Medical University Of South Carolina

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY The ongoing purpose of the Medical University of South Carolina (MUSC) Digestive Disease Training Program is to educate and mentor a cadre of researchers who will drive the future of liver and gastrointestinal (GI)-related biomedical research within three fundamental thematic areas: 1) Inflammation and Fibrosis; 2) Metabolic Disease; and 3) Organ and Tissue Failure. These themes are highly-relevant to major disease states affecting the health of the GI tract and liver and build upon the strengths of our established researchers. The emphasis of the program is to train graduate students in the art of basic biomedical research in a manner that will advance the study of the fundamental mechanisms underlying digestive and liver disease. Success will expand the pool of qualified digestive disease researchers and facilitate the development of novel treatments. Trainees will be selected from a pool of applicants that enter the MUSC College of Graduate Studies. After completing a basic biomedical sciences curriculum during their first year in as graduate students, trainees appointed to the Digestive Disease Training Program will take newly-developed courses that focus on digestive disease research and that complement their dissertation research projects. In addition, they will have access to courses offering instruction in professional development, experimental design and analyses, and rigorous, responsible conduct of research. Students’ coursework will be complemented with a number of enrichment activities including a Digestive Disease Seminar Series, a Journal Club, an Annual Digestive Disease Retreat, and numerous career development opportunities, such as a digital badge in science communication. The program will be supported by a growth in digestive disease research at MUSC that is driven by strategic institutional investments, programmatic support, and the recruitment of key faculty. MUSC’s robust clinical environment, collaborative research environment, and investments in numerous research cores will continue to advance digestive disease research on campus and provide trainees with a robust and scholarly training environment.

NIH Research Projects · FY 2026 · 2026-06

ABSTRACT The recent pandemic exposed the critical need for new and improved treatment interventions for chemosensory dysfunction affecting smell and taste. Smell/olfactory training has emerged as a widely prescribed intervention for hyposmia, a quantitative disorder characterized by a reduced ability to detect odors. Yet a significant gap exists in the evidence-based treatment of qualitative disorders including parosmia, a condition marked by the perceptual disturbances in odor valence that often lead to avoidance behaviors and a considerable decline in quality of life. Building upon evidence from the animal literature indicating a defined neural pathway for odor valence processing and odor-mediated behaviors, and from our preliminary work using transcranial focused ultrasound (tFUS) to modulate subjective ratings of odor valence, we propose an exploratory investigation of tFUS on the perception of odor quality and central processing of unpleasant odors. We will achieve our short- term goal of demonstrating the effects of tFUS through the following aims: Aim 1: to demonstrate the causal effects of tFUS of the amygdala on the perceived qualities of odors using subjective, neurophysiological and objective behavioral indices of odor valence and avoidance, and Aim 2: to demonstrate the causal effects of tFUS of the ventral striatum on the perceived qualities of odors using subjective, neurophysiological and objective behavioral indices of odor valence and avoidance. While our overarching goal is to develop an evidenced-based treatment targeting olfactory distortions in perceived odor valence and reducing negative emotional responses to odors, this preliminary research in healthy volunteers will evaluate whether we have the necessary tools and protocols in place to support future efficacy trials of tFUS in individuals suffering from parosmia. Our results may also provide insights and therapeutic strategies across a broader spectrum of sensory processing deficits and disorders.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Socioeconomically disadvantaged young adults (SDYA) are at a disproportionately greater risk of tobacco- related illness and disease compared to non-disadvantaged young adults in the U.S. Given that quitting smoking before age 30 reduces almost all of the mortality associated with ever smoking, understanding predictors of smoking cessation and relapse in SDYA who smoke is critical to preventing the escalation and continuation of tobacco use in this high-risk group. SDYA who smoke and are transitioning into young adulthood are vulnerable to experiencing a wide range of social-contextual stressors (e.g., financial stress), which can interfere with their motivation to quit and cessation efforts. In line with NIDA’s strategic plans to understand “how social determinants of health increase or decrease risk for addiction over the lifespan,” this MOSAIC K99/R00 grant application aims to provide empirical evidence on the social-contextual predictors of smoking cessation in SDYA who smoke. Social-contextual stressors may be dynamic in nature and vary daily or moment-to-moment. To understand how day-to-day changes in social-contextual stressors affect smoking cessation in SDYA, we propose to combine: a) qualitative interviews focused on the lived experiences of SDYA who smoke to better understand how specific social-contextual stressors are experienced in daily life with b) EMA of these stressors in a real-time, naturalistic environment. The specific aims of the K99 phase are to: 1) gain an in-depth understanding of how social- contextual stressors impact smoking cessation and relapse among SDYA who smoke and attempt to quit smoking in the natural environment; and 2) develop and evaluate the acceptability and feasibility of an EMA protocol. To achieve these aims, a mixed methods approach (qualitative interviews with 30-40 SDYA ages 18- 25 who smoke and previously tried to quit; a pilot EMA study and exit interviews with 15 SDYA who smoke) will be used to refine a protocol for a full EMA study. The R00 phase will include a larger-scale EMA study that will assess the impact of social-contextual stressors on psychopharmacological mechanisms of smoking cessation and relapse experienced at the event-level in 100 SDYA who smoke and are willing to make a serious quit attempt in the next 30 days. The PI, Dr. Mariel Bello, will work with an exceptional team of mentors (Drs. Rachel Cassidy, Suzanne Colby, Jennifer Merrill, Tim Janssen, and Andrea Villanti) to develop expertise in five areas of training: 1) mixed methods research (qualitative + EMA); 2) EMA methodology; 3) intensive longitudinal data analysis; 4) community-engaged research approaches; and 5) professional development skills. Successful completion of the research and training objectives detailed in this proposal will prepare Dr. Mariel Bello for a successful transition to independent faculty researcher, as well as further develop her program of research focused on investigating the etiology and underlying mechanisms of tobacco-related health disparities among marginalized groups. Findings will provide initial evidence on how event-level characteristics lead to smoking relapse in SDYA, which will serve as preliminary data for future R01 applications. 1

