in the development of MASLD-associated skeletal fragility, and its role in the sexual dimorphism of the liver and bone phenotype of DIAMOND mice. Finally, we will investigate the skeletal effects of GLP-1 analogs, extremely popular drugs in MASLD management, in mice with MASLD. In Aim 1, we will conduct a longitudinal assessment of the progression of skeletal fragility in DIAMOND mice with MASLD. We will assess bone morphology, biomarkers of bone metabolism, and liver bone crosstalk. These analyses will be correlated with the progression of MASLD on liver histology. In Aim 2, we will leverage the clinical observation that women are relatively protected from skeletal sequelae of MASLD to elaborate a protective role of estrogen. We will ovariectomize female DIAMOND mice to assess the effect of estrogen withdrawal on MASLD-associated skeletal fragility. We will use the same liver and bone phenotype, serum biomarker, and pathway analyses described in Aim 1 to assess the role of estrogen withdrawal in the progression of MASLD bone disease. In Aim 3, we will determine the extent to which GLP-1 analogs rescue bone loss in MASLD via similar outcomes to Aims 1 and 2. While many observational analyses have recently been conducted on bone disease in MASLD, this proposal will be the first prospective study to assess its molecular mechanisms. We aim to discover candidate pathways for novel, effective therapies for this disease.

NIH Research Projects · FY 2025 · 2025-08

Abstract Firearm-related violence is a major public health problem in the United States. In 2022, over 48,000 people died from firearm-related violence. Beyond the significant and devastating cost of human life, firearm-related violence is an enormous economic burden to the US, costing tens of billions of dollars every year. The rates of violence have risen during the pandemic, and youth have been hit hard by the rise in violence. Homicide is the leading cause of death for African American young males (10-19 years; CDC, 2024), and 7 out of 10 people treated in the hospital for firearm-related injuries were victims of assault. Once discharged from the hospital, victims of violence are 88 times more likely to retaliate violently, and 40% will be reinjured within five years, thus perpetuating the cycle of violence. Therefore, hospitals have become a critical resource to prevent retaliatory firearm violence among high-risk youth. However, high-risk youth are often challenging to engage in intervention, which is why new and innovative strategies are needed to meet youth where their interests are. The goal of the present proposal is to evaluate a virtual reality (VR) violence prevention program, Elevate VR, to prevent incidents of firearm-related violence among youth. Elevate VR is a brief hospital-based violence intervention that engages violently injured youth in culturally relevant immersive stories and gameplay, all while teaching youth psychoeducational skills and using biofeedback (i.e., positive youth development, online and in-person de- escalation training, emotion regulation skill building, trauma management, gun safety awareness, etc.). Elevate VR provides the connection between an immersive individual-level intervention and exposure to community resources tailored to the youths’ local community. This study will conduct a randomized control trial including 360 violently injured youth and their caregivers (N=720) to assess the effectiveness of Elevate VR for preventing firearm-related violence, injury, and mortality in high-risk violently injured youth. The study also aims to identify risk and protective factors that are most malleable (mediators) to change in response to Elevate VR. This knowledge is critical for improving the intervention by more efficiently targeting risk and protective factors. Lastly, we aim to assess the economic efficiency of Elevate VR as a brief hospital-based firearm-related violence prevention strategy. The results from this study may support the use of Elevate VR as a cost-effective strategy for preventing firearm-related violence, injury, and mortality among youth victims of violence.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Adolescents experience high prevalence of obesity and associated chronic diseases, such as type 2 diabetes mellitus, with persistent sociodemographic disparities that begin in childhood and affect quality and length of life. Intensive health behavior and lifestyle treatment (IHBLT) is recommended, with improved treatment responses observed with increasing intervention intensity and duration. As such, the US Prevention Services Taskforce and the American Academy of Pediatrics (AAP) both recommend >26 hours of treatment over 3-12 months. Usually, each “dose” occurs via in-person visits. Pediatric primary care is an ideal setting for IHBLT given family familiarity of services and trust with pediatric primary care practitioners (PPCPs). Unfortunately, clinic-based obesity interventions often have insufficient follow-up related to access barriers (e.g., transportation, childcare, inability to leave work or school, practitioner clinic capacity), reducing their effectiveness. Additionally, clinical advice given without knowledge of the family’s home and community environment is often impractical. Based on our extensive formative work, we propose a redesign of pediatric primary care adolescent obesity treatment, called “Virtual Housecalls.” Virtual Housecalls (VHC) augments typical in-person visits to achieve 26 contact hours: 1) with direct-to-patient video telehealth to tailor behavioral counseling to families’ home and community context, 2) that leverages certified behavior coaches as a part of the care team, and 3) that engages adolescents and caregivers in skill building in real-time within the home environment. The current application will test VHC in a pragmatic randomized clinical trial with 250 adolescents ages 12-15 years with class 1 (non-severe) obesity (BMI≥95% and <120% of the 95%) and a participating parent/caregiver. VHC includes 26 hours of treatment, by combining in-person PPCP visits (every 3m) with 6m of virtual visits conducted by a behavior coach (3m weekly, 3m every 2 weeks), and weekly exercise videos. The control arm will receive enhanced treatment as usual (TAU+), which includes usual care by their PPCP, augmented with publicly available education, sent on an attention-matched contact schedule. All PPCPs will receive training on the AAP Clinical Practice Guideline for obesity treatment and reports of participant progress at 3, 6, and 12m. Assessments of anthropometrics, dietary intake, physical activity, parenting and the home environment will be completed at 0, 3, 6 (post-intervention), and 12m (maintenance), with the primary endpoint at 6m. We will evaluate the efficacy of VHC on adolescent change in body mass index (primary outcome) and dietary and physical activity behaviors (secondary outcomes). We will also evaluate how treatment dose impacts BMI reduction. Results will advance NIDDK’s mission to reduce health disparities via a transformative, patient-centered treatment paradigm to address obesity-related health disparities in adolescents.

