Medical University Of South Carolina

NIH Research Projects · FY 2025 · 2024-08

OVERALL – PROJECT SUMMARY / ABSTRACT The COBRE in Stroke Recovery has been tremendously successful – effectively establishing the Medical University of South Carolina (MUSC) as an international leader in stroke rehabilitation research, with outstanding researchers and core resources. Our Phase 3 strategy is to remain leaders in stroke recovery while widening our scope to fully support research into the restoration of neural-based function in all populations – building upon the diverse and multidisciplined user base built over the first two phases – effectively becoming the COBRE for Restoration of Neural-Based Function. The COBRE will foster continued innovation; technology development; and diverse and multidisciplinary faculty recruitment, career development, and retention. Further, we propose to fully align our COBRE investigators and core infrastructure with three synergistic MUSC strategic research initiatives. Our Specific Aims are to: 1) Optimize successfully established stroke recovery research programs and restoration of neural-based function infrastructure built in prior COBRE phases; and 2) Implement strategies to advance MUSC research excellence in the restoration of neural-based function beyond COBRE funding. First, we will streamline existing Phase 2 cores to better serve the needs of our investigators by refocusing on specialty services not available elsewhere, while transitioning those services which have become more widely available through other university research cores. Specifically, we will consolidate the specialty services of the Brain Stimulation and Neuroimaging Cores to become a more focused Neural Function Core supporting neuromodulation, neural recordings, and combined multimodal studies. Second, we will coalesce COBRE operations and human capital within a newly constructed research home. This will create a truly synergistic research environment for transdisciplinary collaboration to tackle complex restoration of neural-based function research in state-of-the-art laboratories. Next, we will leverage considerable, new university-wide faculty growth and diversity programs – in which COBRE faculty already have leadership roles – to accelerate cluster hiring, career development, and resource allocation for sustained COBRE growth and independent operations post NIH funding. Finally, we will support a robust pilot project program to drive novel mechanistic and technological innovations. MUSC will be leaders in ushering in the era of neural circuit-based medicine as we use our world- class resources to develop novel neuromodulation interventions for restoring neural-based functions across the spectrum of physical function, cognitive function, and psychiatric function for all of those in need.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT Individuals living with likely incurable cancer (ILLIC) are a heterogeneous, growing subpopulation of cancer survivors who have unique survivorship care needs. Principal among these is the need for psychosocial treatment. Treatment of depression is particularly critical as up to half of ILLIC report depressive symptoms, with negative sequalae including lower quality of life, desire for hastened death, and suicidality. Numerous trials and meta-analyses have documented that evidence-based psychosocial treatment improves depression outcomes for ILLIC. However, multilevel barriers limit access. Thus, ILLIC need feasible, accessible depression treatment options. Brief depression screeners are now routinely administered in oncology settings. These data can be used to proactively identify survivors in need of psychosocial treatment. Efficient identification (ID) of ILLIC, though, is more challenging. Data necessary to determine likelihood of curability are recorded in unstructured EHR fields, necessitating labor-intensive, manual chart review to identify ILLIC. To realize the goal of proactive ID and delivery of scalable depression care for ILLIC, accurate, efficient, automated ID approaches are needed. Self- guided digital mental health interventions (DMHIs) can be paired with proactive ID to deliver scalable depression treatment. Our team previously adapted one evidence-based depression treatment, Behavioral Activation, for delivery via a DMHI called “Moodivate” and demonstrated that Moodivate is a feasible, acceptable, and efficacious DMHI. Thus, a proactive treatment delivery model using a self-guided DMHI such as Moodivate may be a promising approach to deliver evidence-based depression treatment to ILLIC. [[We have confirmed feasibility and acceptability of this approach via a recent pilot trial in which we specifically tailored Moodivate to the unique needs of ILLIC and tested all methods proposed herein.]] Importantly, a sustainable model must address the chronic evidence-to-practice gap that limits psychosocial care delivery. Thus, implementation outcomes and determinants must be concurrently evaluated. Directly aligned with RFA-CA-22-027, we propose a Hybrid Type I effectiveness-implementation trial to: 1) comprehensively assess the effectiveness of a proactive ID + DMHI approach among ILLIC, 2) gather information on intervention delivery to guide implementation best practices, and 3) develop an EHR-derived phenotype of likely incurable cancer. Our diverse stakeholder advisory board, which includes ILLIC, oncology providers, and organizational leaders, has guided and refined this proposal to ensure its clinical relevance and will continue to partner with our team on all aspects of the study design, implementation, and dissemination of study findings. This program of research has the potential to expand evidence-based psychosocial treatment access in a manner that is scalable across oncology settings and ultimately decrease the undue burden of depression shouldered by ILLIC.