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Renal cell carcinoma (RCC) is a prototype for the study of epigenetic regulators as major drivers of the cancer phenotype. It is also a notable as a cancer with few effective treatment options, and high degree resistance to many traditional therapies. One important discovery in this cancer is high frequency mutation of SETD2, a histone methyltransferase that is the sole enzyme responsible for placing the histone H3 lysine 36 trimethylation (H3K36me3) mark on actively transcribed genes. We recently made the exciting discovery that SETD2 deficient RCC cells are exquisitely sensitive A1331852, a selective inhibitor for the antiapoptotic BCL-XL protein. Interestingly, we find SETD2 deficiency primes inflammatory signaling and alters cell cycle progression in RCC cells. BCL-XL inhibition further agonizes inflammatory signaling and induces lethal cell cycle transit that culminates in RCC cell death. We show that the activation CGAS-STING pathway is necessary for primed inflammatory signaling and sensitivity BCL-XL inhibition. The CGAS-STING pathway is key to initiating inflammatory signaling in response to certain cytoplasmic DNAs. Our data shows that loss of SETD2 alters mitochondrial dynamics to promote mtDNA leakage, which activates CGAS-STING in these cells. In addition to its antiapoptotic function, BCL-XL is known to delay cell cycle entry and progression. We show that cell cycle transit is necessary for BCL-XL inhibitor-induced cell death in SETD2 deficient cells. This agonizes CGAS-STING to further increase tumor cell-intrinsic inflammatory signaling. Activated inflammatory signaling can increase tumoral immunogenicity and shape the tumor microenvironment (TME) to be more amenable to immune checkpoint inhibitors (ICI). Given the link between tumor-intrinsic inflammation and response to ICIs in RCC, these data open the door for considering SETD2's contribution to RCC progression and treatment in a completely new way via inflammatory signaling via altered mitochondrial dynamics. Based on these data, we hypothesize that altered mitochondrial dynamics promotes mtDNA leakage and primes inflammatory signaling that creates a dependency on BCL-XL, and that this primed inflammatory signaling, in combination with targeting BCL-XL, provides an opportunity to improve response to ICI in SETD2 deficient RCCs. We are proposing a multifaceted collaborative project to: 1) Elucidate the mechanism governing leakage of mitochondrial DNA in SETD2-deficient cells. 2) Establish the role of BCL-XL in cell cycle progression in SETD2- deficient cells, and 3) Determine the extent that SETD2-deficient tumor microenvironment impacts immune cell function. We believe that our studies are innovative and will provide a clear understanding of kidney cancer- intrinsic and -extrinsic inflammatory signaling, related to SETD2 deficiency, contributes to tumor development, progression and response to chemo/immunotherapy.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract Opioid use disorder (OUD) is a devastating public health crisis, characterized by a lack of inhibitory control over drug seeking. Opioid use causes persistent adaptations in the excitatory circuitry governing motivated behavior, enabling drug-paired cues to trigger seeking despite negative consequences. Therefore, understanding how opioids engage and adapt unique glutamatergic circuit elements to promote maladaptive, reward-driven behavior would provide significant insight into habitual heroin use and identify treatment strategies to prevent relapse. This K99/R00 proposal seeks to determine the projection-specific glutamatergic neurons that functionally guide motivated behavior and reveal the pathway-specific circuit adaptations that emerge during heroin use to drive reward seeking. As I begin my independent career, I aim to develop a research program that investigates the spatiotemporal dynamics of drug-naive and drug-experienced glutamatergic networks and causally implicate pathway-specific ensembles in guiding reward-driven behavior and relapse. The Otis laboratory identified that the glutamatergic pathway from the paraventricular thalamus to the nucleus accumbens shell (PVT→NAc) pervasively governs naturalistic reward-seeking behavior, and stimulation of this pathway is sufficient to profoundly inhibit motivated action. Recently, I established that heroin use dampens PVT→NAc projection activity and weakens downstream synaptic efficacy, functionally disinhibiting reward seeking. Using two-photon (2P) calcium imaging in head-fixed, self-administering mice, we found three unique ensembles emerge in the PVT→NAc pathway during taking, with inhibitory neuronal dynamics reliably predicting goal-directed behavior in sucrose- and heroin-seeking tasks. However, it is currently unknown whether this inhibitory ensemble functionally encodes motivated behavior and actively guides reward seeking. During the K99, I will receive world-class training in 2P single-cell optogenetics to selectively photostimulate the inhibitory PVT→NAc ensemble that encodes goal-directed behavior in sucrose-seeking mice, both before and after heroin exposure. I will learn advanced computational analysis to determine the outcome of ensemble photostimulation on the within- projection dynamics guiding inhibitory control and heroin-induced disinhibition of seeking (Aim 1). I will expand my investigations into other key glutamatergic inputs to the NAc and determine the heroin-induced adaptations in hippocampal circuit- and cell-type-specific connectivity that facilitates relapse (Aim 2) and hippocampus-to- NAc-specific projection neurons that guide heroin-motivated behavior (Aim 3). Collectively, this proposal tests the hypothesis that heroin induces functional adaptations in pathway-specific glutamatergic circuit elements to drive maladaptive reward seeking. Results will reveal the network computations that guide motivated behavior in naïve and drug-exposed systems. This K99/R00 will grant me the unparalleled opportunity to receive training in state-of-the-art approaches as I develop my own independent research program in OUD.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY To date, most efforts to address scarring have focused on treatment at the tissue level rather than the cellular level. Therefore, identifying the molecular events involved in scar formation provides an opportunity to develop new drugs and treatment strategies to reduce scar formation. In the early stages of wound healing, hypoxia (low oxygen) stimulates fibroblasts to migrate into the wound bed where they synthesize the granulation tissue needed for healing. In successful wound healing that does not leave a scar, this extracellular matrix (ECM) is processed by proteolytic cleavage, the wound is revascularized, and oxygen is restored. When wound healing is not optimal, the new tissue suffers from poor re-vascularization and hypoxia does not resolve after healing is complete. Chronic hypoxia increases the migration of fibroblasts into the healed tissue, which is a rate limiting step for scar formation. Based on this concept, blocking the ability of fibroblasts to migrate into scar tissue will prevent and/or reduce scar formation. The objectives of this proposal are to determine how hypoxia rewires cytoskeletal dynamics to increase fibroblast migration. Cell migration involves the formation of focal adhesions (FA; mediated by integrin binding to ECM) and protrusion at the leading edge (mediated by actin polymerization). To date, the study of how hypoxia stimulates cell migration has focused almost exclusively on hypoxia-inducible factor-1 (HIF-1), which has limited progress in the field because HIF-1 amplifies well known actin regulatory pathways. As a result, the discovery of new mechanisms and therapeutic targets to address hypoxia in scar formation is lacking. PIM1 is a unique target to oppose hypoxia because it is stabilized in hypoxia at the protein level, independent of HIF-1. My lab recently discovered that PIM1 kinase is essential for hypoxia-induced migration. Mechanistically, we showed that PIM1 phosphorylates Abl interactor 2 (Abi2), a member of the WAVE regulatory complex (WRC), which enhances protrusive activity. Preliminary data from an unbiased phospho- proteomic screen identified kindlin 2 (K2) as a novel PIM1 substrate in hypoxia. K2 is an adapter protein that drives integrin clustering and focal adhesion (FA) maturation. Our central hypothesis is that unresolved hypoxia in hypertrophic scar tissue increases PIM1, which enhances fibroblast migration and worsens scar formation. In our model, PIM1 accumulates at the cell membrane in hypoxia, where it phosphorylates Abi2 (stabilizing the WRC and increasing protrusion) and K2 (activating K2 and increasing FA). Therefore, blocking PIM1 represents a new, HIF-independent, strategy to prevent fibroblast infiltration and restrain scar formation. The knowledge gained from these studies will inform future efforts to control cell migration as a strategy to treat scars and other diseases associated with hypoxia (i.e., cancer, stroke). My lab has a heavy investment in developing PIM kinase inhibitors, so we are in a strong position to lead the translation of PIM inhibitors as anti-fibrotic agents.