NIH Research Projects · FY 2025 · 2025-08

Project summary It’s estimated that more than 30% of cancer-associated pathways involve intrinsically disordered proteins (IDPs) whose lack of structural information poses a major obstacle to rational drug discovery. An example is the fusion protein EWS-FLI1 that is the driver of the childhood cancer Ewing Sarcoma. Although there are some small molecules that engage EWS-FLI1 with moderate potency, the lack of structural validation has recently called their mechanism of action into question. NMR is the ideal technology for characterizing IDPs; however EWS-FLI1’s size, structural disorder, and prevalence of repeat sequences yields extensive peak overlap that challenges conventional resonance assignment strategies. Technologies exist to reduce this spectra crowding, but they either lack selectivity (labeling/unlabeling all residues of a given type) or require mutagenesis which alters protein structure and spectra. This proposal focuses on developing a new technology, termed codon-specific isotope labeling, that overcomes these limitations by segregating isotope labels at the codon rather than the residue level. Each isotopologue (14N, 15N, 15N13Cα) produces a distinct signal (no peak, singlet, or doublet, respectively) in the 2D HSQC spectra that facilitates rapid resonance assignment from a small number of samples. And, as amino acid isotopologues rather than mutants, they do not modify the protein structure or spectra. Our published work shows that the six leucine codons can be split to encode five different isotopologues on small-scale, but significant barriers remain to applying this technology for NMR-scale protein production. The overall goal of this proposal is to establish this technology using EWS- FLI1 as a model IDP cancer target. Aim 1 focuses on the leucine codons. Using a commercial extract-based in vitro translation system, we will first optimize the yields and incorporation efficacy of green fluorescent protein (GFP) using fluorescence and ESI-MS. Following optimization, the technology will be applied to EWS-FLI1. The focus of Aim 2 is to expand our technology to two amino acids overrepresented in IDPs, serine and glycine, by dividing their codons into three isotopologues each. We hypothesize these residues will cluster by type in the 2D HSQC spectrum to enable multiplex codon-specific isotope labeling. This proposal will culminate in the comprehensive structural characterization of EWS-FLI1 in complex with each of the putative two small molecule inhibitors YK-4-279 and TK216. This proposal will establish codon-selective labeling as a new powerful strategy for deconvoluting NMR resonance assignments of IDPs, opening the door to drug discovery for the many IDPs involved in cancer.

NIH Research Projects · FY 2026 · 2025-08

Project Summary. Many important drug targets including protein-protein interactions (PPIs) are still intractable with modern drug discovery methods. In vitro selection technologies, in particular mRNA display, have proven to be powerful methods for discovering macrocyclic peptides that target PPIs. The extreme diversity of mRNA-displayed macrocyclic peptides (10s of trillions of individual peptides) allows rapid generation of a high-affinity hit where other technologies fail. For this reason, mRNA display has been increasingly employed as a tool for lead development in pharmaceutical companies worldwide. Unfortunately, while these hits have high affinity for their targets, they typically greatly exceed even the most generous beyond rule of 5 (bRo5) parameters for drug-likeness. This is because mRNA display relies on in vitro translation to create the diverse libraries and is constrained in monomer diversity by the genetic code. Therefore, accessing the high diversities required to identify hits built from 20 monomers requires random regions of at least 10 residues (20^10 = 10 trillion). To get into the bRo5 space one needs to create shorter peptides of <6 monomers, which are significantly less diverse (20^6 = 64 million). This proposal leverages our expertise in in vitro translation to expand the genetic code in order to increase monomer set available for mRNA display from 20 to >40, dramatically enhancing the diversity of short macrocyclic peptides within the libraries (40^6 = 4 billion) . Our prior research shows that by combining hyperaccurate ribosomes and in vitro transcribed tRNAs one can dramatically break apart the degeneracy of the code. Our first research goal is to leverage these resources and tRNA engineering move as close to a one codon-one amino acid paradigm as possible. A second research area also aims to build monomer diversity through the addition of unnatural base pairs (UBPs). The goal is to show that at least 10 UBP codons are amenable to mRNA display, further enhancing the potential monomer diversity. The third direction focuses on the creation of a strategy for prioritization of monomers to use with a given mRNA-displayed peptide library. This will be achieved by first screening for small molecule fragments that bind followed by appending these fragments onto amino acid side chains within the library. The inclusion of known binding fragments as side chains will improve the affinity and specificity of the downstream hits. Each of the three research goals will utilize model protein targets to validate they are useful within the context of mRNA display. This research is expected to give new, valuable insights into the malleability of the genetic code and the translation apparatus towards engineering. The research will also enable the creation of diverse, bRo5 compliant libraries with monomers tailored to a given target, enabling the downstream discovery of many new drug-like macrocyclic peptide leads to currently intractable targets.