NIH Research Projects · FY 2025 · 2024-07

This application is to request funds to support 15 young investigator travel awards for the annual Winter Conference on Brain Research (WCBR 2025-2027). WCBR is a premier forum dedicated to exploring novel, unpublished, and state-of-the-art advances that change the way we think about the future of neuroscience. With approximately 500 attendees, the conference is intentionally designed to move beyond incremental research review and instead focus on disseminating innovative and potentially paradigm-shifting discoveries. The program features over 80 panel presentations and poster sessions, with an emphasis on merit-based science. This is highlighted by a special judged poster session that features top-ranking submissions, which are predominantly presented by young investigators. The meeting structure provides extended periods for intense scientific discussion and networking, creating a unique opportunity for junior investigators and trainees to engage with established leaders in the field in a relaxed atmosphere. The conference also features highly attended Professional Development Workshops and sessions designed to illuminate the most cutting-edge technologies in neuroscience. The scientific program is developed annually from abstract submissions and is highly relevant to the missions of NIDA and NIAAA. A significant portion of the conference is dedicated to the neurobiological bases of substance use disorders (SUDs), alcohol use disorder (AUD), and related neurological and neuropsychiatric disorders. For example, the 2024 meeting included 17 panels on abused drugs and 46 panels on related topics like CNS plasticity. Thus, a large proportion of the conference is highly relevant to understanding the neurobiological bases of substance use disorders (SUDs) and alcohol use disorder (AUD) as well as neurological and neuropsychiatric disorders consistent with NIDA and NIAAA missions. The fact that a large proportion of the participants are junior investigators and a significant number are graduate students and postdocs ensures that this conference has an impact on how future generations of neuroscientists view these issues.

NIH Research Projects · FY 2025 · 2024-07

Alterations in glycosylation have been associated with the development and progression of many types of cancers and other chronic and acute diseases. Structural glycan analysis on purified proteins often provides the best “biomarker” information but is time consuming and can take days or often weeks for the analysis of only a handful of samples. To address this limitation, our group has developed a streamlined antibody capture slide array approach to directly profile N-glycans of captured serum glycoproteins. This method combines the method of antibody arrays and imaging mass spectrometry to create a new method of multiplexed N-glycan analysis. Importantly, this assay requires only a few microliters of serum and utilizes simplified processing workflows that require no protein purification or sugar modifications prior to analysis. This method is referred to as the GlycoTyper. In this method, N- linked glycans are PNGase F released on slide from antibody captured glycoproteins and are directly analyzed by MALDI-TOF mass spectrometry. We have used this methodology to identify biomarkers of pre-malignant and malignant liver disease. Our plan is to transition this method, which utilizes novel glyco-technology into the commercial setting. To help translate this finding we propose to establish an inter-disciplinary, multi-institutional research team, working in strategic alliance with both industry and clinical partners to validate our identified biomarker. This application represents a true synergistic effort between the group at the Medical University of South Carolina (MUSC), the clinical group at the University of Texas Southwestern Medical Center (UTSW), and an industrial partner GlycoPath Inc, who has licensed this technology. We believe that this multidisciplinary team will lead to the rapid and rigorous examination of the proposed biomarker panel.

NIH Research Projects · FY 2026 · 2024-07

As the tobacco product landscape continues to shift, there has been a dramatic increase in poly-tobacco use, particularly the dual use of combustible and electronic (e-)cigarettes. The health implications of dual use are unclear, as are the treatment and policy decisions as to how to best manage it. On one hand, dual use has the potential to decrease both individual and population harm, insofar that toxicant exposure is lowered and eventual cessation of combustible cigarettes becomes possible, as growing evidence suggests. However, harm reduction is maximized only when dual users transition completely away from combustible cigarette smoking, and when that transition is sustained. Indeed, the potential benefits of e-cigarettes are unrealized if dual users fail to quit smoking. Thus, dual use has the potential to reduce or perpetuate harm. The critical difference between these two outcomes is how these harm reducing/promoting tobacco products are used interchangeably; i.e., patterns and trajectories over time. Unfortunately, the natural course of dual use, particularly in comparison to exclusive smoking or vaping, is unclear. Cohort studies of dual use, often derived as secondary analyses from national surveillance projects with yearly assessments, suggest that, for some, dual use can be either transient or prolonged. Almost all of these studies lack detail on anything beyond use status (using vs. not), and particularly lack detail on daily patterns of use over time. A focused and more granular assessment of dual use patterns is needed to understand who these individuals really are, and how their smoking and vaping behaviors do and do not change over time. Within a nationally based cohort study of dual users (n=396), and exclusive users of both combustible (n=198) and e-cigarettes (n=198), natural use histories will be assessed through a combination of a) detailed daily diaries over 3 months, b) serial bursts of nightly diaries that coincide with c) episodic monthly surveys over a 1-year follow-up, and d) biological verification of combustible cigarette smoking. Study aims are to 1) describe, and 2) compare the consistency of use behaviors over time, within and across cohorts. As a third aim, using a within-subjects approach, we aim to assess the defining day-to-day patterns of dual use that best predict subsequent abstinence from combustible cigarette smoking. The proposed project is the largest and longest study of dual users (vs. exclusive users) ever conducted with a priori design considerations to more fully understand the complex interplay between these two products, one of which is the root cause of significant cancer incidence and mortality, and the other is a controversial harm reduction option with fast growing population appeal. Building upon a successful program of cancer prevention research using naturalistic research designs, remote methods, and team science, the proposed study expands our foundational knowledge regarding tobacco use behavior and cessation among and across different groups of tobacco product users. Ultimately, and regardless of outcome, our results will inform clinical and regulatory decision making of novel products that may enable or impede the proliferation and marketing of the fastest growing segment of the tobacco marketplace.