NIH Research Projects · FY 2026 · 2026-05

SUMMARY/ABSTRACT Poor T-cell tumor trafficking/infiltration and low T-cell survival in the harsh tumor microenvironment (TME) are two critical challenges for the success of T-cell-based immunotherapy against solid tumors. Thus, determining the novel intrinsic mechanism(s) that regulate T-cell infiltration and survival is critical to developing efficient immunotherapy strategies for treating solid tumors. D-type cyclins (D1, D2, and D3) bind cyclin-dependent kinases 4 and 6 (CDK4/6), and the activity of cyclin D/CDK complexes promotes entry into the cell cycle. Cyclin Ds carry out CDK4/6 kinase-dependent and kinase-independent functions. T cells primarily express cyclin D2 and D3. The CDK4/6 kinase-dependent functions of cyclin Ds in T cells were recently reported, but their kinase- independent functions in T cells are not well defined. This study revealed that cyclin D3 deletion in T cells suppressed colorectal tumor growth. Our data indicates that the increased T-cell survival and T-cell tumor infiltration of D3-deleted T cells is due to its kinase-independent function. intracellular cholesterol Sufficient prevents T-cell apoptosis in the harsh solid tumor microenvironment. RNA-seq analysis showed that genes functioning in cholesterol homeostasis were upregulated in D3-deleted T cells. In vitro studies showed that kinase-independent cyclin D3 decreased PPARG expression, which dominates the expression of genes controlling intracellular cholesterol levels. Thus, Aim 1 will determine the mechanism of how cyclin D3 downregulates intracellular cholesterol levels to decrease T-cell survival, promoting colon cancer progression. Meanwhile, adhesion proteins are critical in T-cell tumor infiltration. Aim 2 will determine the kinase-independent function of cyclin D3 in suppressing adhesion protein expression to inhibit T-cell tumor infiltration. Of note, our study showed that cyclin D2 overexpression decreased the expression of cyclin D3, augmenting T-cell capacity to kill tumor cells. Aim 3 will in vivo evaluate the therapeutic efficacy of cyclin D manipulated adoptive T cells on melanoma and colon cancers. We will manipulate cyclin Ds expression in T cells to assess the anti-solid tumor efficacy of adoptive T-cell therapy. Our overarching hypothesis is that manipulating cyclin D expression in T cells augments solid tumor immunotherapy efficacy by increasing T-cell tumor infiltration and T-cell survival through their kinase-independent functions.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Substance use disorders (SUD) and post-traumatic stress disorder (PTSD) are debilitating mental health disorders that frequently co-occur and have onset during adolescence. Approximately 9% of adolescents aged 12-17 meet criteria for a current SUD, with more than 70% of those having experienced a traumatic event and 35% meeting criteria for PTSD. If left untreated, a cyclical relationship between substance use and PTSD serves to maintain or exacerbate the other, leading to a chronic course of illness. Adolescents with co-occurring SUD/PTSD are at increased risk of developing other serious mental health problems (e.g., depression, suicidal ideation), HIV-related risk behaviors, and academic and interpersonal problems. There is a critical need to intervene earlier in the developmental trajectory to prevent the long-term deleterious outcomes associated with SUD/PTSD in adulthood. However, there are no effective individual treatments for adolescents with SUD/PTSD. Clinicians agree that comorbid SUD/PTSD among adolescents is a significant problem, and that a feasible and effective intervention is clearly needed. Efficacious, evidence-based treatments for adults with SUD/PTSD have been developed over the past two decades and can be adapted to address the unique developmental needs of adolescents with SUD/PTSD and improve outcomes and functioning for this highly understudied population. Based on promising preliminary data, the proposed study will directly address this need by evaluating an integrated, trauma-focused intervention, Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure (COPE), specifically adapted for adolescents (COPE-A). A Stage Ia study of COPE-A demonstrated safety, feasibility, and significant pre- to post-treatment reductions in SUD and PTSD symptoms, while a Stage Ib pilot RCT comparing COPE-A to Person Centered Therapy (PCT) showed safety, feasibility, and preliminary efficacy in significantly reducing substance use and PTSD severity. Stage I studies also resulted in a treatment manual, clinician training protocol, and fidelity monitoring procedures, all of which will be used in the proposed study. The primary objective of this Stage II RCT is to evaluate the efficacy of COPE-A, compared to PCT, in reducing (a) substance use frequency and amount, and (b) PTSD severity among a larger sample of adolescents (N = 120) with co-occurring SUD/PTSD. Secondary objectives are to examine the effects of COPE- A on associated areas of functioning including depression, HIV risk behaviors, interpersonal functioning, and quality of life. In line with our prior work, we will recruit nationally and deliver the intervention via telehealth. Ecological momentary assessment (EMA) will monitor daily substance use and PTSD symptoms to examine their temporal and reciprocal relationship and identify underlying mechanisms of change to inform future research.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY: Exercise intolerance in systolic heart failure (HF), defined as physical limitations from fatigue or shortness of breath, is associated with worse mortality and poor quality of life. Causes for exercise intolerance are multifactorial but are not solely attributed to cardiac dysfunction alone. Much evidence has suggested that skeletal muscle microvascular dysfunction (MVD), particularly in the legs, is a key contributor to the reduction in exercise capacity in these patients. Additionally, abnormalities in the skeletal muscle microvasculature have been found to appear early in animal models of heart failure, prior to the development of myocardial alterations like fibrosis or hypertrophy. Yet no study has investigated the relative contributions of peripheral vs central cardiac changes on exercise intolerance in systolic HF. Additionally, despite its association with exercise intolerance and early onset, the mechanisms underlying the development of skeletal muscle MVD remain poorly understood. Noninvasive assessments of microvascular function have shown evidence for a regional disparity in MVD, in which dysfunction is more pronounced in the lower, compared to the upper, extremities. Yet relative differences in peripheral skeletal muscle MVD has never been explored, particularly within the lower extremity. We propose to evaluate pre- and post-exercise assessments of noninvasive measures of skeletal muscle MVD in the distal leg as well as invasive hemodynamics, and compare their prediction of exercise capacity (Aim 1) in patients with systolic HF undergoing cardiac catheterization. We also plan to compare differential gene expression and vascular density between distal and proximal leg muscles by obtaining biopsies of the thigh and calf (Aim 2). Completion of these aims will provide several novel insights. If noninvasive metrics of lower extremity skeletal muscle MVD are more predictive of functional status than cardiac factors, these data will support further investigation of noninvasive measurements of skeletal muscle microvascular blood flow in HF, identifying potential diagnostic and therapeutic targets. Further, data generated from Aim 2 will provide an unbiased analysis of differentially expressed genes that will be further interrogated by pathway analysis to inform mechanistic insight into MVD in patients with HF. This data may help us target molecular signaling pathways for further analysis. The Specific Aims of this proposal will advance the training of the PI as a translational investigator studying advanced heart failure, hemodynamics, and skeletal muscle MVD, and will additionally provide novel insights into the regional disparity of skeletal muscle MVD in HF. Therefore, results from this proposal will provide a foundation for future investigations into skeletal muscle MVD diagnosis, pathogenesis, and treatment in patients with chronic HF.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT The exponential growth of biomedical and socio-behavioral data in the United States (US) presents new opportunities for understanding behavioral and social drivers of health. However, the fragmented nature of these data sources and the lack of specialized training limit their full potential in behavioral and social sciences research (BSSR). The Data Analytics Training and Professional Development (DATA-Pro) for behavioral and social sciences research (BSSR) program aims to bridge this gap by providing advanced training in big data methodologies. Hosted by the Medical University of South Carolina (MUSC), DATA-Pro will deliver structured e-learning modules on big datasets, research designs, traditional modeling, and novel machine learning and artificial intelligence approaches, covering responsible conduct of research and methods for enhancing reproducibility. Participants will gain hands-on experience through expert-guided research projects and develop essential skills in research dissemination. MUSC offers a conducive environment for training, myriad data resources, and robust teaching and research infrastructure, which is ideal for advanced training in data sciences. The program will prepare researchers to apply cutting-edge data analytics to answer complex social and behavioral research questions. By equipping researchers with the necessary skills to harness big data, DATA-Pro has the potential to accelerate discoveries, inform policy, and advance BSSR.