NSF Awards · FY 2025 · 2025-08

Forests provide substantial economic and ecological benefits to human society, including timber resources, wildlife habitat, and water quality regulation. However, an increasing frequency and severity of disturbances that kill trees (such as storms, pests, wildfires, and droughts) threatens the sustainability of these resources and services. This project combines existing field experiments and a recent ice storm in the forests of northern Michigan to evaluate how forest structure and productivity are affected by interacting disturbances. The project is focused specifically on how aspects of prior disturbances, such as timing and severity, might affect the response of the forest to subsequent disturbance. An improved understanding of the effect of interacting disturbances on forest structure and productivity will be highly beneficial to forest scientists and managers in predicting and managing for the effects of changing disturbance regimes. Openly available technical resources are being produced that focus on helping land managers and commercial foresters predict the outcomes of disturbances, such as ice storms, on the sustainability of our forest resources and develop management strategies to promote future forest resilience. Training is being provided to graduate and undergraduate students and a post-doctoral researcher with applicability to future careers in sustainable forest resource and land management, geospatial analytics, and data science. In addition, the data produced in the project and the field experiments at the University of Michigan Biological Station are an open training resource available to a large number of students, researchers, and educators. This project leverages a significant ice storm disturbance and multiple existing long-term ecosystem-scale disturbance experiments at the University of Michigan Biological Station to better understand the effect of prior disturbance severity, pattern, and timing on forest ecosystem structural and functional response to compounding disturbance. Mounting evidence indicates that changing frequency and scale of disturbances is producing more common and extensive instances of compounding disturbance, with uncertain consequences for core ecosystem functions. Based on prior work and preliminary data, forest ecosystem productivity is hypothesized to be more resistant to ice storm disturbance where prior experimental disturbance was: 1) less severe, 2) more focused on the lower canopy stratum, and 3) less recent. Study plots in the three existing disturbance experiments span gradients in prior disturbance timing (6-116 years prior), severity (0-85% basal area loss), and directionality (top-down vs. bottom-up) providing a novel template and extensive existing data resources on which to build an analysis of subsequent disturbance outcomes. In each experiment, the project is tracking change in forest NPP (relative to controls and pre-ice storm baselines) and shifts in structural and functional characteristics that are hypothesized to underlie variable resistance. To address these questions the project is utilizing existing long-term data resources, remote sensing-based analysis of forest canopy structural and functional change using terrestrial lidar and the National Ecological Observatory Network Aerial Observation Platform, and field plot-based assessments of tree damage, vegetation response, and wood production. The data and outcomes of the project are being used, in collaboration with regional and national forestry practitioner communities, to develop and deliver science-based management strategies focused on forest resilience to emerging and compounding disturbance regimes. 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

There is growing evidence connecting certain components of air pollution (AP), such as particulate matter less than 2.5 microns or nitrogen dioxide, and breast and lung cancers in the United States (US). This evidence represents an identified link between highly unavoidable environmental exposures and cancer risk because the air we breathe is ubiquitous. Additionally, the scale of the problem of AP is considerable as it is responsible for approximately 6.5 million deaths per year globally. However, in contrast to the design of most previous research, people do not experience one component of AP in isolation but are exposed to it from multiple sources at once and over their life course. To date, there has been no systematic assessment of the totality of AP exposures on cancer risk in the US. Further development of advanced data science and analytics methods is required to understand how fine-scale AP exposures affect cancer outcomes in a potentially spatially varying manner. The proposed Pathway to Independence Award for Early-Stage Postdoctoral Researchers will provide valuable and interdisciplinary training to Dr. Boyle and will position him as a leader in spatial data science for cancer risk with special emphasis on Big Data sources and environmental exposures. The mentored phase of this proposed research will consist of training in (1) toxicological skills to harmonize AP measurements, (2) the biological and epidemiological background of cancer through coursework, (3) Big Data management for AP database querying and processing, (4) causal inferential techniques for estimating AP mitigation policy efficacy, and (5) grant writing and professional development. The research component will leverage the received training skills to answer the public health questions motivated above: (Aim 1) Design comprehensive, spatially-driven pollutant exposure metrics for census geographies across the US, incorporating information from the Risk-Screening Environmental Indicators and Criteria Air Pollutants databases and aggregating by race/ethnicity/socio-demographic characteristics to identify differences in comprehensive exposure for top candidate locations for mitigation; (Aim 2) Develop novel spatial statistical models to test the associations of these metrics with county-aggregated incidence/mortality rates of breast/lung cancers, in order to identify where AP exposure is most linked with cancer risk; (Aim 3) Create new spatial causal inferential models to estimate the effects of strategies such as reducing certain releases or facility clustering, or increasing targeted cancer screening uptake on cancer rates nationwide. Combined, the training received and research performed in this proposal will provide Dr. Boyle with a strong basis for an independent line of research and subsequent R01 proposals focused on environmental exposures, spatial analysis, data science techniques, and mitigation of cancer risk. Importantly, this proposal is supported by an experienced and well-funded team of mentors and scientific advisors who will support Dr. Boyle in his proposed training and research activities and also by the collaborative research environment at Massey Comprehensive Cancer Center and Virginia Commonwealth University.