NIH Research Projects · FY 2025 · 2024-07

SUMMARY Non-small cell lung cancer (NSCLC) remains the deadliest cancer, and novel therapeutic strategies are needed to improve treatment outcomes of patients with this disease. FTY720 (Fingolimod/Gilenya, Novartis) is a sphingosine analog drug approved for the treatment of refractory multiple sclerosis due to its immune suppressor function. Immune suppression by FTY720 requires its phosphorylation (P-FTY720) mainly by sphingosine kinase 2 (SphK2). However, pro-drug FTY720, without its phosphorylation, exhibits anti-cancer functions in various models, including NSCLC. Our published and unpublished preliminary studies demonstrated that FTY720, and not P-FTY720, directly binds and targets cytoplasmic SET oncoprotein, which is overexpressed in majority of NSCLC cells and tumors. Cytoplasmic SET is a known inhibitor of protein phosphatase 2A (PP2A). FTY720-SET binding prevents inhibitory SET-PP2A association, leading to the activation of tumor suppressor PP2A. Mechanistically, activation of PP2A by FTY720 induces necroptosis and cell death in NSCLC cells in culture and in animal models through the formation of RIPK1-C16-ceramide-non- muscle myosin IIA (NMIIA) enriched pores (we coined the name “ceramidosomes”) at the plasma membrane. Thus, we designed this application to test the novel hypothesis that FTY720 and its functional mimetics mediate NSCLC cell death and tumor suppression, at least in part, by directly binding and targeting SET oncoprotein, resulting in the generation of plasma membrane pores and necroptosis. There are three Specific Aims proposed in this application: Aim 1) Define the mechanism by which FTY720 mediates necroptosis via induction of ceramidosomes. Aim 2) Identify how FTY720-induced ceramidosomes are activated by PP2A to mediate necroptosis. Aim 3) Determine the therapeutic and clinical significance of targeting SET by FTY720 and its functional mimetics, like A7-2, to mediate PP2A-dependent ceramidosome activation and NSCLC tumor suppression. These studies will help define how targeting SET induces necroptosis using molecular, genetic, pharmacologic, and structural tools, including X-ray crystallography and cryo-EM. Moreover, data obtained from this proposal will help predict which of the NSCLC patients are likely to benefit from the treatment with FTY720 and its analog drugs. We will also utilize functional mimetics of FTY720, such as A7-2, which is a recently developed analog that inhibits SET and induces necroptosis at nanomolar concentrations, in the absence/presence of mutant (G12C)-K-Ras inhibitors, such as sotorasib or adagrasib, to suppress NSCLC tumor growth/progression. Thus, these studies will provide first-in-class treatment options and precision therapy for the treatment of patients with refractory NSCLC.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY/ABSTRACT The healing response within the myocardium after a myocardial infarction (MI) is complex and involves both temporal and regional changes including inflammation, cardiac scar formation, and tissue remodeling. Within minutes following ischemic injury neutrophils and monocytes are recruited to the damaged heart. As the monocytes are activated, enter the myocardium and are stimulated by the cardiac environment, they mature into a diverse population of macrophages. In the first days post-MI, inflammatory monocytes and macrophages facilitate the removal of necrotic tissue by secreting proteases and inflammatory enzymes and cytokines. As healing progresses, the reparative less inflammatory macrophages begin to dominate, secreting anti- inflammatory cytokines and communicating with myofibroblasts, endothelial cells, parenchymal and local progenitor cells to help coordinate remodeling and repair of the damaged tissue. Over the last decade the importance of the spleen has been highlighted as a reservoir for the majority of monocytes trafficking to the heart in response to ischemic damage. Upon infarction, increased angiotensin II levels promote the migration of monocytes from the spleen to the heart where they differentiate into macrophages and partake in the inflammatory phase of the insult. Further, the spleen is a major site of monocyte proliferation post MI and contributes significate numbers or monocytes throughout the duration of acute inflammation. Days after the initial injury, the phenotype of monocytes recruited from the spleen changes to one that is reparative, differentiating into macrophages which suppress inflammation, inducing matrix deposition and angiogenesis. We have demonstrated that the systemic inhibition of HDACs results in myocardial preservation after MI, and more recently shown that the delivery of this pan-HDAC inhibitor specifically to the spleen is capable of producing a comparable therapeutic effect, yet at a 33-fold reduced dose. This proposal thus aims to unearth the mechanisms responsible for this observed efficacy, both within the spleen and the heart. As well, the advanced nanomaterials with enhanced splenic retention will also be utilized to dissect the relevant contributions of each HDAC to the therapeutic effect, ultimately resulting in an optimized therapeutic regime.