NIH Research Projects · FY 2026 · 2026-03

Chronic obstructive pulmonary disease (COPD) is a leading cause of death in the U.S. (3rd worldwide) and disproportionately affects individuals living in rural areas. Poor COPD outcomes are influenced by exposures common in rural settings, such as wood smoke, dust, and agricultural byproducts known to adversely affect respiratory health. There is a critical need for accessible COPD interventions that can be delivered in rural communities. Respiratory muscle strength training (RMST) is an empirically validated therapy that can improve ventilation and airway defenses and reduce dyspnea symptoms in patients with COPD. Few studies have evaluated the effects of RMST on respiratory function, respiratory quality of life (R-QOL), dyspnea, and dyspnea-related kinesiophobia in patients with COPD in rural areas. Our multicomponent, mHealth-delivered COPD intervention, Respiratory Muscle Strength Training and Fitness Program (RESP-FIT) is feasible and acceptable. RESP-FIT incorporates home-based RSMT using a portable training device, mHealth, and behavior theory. Integration of remote spirometry and ecological momentary assessment (EMA) allows measurement of lung function and symptoms (including dyspnea) in real-time in a remote setting. This integrated design (RMST + mHealth + EMA) addresses three key areas: 1) COPD-related physical deconditioning and associated symptoms; 2) health behaviors, including dyspnea-related kinesiophobia; and 3) accessibility (i.e., a portable respiratory intervention enhanced by mHealth/remote technology) for intervention delivery in rural areas. In Aim 1, we will conduct a RCT to evaluate efficacy of RESP-FIT on dyspnea, dyspnea-related kinesiophobia, and R-QOL in adults with COPD. Participants will be randomized to the RESP-FIT intervention or enhanced usual care (control) study arms. In Aim 2, we will identify barriers, facilitators, and contextual factors (e.g., environmental exposures, age, distance from healthcare provider, social support, access to care, income) that may moderate intervention engagement, adherence, and outcomes. RESP-FIT has high potential for scalability. Successful completion of these aims will lay the groundwork for subsequent implementation initiatives that support positive health outcomes and respiratory health for patients with COPD.

NIH Research Projects · FY 2026 · 2026-03

PROJECT ABSTRACT Emergency departments (EDs) face significant challenges managing mental health crises, often lacking specialized resources and leading to inappropriate placements and insufficient follow-up care. Emergency Psychiatric Assessment, Treatment, and Healing (EmPATH) units are designed to specially address these issues. However, a significant proportion of individuals experiencing mental health crises also have co-occurring substance use disorders, particularly opioid use disorder (OUD). Buprenorphine has been shown to reduce all-cause mortality. Furthermore, emergency department-initiated buprenorphine (EDIB) has demonstrated a doubling of 30-day treatment retention compared to referral alone. This significant success makes integrating EDIB into the EmPATH unit model a logical and potentially transformative step toward improved patient outcomes. However, adequately addressing workforce training needs is crucial for the successful implementation and sustained improvement of patient care. This project will develop and implement a training curriculum for EmPATH personnel focused on the acute management of OUD, emphasizing initiation of medication for opioid use disorder (MOUD) with buprenorphine. A phased approach will involve stakeholder input, protocol refinement, and rigorous evaluation. Phase 1 (R-61) will focus on curriculum development, incorporating input from an external advisory board, piloting the intervention in one EmPATH unit, and gathering qualitative feedback to refine the protocol. Phase 2 (R-33) will utilize a stepped-wedge design to: 1) assess the number of individuals identified with OUD while in EmPATH units (Primary Outcome) and the number of individuals administered buprenorphine and/or given a prescription for buprenorphine (Secondary Outcome); and 2) assess EmPATH staff satisfaction, burnout, confidence, knowledge, and stigma when working with patients with opioid use disorder prior to implementation and at 3, 6, 9, and 12 months post-implementation/training. This study aims to create a replicable and scalable model for integrating state-of-the-art OUD management into psychiatric emergency settings, improving patient outcomes and workforce preparedness. The collaboration with the South Carolina Hospital Association, Department of Mental Health, and DAODAS strengthens the project's impact and sustainability.