NSF Awards · FY 2025 · 2025-08

This award supports the Richmond Geometry Meeting: New Trends in Homological Invariants scheduled for September 19-21, 2025, hosted at Virginia Commonwealth University in Richmond, VA. The conference is designed to foster connections in algebraic geometry, low-dimensional topology, and mathematical physics amongst experts from a variety of institutions and career stages. The conference will include plenary lectures delivered by internationally recognized experts and will showcase new mathematical developments in the area. Vertical integration will be encouraged by a Career and Mentorship Panel and a poster session that exhibits work of early-career researchers. The proposed Richmond Geometry Meeting will feature novel research in geometry and topology inspired by recent advances in theoretical physics. In the last half-century, the study of string theory and dualities has motivated a steadily increasing number of breakthroughs in our understanding of geometry and topology, including homological mirror symmetry, the geometric Langlands program, and, more recently, the quantum invariants of plumbed 3-manifolds of Gukov, Pei, Putrov, and Vafa. Prior editions of the Richmond Geometry Meeting included reports on advances in knot theory, algebraic geometry, and string theory, such as the study of braid varieties, Khovanov homology, complex Chern-Simons theory, lattice cohomology, and the GW/DT correspondence. The current edition of the Richmond Geometry Meeting is designed to provide an opportunity for mathematicians and physicists to disseminate cutting-edge research connected to physically-inspired new homological invariants. This award supports the fifth edition of the Richmond Geometry Meeting, providing a platform for the dissemination of the latest findings in this dynamic realm of research. The conference is designed to bring together mathematicians at various career stages, from undergraduates and graduates to postdoctoral scholars to recognized leaders in the field. Plenary lectures will highlight the work of internationally renowned experts, while strategic use of travel funds and targeted structuring of the scientific program will encourage participation of scholars from the mid- and southern-Atlantic regions of the United States. The meeting will feature a poster session open to all graduate students and postdoc participants and a Career and Mentor Panel, with panelists including an early-career faculty, a senior faculty, and mathematicians working in industry. For more information, please visit the Richmond Geometry Meeting website: https://math.vcu.edu/rgm 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

ABSTRACT This application is for a Mentored Clinical Scientist Research Career Development Award (K08) for Dr. Lauren Katz. She is currently conducting research on craniofacial skeletal muscle and has observed that this muscle type has a unique regenerative program compared to muscles of the limb and trunk. This K08 will enhance Dr. Katz's ability to 1) become an expert in craniofacial muscle stem cells and regeneration, 2) conduct basic science research at the highest level in a tissue rarely studied, 3) acquire cutting-edge skills in stem cell techniques including single-cell RNA sequencing (scRNA-seq) and ex vivo cell transplantation, 4) gain skills in proposal development, manuscript preparation, and data presentation, and 5) develop a high-quality independent research program that will allow for collaborative opportunities with scientists and clinicians from across disciplines. To achieve these goals, Dr. Katz has devised a clear and focused training plan and has identified individuals who are experts in the aforementioned disciplines. Her multidisciplinary mentoring team consists of: Drs. James White (basic scientist, skeletal muscle regeneration and stem cells), William Maixner (clinician-scientist, oral and craniofacial research), Shannon Wallet (basic scientist, oral and craniofacial research), Elisabeth Barton (basic scientist, skeletal muscle regeneration), Kevin Byrd (clinician-scientist, oral stem cells), Lyndon Cooper (clinician-scientist, oral stem cells), Eric Everett (basic scientist, oral biology), Jimena Giudice (basic scientist, skeletal muscle research), and Simon Gregory (basic scientist, scRNA-seq). There exists a clinical need to rebuild functional craniofacial muscle in patients suffering from certain diseases (muscular dystrophy, hemifacial microsomia), facial trauma, and tumor resections. The lack of a comprehensive investigation of the craniofacial musculature and its stem population has resulted in a poor understanding of the regenerative capacity of this tissue when faced with disease or trauma. Our current knowledge of skeletal muscles and their stem cell populations comes from the limb muscles; however, it is known that distinct differences in embryological origin exist between muscles of the limb and those of the craniofacial region. Therefore, the objectives of this study are to use injury models to elucidate the in vivo regenerative capacity of craniofacial skeletal muscle and to perform deep phenotyping on isolated craniofacial satellite cells to identify molecular targets specific to craniofacial muscle regeneration. Regenerative capacity will be assessed using in vivo models of muscle regeneration and in vitro cellular function assays (Aim 1). scRNA-seq and ex vivo stem cell transplantation will be utilized to identify craniofacial muscle-specific regulators of myogenesis (Aim 2) and identified targets will be investigated using lentiviral vectors and knockout models (Aim 3). Together, the K08 training and mentorship will enable Dr. Katz to transition into an independent research career and become a leader in the field of craniofacial muscle regenerative medicine and translational therapeutics.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is the third leading cause of global cancer mortality, with a higher prevalence in males. Although immunotherapy has lately broadened the landscape of liver cancer treatment, therapeutic resistance and a lack of accurate immune biomarkers remain a significant challenge due to HCC heterogeneity and sexual dimorphism. Owing to the current obesity endemic, metabolic dysfunction-associated steatohepatitis (MASH) has become the fastest-growing cause of HCC. Recently, we identified sphingosine kinase 2 (SphK2), which generates the bioactive sphingolipid sphingosine-1-phosphate (S1P), as a critical determinant of sexual dimorphism in MASH-driven HCC; SphK2 is tumor-protective in females and tumor-inducing in males. In addition, preliminary data showed that SphK2 deletion in male livers reduced the immuno-suppressive M2-like polarization of macrophages and promoted an antitumor phenotype. This led to the hypothesis that liver macrophage SphK2 mediates a pro-tumorigenic microenvironment in HCC. In Aim 1 (F99 phase), the sexually dimorphic role of SphK2 in liver macrophages will be examined in macrophage-specific SphK2 deleted male and female mice using our chronic Western diet model that recapitulates the progression and molecular hallmarks of MASH-HCC in humans. In-depth analyses will determine how SphK2 affects macrophage functions in response to Western diet, macrophage-hepatocyte cross-talk, and immune cell flux in the tumor microenvironment. Furthermore, the proposal will investigate the mechanism for SphK2-mediated regulation of liver macrophages to understand how targeting SphK2 could repolarize macrophages and enhance HCC anti-tumorigenicity. Aim 2 (K00 phase): Owing to the emerging role of immunometabolism as a central mechanism in immune-oncology, the K00 phase will focus on studying macrophage metabolic networks in the HCC tumor microenvironment to uncover novel immunotherapy targets. The study will consider different HCC models in males and females to emphasize on HCC tumor heterogeneity and sexual dimorphism. The F99 doctoral training will involve the study of diet-induced HCC model, primary cell isolation and culture, macrophage characterization, sphingolipid signaling, and epigenetic regulation. Building upon the F99 proposal, my post-doctoral training will involve the study of various HCC animal models, macrophage metabolomics, cell-signaling networks, and immune cell cross-talks to modulate the HCC tumor microenvironment. Collectively, the integrated research plan and training of my F99/K00 proposal will establish my career as an independent researcher and provide an opportunity to extend the boundaries of therapeutic resistance and sex-based cancer immunotherapy.