NIH Research Projects · FY 2024 · 2024-07

PROJECT SUMMARY The goal of this project is to meet the evolving needs of NIH and other research at the Medical University of South Carolina (MUSC), maintain a pathogen-free animal research environment, and maintain full accreditation from AAALAC International and full compliance with NIH/OLAW, USDA and other regulatory agencies. This project will benefit a diverse group of 31 basic and translational investigators who actively use rodent models of human disease housed in the designated facility to conduct research in neurosciences, substance abuse, cancer, metabolomics, regenerative medicine, and biomarker development. The Division of Laboratory Animal Resources (DLAR) is responsible for providing all laboratory animal services and support for the 6 colleges at MUSC. We support the research needs of 164 unique investigators on campus using animal models. The Thurmond-Gazes facility was built in 1996 and was fitted with animal housing and caging in 1997, which are now obsolete. Limitations to our current facility include its small rooms, which only fit 2-3 free standing racks each. The free-standing racks and associated microisolators are obsolete. Upgrading the caging with associated integration of remote monitoring of cage microenvironment would increase housing capacity. To further support this new caging system, the facility plans to upgrade the plumbing for auto watering. This will permit us to decrease cage change frequency to every other week and will eliminate the need for changing water bottles. This will result in decreased costs for labor, decreased risk of allergen exposures, repetitive motion, and ergonomic injury of personnel. Currently, there is no room for change stations to protect personnel from dander or potential exposures to the animals with the current configuration. With the smaller footprint of the vent racks, in the future we will be able to add change stations to decrease the exposure of our personnel to animal allergens which will align this facility to present-day OSHA best practices. Methodologies are also advancing the need for more animals in a limited space. We currently use cutting-edge or “emerging” approaches to study complex rodent behaviors using models for studying substance use disorders and neuropsychiatric conditions. Much of this work relies upon behavioral work in both mice and rats. which, when single housed require substantial housing space. With new caging systems, we can increase our housing in these rooms by 50-100 percent, depending on the room. Increased capacity is critically needed to support rapid, ongoing growth in neurosciences, substance abuse, and other biobehavioral and biomedical research at MUSC that rely on rodent models of human disease. Support is requested to facilitate research productivity, efficiency, and collaboration among NIH-funded investigators by increasing housing capabilities and increasing personnel safety and the repeatability of research.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY/ABSTRACT The overall aim of the proposed K23 Mentored Patient-Oriented Research Career Development Award is to provide Dr. Gex with the training and research activities needed to become an independent investigator. Her program of research will focus on developing and delivering novel brief interventions for problematic substance use and increasing accessibility and uptake of efficacious interventions. Cannabis is the most widely used federally illicit substance among emerging adults (age 18-25) in the U.S., and frequent cannabis use is associated with myriad long-term consequences. Despite this, rates of perceived risk of daily/regular cannabis use have steadily declined over the past two decades. Several cannabis brief interventions have been developed and tested to date; however, meta-analyses indicate that the evidence for efficacy is mixed and that the quality of studies is low, suggesting that novel and more rigorous approaches are necessary. The proposed project will employ the NIH Stage Model for Behavioral Intervention Development to develop and test the feasibility, acceptability, and preliminary efficacy of a novel brief intervention. In addition, cannabis-specific candidate mechanisms of behavior change will be explored, including motives for use, protective behavioral strategies, consideration of future consequences, and proportional substance-free/-related reinforcement. This innovative proposal includes training activities to ensure that Dr. Gex achieves the following new career goals: (1) Develop expertise in the assessment and prevention of cannabis use and cannabis use disorder; (2) Receive training in the development and evaluation of behavioral interventions by (2a) Enhancing qualitative and mixed methods research skills and (2b) Receiving advanced training in the design and implementation of clinical intervention trials; (3) Develop expertise in the science of mechanisms of behavior change; and (4) Enhance skills in scientific and grant writing and professional development. Under the mentorship of a multidisciplinary team of outstanding investigators (Drs. Kevin Gray, Rachel Tomko, and Shannon Phillips at the Medical University of South Carolina, Dr. Christine Lee at the University of Washington, and Dr. Ben Ladd at Washington State University), the candidate will develop and evaluate a novel in-person brief intervention addressing frequent cannabis use in emerging adults. The combination of outstanding mentorship, hands-on experiences, and didactics and formal coursework afforded by the proposed K23 award will significantly enhance the candidate’s career development in patient-oriented research focused on the prevention and early intervention of substance use disorders in emerging adults and will provide a valuable training experience and critical preliminary data to support future R- series applications. This K23 application is directly responsive to NIDA’s Strategic Plan to develop new and improved strategies to reduce cannabis use and prevent long-term consequences, specifically to develop and test innovative prevention interventions that target relevant mechanisms underlying salient risk factors.