NIH Research Projects · FY 2026 · 2026-03

The objective of the proposed K23 research and training plan is to support Dr. Emily Tilstra-Ferrell in obtaining training needed to become an independent clinical scientist with a program of research focused on developing highly scalable, efficient evidence-based treatments (EBTs) for adolescents with posttraumatic stress disorder (PTSD) that can be delivered in accessible, real-world, multidisciplinary settings. Over four million adolescents in the United States (US) have PTSD. Although PTSD EBTs are available, only one third (37%) of adolescents access these treatments. Among the few who access PTSD EBTs, over one-third (34%) prematurely drop out due to barriers including lengthy protocols (the majority of dropout occurs before session seven). The proposed study directly addresses this clinical gap by adapting Written Exposure Therapy (WET), an EBT for adult PTSD, for adolescents. WET is an efficient, five-session PTSD treatment that is non-inferior to lengthier gold-standard PTSD EBTs for adults. WET addresses many barriers faced by adolescents who seek EBTs for PTSD due its brevity and related cost-effectiveness. However, WET has not been formally adapted or rigorously tested with adolescents. In Aim 1, WET will be adapted following a systematic model: Assessment, Decisions, Administration, Production, Topical Experts, Integration, Training, and Testing (ADAPT-ITT). In Aim 2, a proof- of-concept randomized controlled trial (RCT) will be employed to compare WET to Trauma-Focused Cognitive Behavior Therapy (the gold-standard PTSD EBT for youth) delivered in a pediatric primary care setting to adolescents with PTSD. The final exploratory aim will examine the potential emotional (fear extinction) and cognitive (changes in ruminative cognition) mechanisms of action in WET. The mentorship team is comprised of numerous highly experienced mentors with NIH-funded research related to the proposed project including RCTs for adolescents with PTSD (Primary Mentor: Dr. Carla Kmett Danielson), ADAPT-ITT (Dr. Cristina López), advanced qualitative and mixed methods (Dr. Byron Powell), WET (Dr. Christine Hahn), dissemination and implementation science and EBTs for trauma-exposed youth in primary care settings (Dr. Rochelle Hanson), and longitudinal data analysis (Dr. Naomi Brownstein). The research opportunities, mentorship, and formal coursework afforded by the proposed K23 will ensure Dr. Tilstra-Ferrell gains the following skills needed to achieve her career goals: (1) conducting clinical trials with trauma-exposed adolescents, (2) using qualitative and mixed methods design to adapt and implement EBTs, (3) longitudinal data analysis, (4) dissemination and implementation science methods, and (5) improved scientific communication. The candidate will complete all proposed activities at the Medical University of South Carolina in the National Crime Victims Research and Treatment Center, which is internationally renowned for research on adolescent PTSD EBTs with a strong history of catapulting early career scientists to independence. The proposed K23 will ultimately prepare Dr. Tilstra-Ferrell to launch a program of research developing efficient and scalable PTSD EBTs for adolescents.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Stroke is the fourth leading cause of disability within the United States. Large vessel occlusion (LVO) subtype of acute ischemic stroke (AIS) is the most devastating among all. Recent pivotal trials demonstrated endovascular thrombectomy (EVT) to be highly beneficial in selected subsets of AIS patients. In the wake of these breakthrough studies, an urgent need exists to assess the benefit of EVT in broader populations that are likely to benefit and determine the limits of this therapy, and to address multiple pressing related issues of management and concomitant therapies, in formal clinical trials. To answer multiple EVT management questions efficiently and concurrently, the NIH StrokeNet National Data Management Center (NDMC) at the Medical University of South Carolina, along with the National Coordinating Center and StrokeNet Thrombectomy Endovascular Platform (STEP) Executive Committee, will develop a robust EVT clinical trial platform within NIH StrokeNet. STEP will be optimized to definitely answer EVT-related questions under an overarching Master Protocol, providing an inferentially integrated framework and shared infrastructure, as a randomized, multi-factorial, Bayesian, adaptive platform trial. The STEP trial team will develop operational cores and scientific advisory groups designed to support three broad categories of trials: expansion of EVT indications, innovative EVT devices and concomitant medical therapies, and novel pre- and early-hospital technologies and systems of care. The foundational STEP Master Protocol will define the largest set of inclusion/exclusion criteria to allow study of all consecutive AIS patients with a visible large or medium intracranial vessel occlusion. It also will outline overall study procedures and terminologies, and the unifying statistical inferential model. As a registry-leveraged trial, STEP will minimize burden on the sites by collecting data using an automated transfer mechanism from existing robust, high-quality national clinical registries. Assessment of distinct interventions will be feasible on the platform concurrently or in tandem, and co-enrollment in multiple interventions and sharing of controls will be allowed to maximize efficiency. Details of a mutually exclusive set of interventions are called Domains. The details of patients eligible for a given domain, details of intervention, rules for randomization and adaptation would subsequently be detailed in domain-specific Appendices to the STEP master protocol. The primary endpoint of the STEP trial is favorable global disability level at 90 days, assessed using utility-weighted analysis of the modified Rankin scale (mRS). The STEP trial will allow most efficient testing of treatment strategies and allow rapid optimization of endovascular treatment landscape and acute stroke care.

NIH Research Projects · FY 2026 · 2026-02

Project Summary/Abstract Calcific Aortic Valve Disease (CAVD) will affect 3% of people over the age of 75. CAVD disease progression is characterized by an active deposition of calcific noduli and extracellular matrix proteins. This excessive deposition results in valvular thickening, outflow tract narrowing, restricted blood flow, left ventricular hypertrophy, and eventual heart failure. Despite the clinical significance of this disease, patients must “watch and wait” until surgical AV replacement and repair is necessary, as currently no pharmacotherapeutics exist. This proposal focuses on identifying novel epigenetic mechanisms underlying calcific aortic valve disease progress and pathophysiology. For preliminary investigation on the role of epigenomic regulators in valve calcification, we re-mined proteomic datasets to specifically probe differential abundance of epigenetic factors – that is, proteins involved in histone post-translational modification reading, writing, and erasing. The preliminary data presented in this proposal shows that enzymes responsible for histone regulation are differentially abundant in valvular tissue as a function of disease stage, structural localization within the valve leaflet, as well as within VIC cultures as a function of calcification induction media (inorganic vs. organic phosphate media). However, the dataset mined was not exhaustive in identification as it was untargeted. Additionally, our preliminary data did not investigate the regulatory role epigenetics plays in downstream translational and post-translational signaling required for cell-cell, cell-matrix, and cell-vesicle mediated signaling. The proposed research capitalizes on an ever-expanding cohort of clinically defined human adult CAVD aortic valve tissue, as well as an extensive biobank of valvular interstitial cells isolated from human donors. It is our central hypothesis that there are unique histone modifications that contribute to pathological development of calcification in human aortic valves. Aim 1 will use novel mass spectrometry approaches to define the histone code of CAVD along with corresponding transcriptional regulation via Chromatin Immunoprecipitation sequencing. Aim 2 will determine cell-mediated spatially localized translational targets downstream of epigenetic regulation, utilizing multi-modal histopathological imaging, laser capture microdissection, and low-input proteomic strategies. Aim 3 will investigate the role of epigenomic modifications on microenvironment signaling mediated by N-linked glycosylation. By mapping the histone code of aortic valve calcification and identifying both upstream epigenetic regulators and downstream transcriptional, translational, and post-translational targets of this epigenetic regulation, we aim to identify potential pharmacotherapeutic targets that may halt progression of CAVD. These studies will be conducted by Dr. Clift under the mentorship of Dr. Elena Aikawa, a pioneer in cardiovascular systems biology, as well as an advisory committee dedicated to proposed research and trainee. By utilizing this mentorship and professional development via the MOSAIC UE5, Dr. Clift is primed for successful independence.