NSF Awards · FY 2025 · 2025-08

The goal of this project is to develop CueLearn, an educational web application that will foster effective peer collaborations to improve mathematical problem solving amongst middle school students. Research suggests that learning is often better and longer lasting when students engage in well-scaffolded, shared, and collaborative learning experiences. However, educational technologies do not often leverage this research, with the focus most often being on the individual rather than a group. The CueLearn project will thus develop, test, and implement two intelligent strategies to improve students' collaborative problem solving: 1) facilitating effective student collaborations through the creation of effective peer groups within CueLearn, and 2) using real-time supports to increase student engagement and help students persist productively. The project's key aim is to design a system that will easily facilitate quality peer collaboration for all students, while also supporting teachers in their use of technology for collaborative work. The project focuses on social learning experiences by automatically assigning students to work with optimized peer groups. Multiple grouping strategies will be tested through a series of observational studies and experiments to identify which grouping strategy works best. For example, students may be grouped based on their intended problem-solving strategy, so that students will be exposed to diverse approaches from peers who are using different strategies. However, intelligent student grouping methods may not be effective for learning by themselves, unless students are also provided with additional support during problem solving. Machine learning approaches will therefore be used to monitor engagement and detect unproductive forms of persistence in real-time in order to provide in-the-moment support as needed. Critically, these supports will be co-designed with students. Automated ideal grouping combined with just-in-time supports are hypothesized to improve students' problem solving performance and mathematical beliefs. Through all of these design innovations, the project aims to provide a new and effective educational technology for students and teachers. The Discovery Research preK-12 program (DRK-12) seeks to significantly enhance the learning and teaching of science, technology, engineering and mathematics (STEM) by preK-12 students and teachers, through research and development of innovative resources, models and tools. Projects in the DRK-12 program build on fundamental research in STEM education and prior research and development efforts that provide theoretical and empirical justification for proposed projects. 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

PROJECT SUMMARY Visual diagrams are playing an increasingly dominant role in providing information in education, employment and daily living. Unfortunately, individuals who are blind or visually impaired (BVIs) experience enormous obstacles in independently accessing this information, impacting their success in all aspects of their lives. The proposed project intends to addresses this critical need through the development of a low-cost system for the real-time automatic conversion of visual diagrams into accessible dual vibrotactile and enhanced visual forms rendered on aligned, refreshable tactile and visual displays, allowing BVIs to use touch, their residual vision or a combination of both to access graphical information. To ease the significant time and cognitive load required by users to interpret accessible diagrams, automated haptic guidance will be available to help BVIs explore a diagram through shared control with the user. Basic alt-text descriptions will also be available, both in Braille and in spoken form, to also support the effective exploration of the diagram. A participatory design approach will be used for the system’s development, involving BVIs and other stakeholders in: focus groups, low technology prototyping and user testing both in the laboratory and in the field. The display system will consist of a low-cost refreshable haptic display, previously developed in one of the PI’s laboratories, combining multi-fingered tactile feedback with shared control of movement between the user and haptic guidance fixtures (with user adjustable weightings) to which an enhanced vision display will be added. Machine learning will be used to convert visual diagrams to an accessible form useful for both lower level and higher-level thinking. To obtain a more effective model for conversion, the key component to our approach is to take advantage of the underlying structure of known diagram types, with separate models for graphs and charts (simple and highly structured), illustrations and photos (complex and least structured), and maps and engineering diagrams (focused on the connectivity of elements and using a symbol set). The R61 Phase of the project will focus on providing a beta version of the complete system for simple, high impact graphics (graphs and charts) through multiple design iterations with BVI user testing in the laboratory. The R33 Phase of the project will deploy the beta version in the field with BVI users to further assess and improve the design for real world use. This phase will also work on the development of conversion methods for illustrations and photos, and indoor/outdoor maps and engineer diagrams, again through multiple design iterations with BVI user testing the laboratory. Dissemination will also occur during this stage.