NIH Research Projects · FY 2026 · 2024-06

Project Summary Caregivers in emerging and young adulthood account for nearly half of all caregivers in the United States; however, they are significantly underrepresented in cancer caregiving scholarship. Little is known about their unique psychosocial needs, and there is a dearth of cancer caregiving resources to support them. Emerging and young adult caregivers (EYACs, ages 18-35) are a particularly vulnerable caregiving population. They experience higher rates of psychological distress than their older counterparts, as well as lasting impacts to their developmental trajectory as a result of their caregiving experience. Caregiving at this age is particularly challenging when an EYAC must provide care to a parent with cancer, as they must undergo a distressing relational shift = that creates psychological and communication challenges unique to this patient-caregiver dyad. Diagnosed parents are known to withhold information about their cancer from their adult children, which creates further difficulties for EYACs in communicating and coping with their parents. Open family communication during cancer has been linked to better social, psychological, and physical health outcomes for both caregivers and patients. Thus, there is a significant need for a communication skills intervention directed at EYACs of their parents with cancer to help them navigate the interpersonal challenges associated with their caregiving role that can lead to distress. The goal of this project is to identify the complex communication needs unique to this age group and adapt an existing caregiver communication skills training intervention (Healthy Communication Practice, HCP) to meet their age-specific communication needs. The K99 phase of this project will include two aims: 1) identify EYACs’ unmet communication skill needs via online survey, and 2) use the survey findings to adapt the intervention materials and pre-test them in EYAC focus groups. The R00 phase of the project will pilot test the new EYAC-tailored intervention for feasibility and acceptability. The objective of this application will not only create the first communication support intervention specifically designed for EYACs, but it will also equip Dr. Kastrinos with the necessary skills and training to complete the proposed research and transition to research independence. She will advance her training in four key areas: 1) psychosocial intervention development and adaption in cancer caregiving, 2) advanced mixed-method and quantitative design and analysis, 3) designing and conducting RCTs, and 4) professional skills development. She will complete both her training and the proposed research with the full support of her mentors (Drs. Allison Applebaum, Smita Banerjee, Yuelin Li), her collaborators (Drs. Carma L. Bylund and Carla L. Fishers) who are the creators of HCP, and her advisory board (Drs. Kathryn Greene and Youngmee Kim). At the end of her R00 phase, Dr. Kastrinos will submit an R01 application to test the efficacy of the new intervention in a fully powered randomized controlled trial. This K99/R00 plan will enable Dr. Kastrinos to achieve her goal of filling a critical research and resource gap for EYACs and launch a research program addressing their needs.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY/ABSTRACT The co-use of tobacco and cannabis is prevalent, appears to be increasing among adults in the United States (US), and has been shown to adversely affect treatment and other clinical outcomes. Yet, there are currently no recommended treatment strategies for tobacco-cannabis co-use, nor are there tailored treatment strategies for tobacco cessation among those who use cannabis. Treatment interventions addressing co-use have been preliminary and none have been designed to evaluate an intervention compared to a control condition through a fully-powered randomized controlled trial. Our preliminary data, supported by the larger literature, has shown that: 1) cannabis co-use has a profound negative impact on cigarette abstinence, and 2) varenicline, an FDA approved pharmacotherapy for tobacco cessation, may be beneficial in reducing cannabis use. Collectively, our results show promise for varenicline in reducing cannabis use and given its established efficacy for tobacco cessation, there is strong justification for its evaluation for tobacco-cannabis co-use treatment, as proposed here. We propose to pair a promising pharmacotherapy (varenicline) with psychosocial support targeting co-use in order to bolster treatment outcomes and reduce harms. This study is a completely remote 12-week treatment trial among adults in South Carolina (ages 18+; N=200) who co-use cigarettes and cannabis regularly. Participants will be included who smoke cigarettes daily or near daily (20+ days in the past 30; other regular tobacco product use is exclusionary) and have used cannabis at least 3 times per week in the past month (exclusive medical cannabis use is exclusionary). Participants will be randomized 1:1 to varenicline or placebo and both groups will receive an evidence-based psychosocial intervention that includes real-time and asynchronously delivered content (all delivered virtually). The aims of the study are to: 1) evaluate rates of 7- day biochemically confirmed point prevalence abstinence (PPA) from cigarettes at the 12-week end of treatment (EOT) visit comparing varenicline + psychosocial intervention to the placebo + psychosocial intervention participants (Aim 1), 2) compare cannabis use frequency and amount between varenicline and placebo groups from the target quit date until EOT (Weeks 1-12; Aim 2), and 3) explore differential treatment outcomes among male vs. female participants (Exploratory Aim). There is an urgent need to evaluate treatment interventions addressing the co-use of tobacco and cannabis in a general population of adults. The proposed intervention is supported by rigorous prior research, including our own work, and the decentralized design and remote intervention delivery contribute to the scalability of this intervention to address co-occurring tobacco and cannabis use.