NIH Research Projects · FY 2025 · 2025-12

Project Summary Alcohol use disorder (AUD) is a prevalent, affecting over 10% of Americans, with only a fraction of individuals seeking treatment. Chronic alcohol exposure induces maladaptive changes in neuronal physiology, particularly within neural circuits that mediate reward and consumption behaviors, hallmarks of AUD that render treatment difficult and increases the likelihood of relapse. Despite substantial progress in understanding neurotransmitter- mediated changes in AUD, the role of neuropeptides such as orexin (hypocretin) remains underexplored. Orexin is a hypothalamic neuropeptide that contributes to a number of physiological conditions, including regulation of arousal, feeding, and stress. Orexinergic neurons from the lateral hypothalamic area (LHA) innervate a number of brain regions implicated in AUD, such as the ventral tegmental area (VTA) and nucleus accumbens (NAc). In my preliminary data, I have found that chronic voluntary EtOH consumption leads to activation of orexinergic neurons in the LHA in male and female C57BL/6J mice. Furthermore, I have demonstrated that I can track orexinergic activity in a free-moving mouse while it is consuming EtOH through the use of fiber photometry and the orexin peptide sensor, OxLight1. This proposal aims to investigate the impact of alcohol dependence on orexinergic circuits, particularly the LHA-VTA pathway, and its role in excessive alcohol consumption. Using cutting-edge tools, including the OxLight1 biosensor for real-time orexin monitoring, optogenetics for pathway- specific neuronal silencing, and whole-cell patch-clamp electrophysiology, this study will elucidate the functional changes in orexinergic activity in male and female mice following chronic intermittent ethanol (CIE) exposure. The innovative approach includes sex-specific and within subject analyses and behaviorally guided experiments to address critical gaps in the field. Aim 1 of this proposal will determine how silencing LHA orexinergic neurons projecting to the VTA modulates voluntary alcohol consumption in ethanol-dependent mice. Aim 2 of this proposal will assess functional adaptations in the LHA orexinergic circuits to regions implicated in AUD following ethanol dependence and their impact on voluntary alcohol consumption. The expected outcomes will reveal how chronic alcohol exposure alters orexinergic signaling, contributing to excessive drinking and relapse. These findings will enhance our understanding of AUD's neural mechanisms, identify potential sex differences, and detect therapeutic strategies targeting orexinergic pathways. This research holds significant translational potential, advancing efforts to mitigate the global burden of AUD.

NSF Awards · FY 2025 · 2025-11

The award will support student participation and travel to the Pacific Symposium on Biocomputing (PSB) for the 2026 meeting, to be held January 3–7, 2026. PSB is one of the oldest continuous conferences in computational biology and bioinformatics. Its unique format—small size, no parallel sessions, and a dynamic, community-driven structure— fosters interdisciplinary discussion and collaboration. Participants (200-300 each year) come from around the world, and the meeting setting promotes open dialogue and sustained collaborations. This award will provide support only for students at US-based institutions, aiming to strengthen the competitiveness of the US in the science and technology areas. This award will provide travel support to U.S.-based students presenting research at PSB. Like a Gordon Research Conference, it encourages deep engagement across all levels of the field. The meeting is built from the ground up each year through a call for session and workshop proposals. Approximately 15 proposals are submitted annually, of which 5–6 sessions and 4–6 workshops are selected. This model supports innovation and the timely introduction of new research topics. All accepted presenters receive information about the travel award application process, and support is prioritized for students giving oral presentations, though poster presenters are also eligible. The small size of PSB creates an ideal environment for students to engage with senior researchers, forge professional connections, and create opportunities for mentorship and future collaborations. Many student participants also take part in session or workshop planning, gaining hands-on leadership experience early in their careers. Because sessions are proposed and developed by participants, PSB often becomes the first venue to highlight emerging research areas. This commitment to community-driven innovation promotes scientific advancement and fosters the next generation of leaders in computational biology 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 Alcohol use disorder (AUD) is the fourth leading cause of preventable death in the United Sates and according to the Centers for Disease Control and Prevention alcohol is responsible for over 178,000 deaths in the last year. Chronic stress can be a key factor that leads to increased alcohol consumption, and thus increases risk for the development of AUD. The medial prefrontal cortex (mPFC) is a key brain region involved in decision making and impulsivity and becomes dysregulated following both chronic alcohol and chronic stress. Corticotropin releasing factor (CRF) is a pro-stress neuropeptide that is primarily released from the hypothalamus in response to stress, however, the role of CRF in extra-hypothalamic brain regions, primarily the mPFC, is widely understudied. CRF has multiple binding partners, the most prominent in the mPFC being CRF receptor 1 (CRFR1). While both CRF+ and CRFR1+ neurons are prevalent in the mPFC, their function in regulating voluntary alcohol consumption following chronic alcohol and stress is unknown. Preliminary electrophysiology data from the lab shows that chronic alcohol and stress increase intrinsic excitability of cortical CRF+ neurons, while others report that one of the putative downstream targets of cortical CRF+ interneurons, CRFR1+ neurons, have weakened excitability following chronic alcohol and withdrawal. To date, no one has examined the effects of the combination of chronic alcohol and stress on these discrete neural populations in the mPFC. The overall hypothesis of this proposal is that the CRF system in the mPFC is altered after chronic alcohol and stress, which drives escalated alcohol consumption. Specifically, CRF+ and CRFR1+ neurons in the prelimbic cortex are differentially engaged during voluntary alcohol consumption and have opposing mediation of stress-induced alcohol drinking. To examine this, this proposal will use a model of chronic alcohol and stress and measure the cellular activity of cortical CRF+ and CRFR1+ neurons during alcohol drinking, as well as manipulate these cells using chemogenetics to demonstrate their functional role in mediating these effects. Specifically, in Aim 1 we will use fiber photometry to record in vivo calcium dynamics of CRF+ GABAergic interneurons by expressing a Cre-dependent calcium biosensor (GCaMP) in Crh-ires-Cre mice. Aim 2 will use Crhr1-ires-Cre mice to examine cortical CRFR1+ projection neuron calcium dynamics using a Cre-dependent GCaMP and fiber photometry while simultaneously inhibiting CRF+ cortical neurons using a Crh-promoter expressing viral vector to drive expression of an inhibitory DREADD (designer receptors exclusively activated by designer drugs) in CRF+ neurons in the same mice. The results from these experiments will be the first to examine the activity and function of these neurons in the context of chronic alcohol and stress and will provide a foundation allowing us to further understand the impact of cortical dysregulation following chronic alcohol and stress.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Cancer cachexia involves the accelerated loss of skeletal muscle mass and function which significantly reduce patient treatment options, quality of life, and survival time. In addition to atrophy of myofibers, ectopic accumulation of adipocytes between and within muscle tissues, generally referred to as myosteastosis, is a distinguishing feature of muscle degeneration during cancer and its comorbidities which independently predicts poor muscle function and prognosis. However, the exact mechanisms regulating myosteatosis during cancer, and their relevance to muscle wasting, are unknown. Adipocyte formation in skeletal muscle is indicated to result from the adipogenesis of a population of mesenchymal stem cells known as fibro-adipogenic progenitor cells (FAPs) that reside in the muscle tissue microenvironment. Preliminary experiments using mouse models of cancer cachexia and single-cell RNA sequencing revealed that muscles from tumor-bearing mice had more adipocytes than non-tumor bearing controls, which coincided with an increase in FAPs expressing adipogenesis promoting genes. One of the top-most upregulated genes in FAPs from cachectic muscle encodes the enzyme xanthine oxidoreductase (XOR) which is known to be essential for adipogenesis in vitro and in vivo. XOR is also known to be a major source of reactive oxygen species production that can activate NF-B, a transcription factor that promotes muscle wasting during cancer cachexia. Therefore, this proposal will seek to elucidate the role of XOR in FAPs to myosteatosis and muscle dysfunction during cancer cachexia. In Aim 1, multiple mouse models of cancer cachexia will be used, in combination with Pdgfrα-CreER; tdTomato and XORfl/fl mice, to determine if cancer promotes FAP adipogenesis through a XOR-dependent mechanism. In Aim 2, in vitro and in vivo experiments will be conducted to determine if increased XOR activity in FAPs contributes to NF-B activation in muscles during cancer cachexia.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Inflammatory bowel disease (IBD) has emerged as a substantial health concern not only in the developed world but also in developing countries. The incidence of IBD is increasing on a global scale, highlighting its significance as a growing health issue. The exact cause of IBD remains unclear, but it is postulated to result from a combination of genetic, environmental, and immunological/microbial factors. Preliminary data suggests that Myosin 5b may play a role in the pathogenesis of inflammation in the gastrointestinal tract. Myosin 5b is a molecular motor that regulates intracellular trafficking of diverse cargo in intestinal epithelial cells. Among its many functions, Myosin 5b transports essential proteins to the apical membrane in the intestine. Loss of Myosin 5b in experimental models and in humans results in shortened microvilli which normally line the intestinal epithelial cells. In healthy individuals, microvilli act as a barrier to harmful luminal contents and bacteria. An important function of intestinal microvilli is the generation of luminal vesicles from the tips of microvilli that contain catalytically active enzymes. Intestinal alkaline phosphatase (IAP) is enriched in microvilli derived vesicles and in microvilli. IAP removes phosphate groups from bacterial lipopolysaccharide and flagellin. Dephosphorylation of bacterial products by IAP dampens the release of pro-inflammatory signals thereby protecting the intestinal epithelium. This research proposal aims to investigate the interplay between pro-inflammatory stimuli and the expression of Myosin 5b in the setting of IBD. We hypothesize decreased Myosin 5b results in decreased trafficking of IAP to microvilli. This disruption compromises the function of microvilli at the apical membrane, ultimately leading to increased inflammation. The proposed study will employ a multidisciplinary approach, leveraging our lab’s expertise in gastrointestinal epithelial cell biology, intracellular trafficking, advanced microscopy, animal models and physiology. We will use both in vitro and in vivo models to dissect the relationship between Myosin 5b and IAP in intestinal inflammation. This proposal will provide a better understanding of the function of Myosin 5b in the distal intestine and the impact of alterations in Myosin 5b on gut homeostasis and inflammation. Results from this study will provide experimental evidence of inflammation resulting from decreased intestinal Myosin 5b and its effect on microvilli function.