NSF Awards · FY 2025 · 2025-08

It is estimated that approximately one-third of the world’s gross domestic product involves passes through a catalytic processes at some stagereactor, and the majority of industrial chemistry relies on catalysts. Industrial catalytic processes—such as those used in the production of commodity and specialty chemicals, petroleum refining, pharmaceuticals, and pollution abatement—form the foundation of the global economy and standard of living. Most of these processes utilize heterogeneous catalysts. A significant portion of heterogeneous catalyststhese includesare supported metal catalysts, such aslike those used in automobile catalytic converters. These systems consist of nanoparticles made from expensive metals like platinum and rhodium, which are anchored onto stable, highly porous supports (e.g., aluminum oxide). In a catalytic converter, harmful exhaust gases—including carbon monoxide, nitric oxide, and unburnt hydrocarbons—are adsorbed onto the surface of these metal nanoparticles. There, they undergo chemical reactions that transform them into less harmful products: carbon dioxide, water, and nitrogen. Due to the high cost of the metals involved, the nanoparticles are engineered to be as small as possible to maximize surface area and catalytic activity. However, without anchoring the particles onto a support, these nanoparticles tend to coalesce at elevated temperatures, which significantly reduces their surface area and effectiveness. Developing improved supported metal catalysts is therefore both time-consuming and cost-intensive with the current state-of-the-art. The Center for Rational Catalyst Synthesis (CeRCaS) is tackling this challenge by seeking to understand the fundamental chemistry and engineering principles involved in synthesizing ultrasmall metal nanoparticles on supports. In systems requiring two metals—such as catalytic converters—CeRCaS also focuses on strategies to position both metals in close proximity to enable synergistic activity. These efforts aim to create a more rational, scientifically guided, and streamlined approach to catalyst development across the many industries that rely on heterogeneous catalysis. CeRCaS is composed of three university sites: The University of South Carolina (USC) serves as the lead site and houses the broadest range of catalyst synthesis methods along with high-throughput catalyst evaluation capabilities. Virginia Commonwealth University (VCU) is the second site and contributes specialized expertise in pharmaceutical catalysts, reactions, and processes. The third site, jointly operated by the University of California at Davis and Berkeley (UCD/B), provides deep expertise in metal/zeolite catalyst synthesis, which is particularly relevant to petrochemical applications. Together, these institutions bring complementary strengths to advance the science and engineering of heterogeneous catalyst design. 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: Sneathia vaginalis (Sv) is emerging as a pathogen that is significantly associated with preterm birth and preterm premature rupture of membranes. Due to its fastidious nature, it has only recently been recognized as a pathogen through the use of DNA-based methods. Because it has historically been under-recognized, the biology and the pathogenesis of S. vaginalis remain almost entirely uncharacterized. We have substantial evidence supporting that S. vaginalis damages host tissues, and damage to the amnion could play a causative role in preterm premature rupture of membranes. The goal of this application is to lay the foundation to characterize the damage that S. vaginalis causes to the cellular and acellular components of amnion and the effect that it has on the mechanical properties of amnion as a whole. To achieve this goal, we will delineate the time and dose dependance of damage inflicted by S. vaginalis on mitochondria and microtubules and define the type of cell death that exposure to the bacteria causes in Aim 1. In Aim 2, we will perform proteomics on proteins released from untreated and S. vaginalis-treated amnion to detect changes both in proteins secreted by the cellular components of amnion as well as changes in the integrity of the extracellular matrix components of the amnion. In Aim 3, we will quantitatively assess the mechanical properties of amnion and the effects that S. vaginalis has on those properties.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY / ABSTRACT The Virginia Commonwealth University (VCU) High Performance Research Computing (HPRC) core facility provides high performance computing resources and user support to 475+ researchers university- wide. The HPRC operates two main computing clusters: athena (general purpose computation) and fenn (biomedical research). The goal of this proposal is to replace the outlived 9-year old fenn cluster with a new state of the art computing cluster that will support ongoing projects and enable new research activities. The new cluster will accomplish the following: 1) renew and expand CPU computing and memory capacity, 2) add GPU computing (unavailable on the current cluster), 3) renew and expand the shared storage system, and 4) upgrade the network connectivity. The new equipment will make a significant impact on more than 38 ongoing NIH-funded projects (including 23 R01s) led by the 21 major and minor users supporting this proposal. The new cluster will meet a rapidly growing demand and need for research computing (98% utilization growth in 2023) in research areas such as genetics, genomics, sequencing, substance use disorders, computational structural biology, bioinformatics, biomaterials, cryo-electron microscopy, molecular modeling and simulation, cancer therapeutics, etc. The HPRC provides computing resources and support to many other faculty labs, core labs, and research centers in the biomedical research area such as the Genomics core, Cryo-EM core, Bioinformatics core, Rodent Behavioral Core, Cohort and Registry Administration Core, Biobehavioral Research Laboratory, Alcohol Research Center, Massey Comprehensive Cancer Center, Center for Biomarker Research and Precision Medicine, Center for Biological Data Science, Wright Center for Clinical and Translational Research, Center for Microbiome Engineering and Data Analysis, Center for Drug Discovery, Institute of Molecular Medicine, and the Virginia Institute for Psychiatric and Behavioral Genetics. By using computational modeling and analysis, researchers can dramatically accelerate their work, reduce the costs for wet-lab experiments, and shorten the period of drug discovery for diseases. A shared computational facility enables an environment to facilitate collaborations between scientists and enhance interdisciplinary and translational research at VCU. Renewed computational resources will also allow us to attract and retrain new investigators in biomedical research at VCU.