NIH Research Projects · FY 2025 · 2024-05

Project Summary Myosin 5b is responsible for transporting key apical proteins to the surface of epithelial cells. Myosin 5b is most widely studied because of its association with Microvillus Inclusion Disease, a congenital diarrhea disorder in which inactivating mutations in Myosin 5b is a primary cause. Individuals with Microvillus Inclusion Disease frequently present with cholestasis in addition to their intestinal defects; indicating potential alterations in liver function arising from loss of Myosin 5b. Data acquired under my NIDDK K01 career development award demonstrates that germline Myosin 5b knockout mice exhibit alterations in liver function in terms of polarity and bile acid profiles. We also observed that Myosin 5b knockout mice had lipid accumulation and altered mitochondrial function which suggests that Myosin 5b has diverse roles in liver metabolism. This R03 proposal seeks to build upon findings from my K01 award and identify the role of Myosin 5b in regulating liver metabolism. The central hypothesis of this research proposal is that Myosin 5b transports and positions lipids, glycogen stores and mitochondria within hepatocytes. We propose that in the absence of Myosin 5b lipids and glycogen stores are immobilized preventing the proper process of these molecules. Additionally, we postulate that Myosin 5b regulates mitochondria dynamics and function. We base our hypothesis on preliminary data generated from our mouse model which shows changes in lipids, glycogen stores and mitochondria in the liver of Myosin 5b knockout mice compared to littermate control mice. Liver organoids generated from Myosin 5b knockout mice exhibited decreased oxygen consumption rates compared to control organoids demonstrating decreased mitochondrial function. For this R03 application, we propose to use germline Myosin 5b knockout mice to address deficits in lipid metabolism, glycogen mobilization and mitochondria in vivo and in vitro. Specific Aim 1 will define changes in lipid and glycogen in hepatocytes resulting from loss of Myosin 5b. Specific Aim 2 will determine the role of Myosin 5b in regulating liver mitochondrial function. We will use cutting edge research techniques including high resolution confocal imaging, live imaging of liver organoids as well as metabolic profiling. At the completion of these studies, we expect to have elucidated the role of Myosin 5b in the regulation of metabolic pathways in hepatocytes. Funding of this R03 proposal would provide support and new preliminary data to base a NIDDK R01 application. Additionally, this project will provide new research avenues for my lab that are very distinct from my postdoctoral work and my postdoctoral mentor’s scientific interests. This R03 proposal highlights the need for a better understanding of the function of Myosin 5b within the liver and in regulating pathways that have historically not been linked to Myosin 5b.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY / ABSTRACT Systemic sclerosis (SSc) is a rare and devastating connective tissue disorder that results in fibrosis and vascular abnormalities that can affect the skin, lungs, gastrointestinal tract, heart, and kidneys. The underlying mechanisms are complex and largely unknown, and no effective treatment exists to stop the progression of fibrosis in SSc or reverse it. Interstitial lung disease ILD) associated with SSc is a leading cause of death inSSc patients. The focus of this proposal is on the epigenetic regulation of KLF4, a transcription factor with anti-fibrotic function in pulmonary fibroblasts (pFBs). KLF4 is downregulated during active fibrosis. The goal is to identify targetable epigenetic factors regulating KLF4 as premises to develop effective therapies for SSc-ILD. To accomplish this, Dr. Renaud will (1) determine the involvement of HDAC(s) in the transcriptional repression of KLF4 in pFBs, (2) build a comprehensive regulatory network based on differentially expressed (DE) genes, microRNAs, and long non-coding RNAs (lncRNAs) to identify and validate the role of miRNAs and lncRNAs in the regulation of KLF4 and (3) track KLF4 regulation within the different cell types and subpopulations of fibroblasts present in lung tissues. Dr. Renaud is a molecular/cellular biologist in the Division of Rheumatology at the Medical University of South Carolina (MUSC). Her long-term career goal is to become an independent translational researcher in fibrosis with a specific interest in epigenetic factors that regulate early phases of fibrosis. To facilitate her transition into an independent investigator, she seeks to further her training in bioinformatics and computational tools for the analysis of single-cell RNAseq data, and in the field of network biology. Dr. Renaud’s successful transition to an independent career will be supported by (1) her primary mentor Dr. Feghali-Bostwick an authority in SSc research with an excellent track record of mentorship, (2) an advisory committee with the relevant expertise, (3) institutional centers and cores, and (4) the Department of Medicine’s support and robust mentorship program. By defining the epigenetic factors responsible for KLF4 downregulation in SSc-ILD, therapeutic strategies aiming to restore antifibrotic levels of KLF4 can be developed to prevent, stop, and possibly reverse the progression of fibrosis. The results of this proposal will provide critical preliminary data supporting extramural applications. The proposed training will enable Dr. Renaud to achieve her long-term objective of becoming an independent investigator.

NIH Research Projects · FY 2026 · 2024-05

Summary: For patients who have a heart attack (myocardial infarction; MI), 1 in 3 will not survive 5 years after the event. Therefore, there is a critical need to facilitate the long-term goal of providing potential intervention targets to prevent, slow, or reverse progression to heart failure in heart attack patients. The long-term goal of the proposal is to understand how CD8+ T-cells are impairing the wound healing response after MI leading to eventual development of heart failure. The specific objective is to understand the temporal changes in the genetic and physiological profiles of the CD8+ T-cell population and how this regulates cardiac wound healing after a heart attack. The central hypothesis is that temporal changes in CD8+ T-cell heterogeneity mediates alterations of the constitutive properties of the ischemic scar and subsequent ventricular dysfunction. Aim 1 will test the hypothesis that temporal regulation of CD8+ T-cell activation is a fundamental determinant of the constitutive properties of ischemia induced myocardial scar. Aim 2 will test the hypothesize that CD8+ T-cell downstream effects during post-MI remodeling are not fully regulated by antigen presentation. This proposal will take a cutting-edge and integrative multidisciplinary approach to evaluate CD8+ T-cells in the MI setting. The completion of the study will provide a better understanding of critical mechanisms underlying adverse effects of the adaptive immune response and wound healing after MI. The proposed study aligns with the mission of the healthcare system by providing molecular knowledge to clinical practices so that we can continue to provide exceptional health care that improves patient health and well-being.