NIH Research Projects · FY 2025 · 2025-09

COMMUNITY ENGAGEMENT & OUTREACH CORE – PROJECT SUMMARY / ABSTRACT The goal of the Community Engagement & Outreach (CEO) Core is to maximize stakeholder engagement for the Neuro-PRECISE Center, including researchers, clinicians, students, the public, and, importantly, consumers of rehabilitation services and their care partners and support organizations (people with lived experience, PWLE). To have a significant impact, the Neuro-PRECISE Center must substantially integrate the voice and expertise of PWLE across all levels of the center (i.e., leadership, advisory committees, administration, research and resource cores, etc.), as well as disseminate critical research findings across the domain of rehabilitation research and to a national audience. Similarly, the CEO Core will work diligently to communicate and collaborate with other funded Medical Rehabilitation Research Centers (MRRCs) and the NIH/NICHD National Center for Medical Rehabilitation Research (NCMRR) to materially contribute to a national network that is greater than the sum of any single P50 award. The CEO Core aims, goals, and approach will be guided by NIH and National Academy of Medicine reports. The Core’s specific aims are to: 1) Engage the wider stakeholder community, especially People with Lived Experience. Engaging community stakeholders to ensure their voices permeate all levels of Center programming and planning is fundamental to realizing the vision of precision neurorehabilitation in a way that is meaningful and impactful for those we serve and with whom we partner. 2) Engage the neurorehabilitation research scientific community. The CEO Core will develop, implement, and continually enhance a catalog of services and tools geared towards the wider neurorehabilitation research community that includes ongoing quarterly webinars, high-quality trainings focused on precision neurorehabilitation both locally and as satellite symposia at national conferences, and collaborative opportunities with other funded MRRCs. 3) Develop and continually enhance the Neuro-PRECISE Center outreach initiatives, communication platforms, and website. Bi-directional communication is critical to the success of an effective research center – both for sharing important research findings and building collaborative research partnerships across the field of neurorehabilitation, and for keeping abreast of the needs and desires of the Center’s multiple stakeholders to drive the science in a direction that benefits everyone. Partnerships developed through open, bidirectional communication across a cadre of vested individuals who appreciate, and value different perspectives, expertise, and experiences are needed to solve complex problems. Including PWLE throughout Center components will allow PN scientists to better understand the needs of those living with disabilities and for continual improvement of research efforts.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Congenital deafness is among the more prevalent chronic conditions seen in human infants, and genetic causes are thought to explain the majority of cases in developed countries. While progress has been made in identification of primary deafness causing genes, it is also evident that no given gene mutation acts alone. That is, additional variants throughout the genome (genetic modifiers) result in a spectrum of phenotypic outcomes. These modifiers are important to understand because they reveal new cellular and molecular mechanisms that participate in a phenotype of interest. They are also important for diagnostic, prognostic, therapeutic and patient management strategies. So far, there is no insight as to what these modifiers are or how they act. Waardenburg-Shah syndrome (WS4) is an example in which hearing loss is an incompletely penetrant trait within the larger group of patients with Hirschsprung disease (congenital gut motility disorder). Both are associated with mutations in endothelin signaling genes. As described in a recently published study, we recapitulated the variable penetrance of hearing impairment in endothelin signaling gene mutant mice by utilizing the genetically diverse outbred ICR strain background. We also determined that the primary cause of hearing impairment in these mice is in auditory synaptic function, and demonstrated unique and independent roles of endothelin signaling in spiral ganglia neurons and glia. This project seeks to identify genetic modifiers that influence the penetrance of hearing impairment in the context of endothelin receptor Ednrb deficiency. We performed a large scale genome wide association analysis which is uniquely possible with our mice, and identified two lead candidate genes that are presented here for further exploration. In Aim 1, we address the role of the gene Kcnj16 (encoding the potassium channel Kir5.1), which we propose influences hair cell excitability and auditory neuronal maturation. In Aim 2, we explore neuronal Dchs2 (which encodes a cadherin-type adhesion molecule) and address how it influences auditory synapse formation and function. The results from this study will elucidate genetic components of phenotypic heterogeneity and will reveal new mechanisms that are involved in auditory function. The experimental material is specific for WS4, although the insights are likely to be relevant to a much broader range of congenital hearing disorders in mice and humans.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Alcohol use disorder (AUD) is characterized by the progression from recreational drinking to uncontrollable and excessive consumption resulting in myriad of social and neurobiological complications. While the mechanisms underlying the dependence-induced escalation in drinking are not completely understood, a key brain region disrupted in individuals with AUD is the orbitofrontal cortex (OFC). Previous studies from the Woodward laboratory showed that acute ethanol inhibits action potential firing of lateral orbitofrontal (lOFC) cortex pyramidal neurons via activation of astrocytic D1/D5 dopamine receptors, depolarization of the astrocyte membrane potential and the release of glycine via reversal of the astrocytic GlyT1 glycine transporter. Following chronic intermittent exposure (CIE) to alcohol, lOFC neurons become hyperexcitable and are tolerant to acute ethanol. Although our work has defined how acute and chronic ethanol alter lOFC neuron excitability, there is virtually nothing known about the effects of CIE exposure on lOFC astrocytes and how this contributes to changes in lOFC neuronal excitability. The overarching goal of this proposal is to address this major shortcoming in our knowledge by identifying CIE-induced changes in lOFC astrocyte physiology, structure and gene expression and test whether these changes contribute to the excessive drinking observed in alcohol-dependence. To accomplish this goal, studies in Aim 1 of this proposal use ex vivo slice electrophysiology and calcium imaging approaches complemented by in vivo fiber photometry measures of astrocyte calcium signaling following repeated cycles of CIE exposure. Aim 2 studies use super-resolution confocal imaging to measure CIE induced changes in lOFC astrocyte morphology and synaptic proximity and single nuclei RNAseq approaches to reveal changes in lOFC astrocyte and neuron gene expression. Aim 3 studies use a calcium exporter to blunt lOFC astrocyte calcium signaling and determine how this affects CIE induced alterations in lOFC astrocyte physiology, morphology, gene expression and voluntary ethanol consumption. Results from these studies will fill an important gap in our understanding of the role of lOFC astrocytes in alcohol action and will generate novel and testable hypotheses to support future studies.