NIH Research Projects · FY 2026 · 2025-07

Opioid use disorder (OUD) is a leading cause of death, demanding improvements in OUD treatments. Medica- tions for OUD are life-saving; increasing their consistent utilization is the most effective pathway forward to combat this public health crisis. However, after treatment engagement, multiple factors can hinder outcomes, such as sleep problems and neurofunctional impairment that can leave patients at persistent overdose risk. NIDA has promoted targeting the mechanisms underlying each individual patient's addiction as an avenue to advance precision medicine and improve treatment quality. Targeting the orexin system is one mechanism that could ultimately lead to improved treatments. The orexin system is hypothesized to be a predominant mecha- nism linking poor OUD outcomes with disturbances in sleep/wake cycles and with other orexin-activity effects on reward-related neurofunctional domains known to underlie OUD. Consistent with this advancing science, our group has identified how insomnia exists as part of a constellation of symptoms related to neurofunctional dysfunctions among buprenorphine-treatment patients. Thus, we propose that targeting insomnia by way of orexin perturbation shows high potential to advance OUD medication development, such as via identifying tar- gets for adjunctive relapse prevention therapeutics to medications for OUD. However, how the orexin system and insomnia engage neurobiological mechanisms in humans with OUD has not been investigated. Using in- novative dynamic causal modeling, our group has identified a neurocircuit connectivity (Anterior cingulate cor- tex (ACC) to Hippocampus) that is associated with drug cue driven attentional bias in individuals with OUD, making this a promising marker in the evaluation of potential relapse prevention therapeutics. We propose herein a mechanistic study where we will recruit OUD treatment patients receiving buprenorphine with and without clinically significant insomnia (N=100). We will experimentally manipulate the orexin system using lem- borexant, a dual orexin receptor antagonist, which our group has found to be safe and tolerable with buprenor- phine in our Phase 1 clinical trial. We will rigorously measure sleep (actigraphy) and fMRI-based brain connec- tivity before and after randomization to 14 days of placebo or lemborexant added to their ongoing buprenor- phine treatment. Building from our group's extensive preliminary data, we propose that the effective (direc- tional) connectivity of the ACC to Hippocampus pathway, with its overlapping system involvements related to orexin, drug use, and sleep, represents an optimal primary outcome for this mechanistic trial in response to RFA-DA-25-044. In Aim 1, we will identify differences in this baseline drug cue-elicited brain connectivity be- tween insomnia groups. In Aim 2, we will determine whether pharmacologic orexin antagonism attenuates this connectivity, regardless of insomnia status. These mechanistic findings will characterize the interplay between insomnia, orexin and OUD in a buprenorphine treatment sample to advance the development of personalized relapse prevention therapeutics which are urgently needed in the ongoing overdose crisis.

NIH Research Projects · FY 2025 · 2025-07

ABSTRACT: Cocaine use disorder (CocUD) imposes significant medical, economic, and psychosocial burdens globally. Here we propose to explore the potential efficacy and safety of psilocybin, a serotonergic hallucinogenic compound found in psychedelic mushrooms, as a possible treatment for addiction to cocaine, which is a form of stimulant use disorder, but which we refer to herein as CocUD. Psychedelics are being explored as a novel therapy for mood, anxiety, and addictive disorders due to their ability to induce acute perceptual changes (i.e., a psychedelic effect). Studies suggest psychedelics may have lasting effects on behavior after only one or two doses. Psychedelics are generally safe and well-tolerated in human subjects, especially when used under medical supervision. Psilocybin may reduce cocaine consumption, potentially through emotional modulation, attentional bias alteration, and craving reduction via interactions with serotonin receptors and subsequent induction of neural plasticity. Our research will evaluate the treatment effects of psilocybin combined with psychedelic integrative therapy and cognitive behavioral therapy (Psy+T) for CocUD. The initial phase will involve a proof-of-concept randomized controlled trial focusing on safety, tolerability, a comparison of two doses (25mg and 40mg), and potential efficacy. If we are successful in reaching all milestone goals of the initial UG3 pilot study, we will progress to a larger trial (UH3) that aims to demonstrate efficacy and explore possible reasons for some patients responding better than others. Understanding how psilocybin influences attentional bias, craving, emotional states, mystical experience, and metacognition may lead to more effective personalized CocUD treatment strategies. We will use resting state and task-based functional Magnetic Resonance Imaging to explore ways to eventually personalize and optimize the treatment with precision.