NIH Research Projects · FY 2025 · 2024-05

Project Summary Cardiovascular disease (CVD) is the leading cause of death in the United States. Multiple studies indicate that Post-Traumatic Stress Disorder (PTSD) is a risk factor for CVD. Clinical studies suggest that PTSD stimulates chronic and uncontrolled inflammation through various cytokines and immune cells like macrophages and matrix metalloproteinase (MMP)-9. While these presented studies highlight associations, literature is lacking in mechanisms connecting both CVD and PTSD, leaving patients vulnerable to CVD associated events. Accordingly, the proposed study aims to determine the association between PTSD-induced chronic inflammation and the resetting of cardiac homeostasis. The central hypothesis is that PTSD stimulates recruitment of monocyte-derived macrophages to the heart, resulting in increased cardiac fibrosis and resetting cardiac homeostasis via MMP-9 dependent mechanism. Aim 1 will test the hypothesis that monocyte specific MMP-9 stimulates PTSD-mediated cardiac remodeling and dysfunction. Aim 2 will test the hypothesis that PTSD-induced hyperactivation of monocytes stimulate fibroblast ECM production. Together the data will provide a foundation for future mechanistic studies between CVD and PTSD to further the fields of both cardiology and neuroscience. Collectively, the proposed studies align with the mission of NIH and NHLBI and will enhance overall health, quality of life, and reduce disability.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY/ABSTRACT: Post-traumatic stress disorder (PTSD) has a high rate of comorbidity with cannabis use disorder (CUD). Indeed, in veterans diagnosed with CUD, PTSD is the most highly co-occurring disease. Moreover, patients with comorbid PTSD and CUD have greater drug use severity and show poorer treatment outcomes than patients diagnosed with either PTSD or CUD alone. Conversely, PTSD is often listed as a medical condition potentially ameliorated by cannabis use. However, the clinical literature is mixed regarding the effect of cannabis use on PTSD symptoms, with some earlier studies indicating cannabis use may self- medicate PTSD and newer literature arguing that it exacerbates PTSD symptoms and reduces treatment efficacy. Thus, the prevalence of PTSD/CUD comorbidity and the increasing legal status of cannabis in United States make it imperative to understand the mechanisms whereby cannabis use is potentially promoting or ameliorating PTSD symptoms. Using acute restraint stress combined with a rat cannabis self-administration paradigm, I recently found that cannabis use promotes two primary PTSD-like symptoms, avoidance coping behaviors (immobility in the defensive burying task) and the generalization of stress coping responses to a neutral stimulus not previously associated with stress exposure. These clinically relevant discoveries are the foundation for my K99/R00 Pathway to Independence proposal. This proposal aims to identify neurobiological mechanisms underpinning how cannabis use changes and potentially exacerbates PTSD-like symptoms. During the K99 portion, I will characterize, in a cell-specific manner, the neuroadaptations induced by the interaction between stress and cannabis use in the nucleus accumbens core (NAcore). To this end, I will combine in vivo zymography with confocal microscopy and digital rendering approaches to quantify changes in the tetrapartite synaptic plasticity, which includes changes in: morphology of D1- and D2-medium spiny neurons (MSNs), astroglia, and the extracellular matrix (ECM) (Aim 1). I will then use the in vivo single-cell Ca2+ recording from D1- and D2-MSNs in NAcore, to determine which cell type and what patterns of activity are associated with the exacerbating effects of cannabis use on stress responses (Aim 2). In the R00 portion, I will apply my K99 training to study how stress and cannabis affect the tetrapartite synaptic plasticity in ventral pallidum (VP), a primary accumbens output nucleus that translates rewarding and aversive stimuli into behavioral responses. I will assess the signaling between ECM, astrocyte and GABAergic neurons (VPGABA), as well as the expression of perineuronal nets (PNNs) following acute stress and cannabis use (Aim 3a). I will then evaluate the specific role of PNNs in the altering effects of cannabis use on stress responses (Aim 3b). Finally, I will use changes in intracellular Ca2+ to determine if exposure to stress-conditioned stimuli or neutral stimuli changes the activity of VPGABA after cannabis use (Aim 4). By examining tetrapartite plasticity in a brain circuit known to strongly regulate both reward and avoidance behaviors, I expect to identify new targets for regulating PTSD and CUD comorbidity.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY The Children's Heart Program of South Carolina is a statewide consortium of pediatric cardiologists who provide pediatric cardiac care for >90% of the 5.1 million residents in the state. The Pediatric Heart Program at MUSC performs all of the cardiac surgery and interventional cardiac catheterizations for this racially and ethnically diverse patient population. Clinical outcomes are consistently among the best in the country. MUSC has all the critical elements to be a successful contributor in the Pediatric Heart Network (PHN): adequate patient volume, established clinical research infrastructure, a track record of outstanding subject enrollment, and a dedication to hypothesis driven research. These elements have allowed our site to be a highly successful and administratively active participant in the PHN and one of only 5 core centers to be continuously funded since its inception in 2001 The combined resources of patient volume, research infrastructure and dedication have enabled MUSC to be among the top subject enrollers in the PHN. During this period, we have introduced numerous trainees and junior faculty to the PHN and mentored them toward successful careers in clinical investigation. MUSC faculty, nurse practitioners, and ancillary staff have participated as Pls in a wide variety of multicenter studies, including many NIH-funded trials, analyses of clinical registry data, and industry sponsored/FDA regulated trials. Our nationally recognized team of investigators have an extensive track record of extramural funding, national presentations, publications in leading journals, and an extensive network of diverse collaborators across North America. MUSC faculty also currently direct numerous local clinical research protocols. In this application, we have submitted a concept proposal for a novel and highly impactful study of the impact of environmental neurotoxins on early clinical and 18-month neurodevelopmental outcomes of neonates undergoing cardiac surgery. The aims and hypotheses in this proposal are supported by strong pilot data generated by our research team in collaboration with external investigators that demonstrate significant exposure to cyclohexanone, phthalates, and volatile organic compounds in neonates undergoing cardiac surgery. These exposures occur both in the hospital setting and/or the home environment and have the potential to explain some of the disparate outcomes observed in this patient population. Our preliminary work has established the feasibility of the project and the directionality of the findings in terms of impact on patient outcomes. Given the prior success of PHN centers in enrolling neonates undergoing cardiac surgery in clinical trials, the project is likely to be completed in a timely fashion and lead to actionable changes in patient care.