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Purines are important signaling molecules that influence multiple pathways in the human body by activating purinergic receptors on target cells. Recent research has identified that purines and their corresponding purinergic receptors play critical roles in infectious disease. However, much of this research has focused on purinergic signaling within immune cells and the enteric nervous system, leaving the role of epithelial cells in the gastrointestinal tract largely unexplored. Our group has identified that the purinergic receptor P2Y1 is highly expressed in the human intestine and in human intestinal organoids. We found that activation of P2Y1 stimulates robust calcium signaling and cell-cell communication; pathways known to be involved in epithelial responses to injury. We generated CRISPR-Cas9 knockout (KO) organoids of P2Y1 and found that these cells had reduced calcium signaling and decreased wound closure rate. We also generated epithelial specific P2Y1 KO (VillinCre:P2Y1flox/flox) mice and found that these P2Y1 KO animals were more susceptible to dextran sodium sulfate (DSS) induced colitis. Both our organoid and animal models suggest that P2Y1 is critical for proper intestinal wound healing and response to injury. Finally, we found Ulcerative Colitis patients with active inflammation have a significant reduction in P2Y1 expression, but P2Y1 expression returns to normal when grown as organoids and removed from the inflammatory environment. These data suggest that P2Y1 is influenced by inflammatory signals and maybe a target for promoting wound repair in the inflamed gut. Our central hypothesis is that epithelial purinergic P2Y1 signaling is involved in intestinal inflammation during colitis and plays an important role in repair. The objective of this research is to elucidate the role of epithelial purinergic signaling in intestinal inflammation and the mechanistic consequences of these pathways. Aim 1 will delineate the role of epithelial P2Y1 purinergic signaling in vivo during acute and chronic colitis and wound biopsy punch. We anticipate that deficiency of P2Y1 (Villincre:P2Y1flox/flox mice) will result in worsened DSS and T-cell transfer induced colitis and delayed healing compared to WT mice. In Aim 2 we will identify the mechanism by which P2Y1 signaling drives wound healing and determine how inflammatory signals affect P2Y1 signaling pathways using human colonic organoids derived from healthy and ulcerative colitis patients. We anticipate P2Y1 activates both proliferative (ERK1/2) and cell migration (Itpkb) pathways to promote proper repair following injury. However, in the presence of pro-inflammatory stimuli, we postulate that P2Y1 expression and its downstream signaling pathways will be downregulated. This study will provide evidence for the importance of P2Y1 purinergic signaling in epithelial cells in the context of intestinal inflammation during colitis. Collectively, these experiments will advance our understanding of intestinal inflammation and may unveil potential novel therapeutic targets.

NIH Research Projects · FY 2025 · 2025-09

One of the most pressing and significant public health crises currently facing the United States and beyond is the gaping need for exponential improvements in access, quality, and healthcare for individuals affected by trauma and adversity. Stress that extends from adverse life events, such as discrete traumatic events (e.g., assault, serious injury) and chronic stressors, is a well-documented and consistent predictor of a wide range of mental health and physical health problems across the lifespan. The individual and societal costs associated with biomedical conditions that are caused or worsened by traumatic stress are estimated to exceed $300 billion annually. Factors, such as poverty and inconsistencies in healthcare access or utilization, are highly prevalent among trauma-exposed populations, rendering some individuals more vulnerable to adverse health outcomes – exacerbating already-existing unbalanced health indicators. South Carolina (SC) ranks among the poorest in the US with regard to traumatic events, health care, and differences in health outcomes. The overall goal of the SC Building Resilience through Innovative Interventions to promote Growth and Health after Trauma (BRIGHT) Center of Biomedical Research Excellence (COBRE) is to strengthen immediate and long term capacity of early-stage investigators (ESIs) to conduct high-impact independent research with an emphasis on development and rigorous testing of innovative interventions and implementation strategies that aim to improve access and/or quality of care among individuals affected by trauma and adversity. We will establish a multi-disciplinary traumatic stress research center with critical cores in digital health, community engagement, and implementation science to strengthen MUSC’s biomedical infrastructure and capacity to achieve meaningful population impact in SC and nationally. Through BRIGHT, we will: 1) Mentor a “deep bench” of promising ESIs and new investigators (NIs) to become independently funded investigators in technology-enhanced and constituent-engaged biomedical research to improve health care and outcomes among trauma-affected populations; 2) Build research infrastructure that dramatically accelerates the growth in expertise and readiness of ESIs/NIs to conduct high-impact independent research; and 3) Promote sustainability of the COBRE by developing innovative multidisciplinary research programs, rigorous evaluation, ongoing improvement strategies, and mission alignment with other Centers at MUSC and across the state of SC. Four exceptional ESI who are committed to leading innovative, cross-disciplinary initiatives at the intersections of traumatic stress, digital health, and community engagement will be provided funding as well as expert mentorship, consultation, and training through three Research Cores in each of these areas. Opportunities for faculty interaction, networking, and collaboration will be provided by a Pilot Project Program, mentoring and enrichment activities, and an annual retreat to bring more investigators into the field of traumatic stress and adversity-related health.