NIH Research Projects · FY 2025 · 2025-07

Title: Comparative Experimental Evolution of Gene Essentiality in Streptococcus sanguinis and S. mutans Project Summary/Abstract Streptococcus sanguinis and S. mutans are important oral microbiota. Despite both belonging to the Streptococcal genus, these bacteria exhibit distinct roles in oral health, with S. sanguinis serving as a pioneer colonizer and commensal on teeth, while S. mutans is notorious for its major pathogenic role in dental caries development. The contrasting virulence in dental caries is underscored by the similarities and differences in their essential genomes. S. sanguinis SK36 possesses 218 essential genes (EGs), whereas S. mutans UA159 has 295. As key regulators for fitness and viability, EGs control the pathogenesis of these bacteria. However, our understanding of gene essentiality has been hindered by the traditional belief that generating EG-deletion mutants is impractical due to the indispensable nature of these genes for survival. Recognizing the quantitative characteristics of gene essentiality, we have recently developed a high-throughput method that enables the generation of dozens of EG deletion mutants in S. sanguinis SK36. We categorized the 218 EGs into three groups:186 “non-evolvable EGs”, 23 “evolvable EGs” and 9 “conditional EGs”, marking a significant advancement across the entire Streptococcus species. We hypothesized that A) the list of “evolvable EGs” and “non-evolvable EGs” and B) the profile of suppressor genes for the same “evolvable EGs” are different between S. mutans and S. sanguinis. Using an experimental evolution approach combined with whole-genome sequencing, we have identified >1000 suppressor mutation in evolved populations deled of “evolvable EGs” of S. sanguinis SK36. These suppressors were further be classified into three categories: “activation,” “inhibition,” and “unknown.” in the previous study. Our primary objective is to categorize the 295 EGs in S. mutans UA159, identify and classify corresponding suppressor mutations for its evolvable EGs. By examining essential gene mutants and their corresponding suppressors, we aim to construct a comprehensive functional network of gene essentiality. Through a comparative analysis of suppressor mutation profiles evolved in essential-gene mutants between S. sanguinis and S. mutans, our goal is to comprehend gene essentiality of these two Streptococcus species. This thorough examination will provide valuable insights into the conservation and diversity of essential gene functions within the broader context of Streptococcus biology. Ultimately, these findings will be instrumental in rational design of targeting S. mutans-specific anti-caries strategies by targeting EGs whose deletion is lethal in S. mutans, while leaving S. sanguinis unaffected or allowing for compensatory mechanisms through suppressor mutations.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY: Concussions are a significant health problem, with their incidence increasing largely due to a significant rise in adolescents. While most concussions resolve within two weeks, presentation is heterogeneous, and standard clinical assessments have yet to identify a true recovery window. Psychophysiological measures have the power to elucidate lingering and subtle sensorimotor and cognitive- affective impairments. These impairments may contribute to the increased risk (~2x) of subsequent musculoskeletal (MSK) injury observed in the months following concussion. However, the underlying mechanisms of the concussion-MSK injury relationship have yet to be fully established, leaving a critical need to illuminate potential deficits. This may ultimately identify who is at risk for acute subsequent MSK injury following concussion. The long-term goal of this proposal is to simultaneously characterize the persistence of concussion-related sensorimotor and cognitive-affective deficits while laying the foundation for identifying effective, clinically feasible markers of elevated MSK injury risk following concussion. The primary objective of this NINDS R01 application is to examine the utility of psychophysiological measures for detecting lingering sensorimotor and cognitive-affective deficits following concussion. Further, we will investigate their association with future risk for subsequent acute MSK injury. The rationale behind this proposal is our preliminary data, which demonstrates a suppressed brainstem-mediated general startle (GS) response following concussion, compared to healthy athletes. This suppressed GS provides evidence of post-concussion brainstem dysfunction and may reflect the lingering sensorimotor deficits that could be driving the elevated acute MSK injury risk. Additionally, risk for injury may also be influenced by higher order brain structures that project onto the brainstem and potentiate startle (SP) in response to unpredictable, environmental threats. Our preliminary data also indicates an exaggerated SP after concussion. Given that unpredictable threats in sports often come with higher injury risk, an exaggerated response may lead to high-risk movements and behaviors. This research study will pursue three primary specific aims: to use validated NIH psychophysiological measures longitudinally to (1) examine GS as a marker for lingering sensorimotor impairment in post-concussion adolescent athletes compared to both their own premorbid GS and healthy controls, (2) examine SP during unpredictable threat as a marker for lingering cognitive-affective impairment in post-concussion adolescents compared to both their own premorbid SP and healthy controls, and (3) investigate the utility of GS and SP as moderators of the increased subsequent acute MSK injury seen following concussion. This proposal is innovative in that it will use a pre-post, longitudinal approach to elucidate psychophysiological dysfunction and risk factors for subsequent acute MSK injury following concussion. This proposal is significant as it will further aid clinicians in identifying adolescent athletes who are at increased risk of post-concussion MSK injury.