NIH Research Projects · FY 2025 · 2024-04

Project Summary/Abstract Inflammatory bowel disease (IBD), comprising Crohn's Disease and Ulcerative Colitis, is a chronic condition characterized by gastrointestinal inflammation. Among the IBD subtypes, Crohn’s disease is the most common, affecting 1.6 million individuals in the United States today. The prevalence of IBD is increasing worldwide, underscoring its significance as a major health issue. Despite being a significant healthcare and economic burden there is no cure for the disease currently. The complex etiology of IBD involves a combination of genetic, environmental, and immunological/microbial factors. Currently, the precise triggers of gastrointestinal inflammation in IBD remains unclear. Recent studies highlight that patients with Crohn’s disease have increased pathogenic bacteria levels and individuals with Crohn’s disease are more susceptible to bacterial infections. Other studies have shown that microvilli and the proteins responsible for linking microvilli together, the intermicrovillar adhesion complex (IMAC), are disorganized in Crohn’s disease patients. Under normal physiological conditions, the IMAC are found at the tips of microvilli where they provide physical interactions between neighboring protrusions. The IMAC increase the functional capacity of intestinal absorptive cells by promoting dense packing of microvilli and by regulating microvilli length. To reach the microvilli tips, IMAC components must be trafficked to the apical membrane and be correctly targeted to the tips of microvilli. It is well documented that the molecular motor Myosin 7b traffics and anchors IMAC proteins from the apical membrane to the tips of microvilli. Recent findings from our group have demonstrated that Myosin 5b is the molecular motor responsible for trafficking IMAC proteins to the apical membrane of enterocytes. Interestingly, preliminary data also suggests that Myosin 5b may play a role in the pathogenesis of IBD. However, there has yet to be a single study that has investigated Myosin 5b, IMAC, and Crohn’s disease. This research proposal aims to investigate how Myosin 5b regulates microvilli assembly in the intestine and investigate the degree of susceptibility of microvilli exhibiting aberrant packing and size to pathogenic bacteria that are elevated in Crohn's disease patients. We hypothesize that Crohn's disease patients have reduced Myosin 5b protein levels, leading to mislocalization of IMAC components. We further hypothesize that the lack of IMAC delivery results in disordered microvilli thereby increasing the susceptibility of the intestinal epithelium to bacterial insults. We will use both in vivo and in vitro models to explore the alterations in Myosin 5b and IMAC components that occur in Crohn’s disease (Aim 1), and how loss of Myosin 5b affects microvilli regulation, organization, and susceptibility to bacterial insults (Aim 2). By employing Myosin 5b deficient mouse models and leveraging human Crohn’s disease tissue, we aim to gain better understanding of the function of Myosin 5b in microvilli assembly and gain novel insights into the pathogenesis of Crohn’s disease.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY Colorectal abnormalities such as pre-cancerous fibrotic disease and colon cancer are prevalent. However, the mechanisms that link the extensive extracellular matrix (ECM) remodeling that occurs during fibrosis to pro- tumorigenic cell transformation are still poorly understood. Compromised epithelial integrity is a common feature of these colorectal conditions. Recently, we discovered a mechanism that links epithelial tissue integrity with the RNA interference (RNAi) machinery, miRNA regulation, and colon cell behavior. We have shown that the adherens junctions, which is an essential architectural component of the cell, recruit the microprocessor and the RNAi-induced silencing complex (RISC), the core components of the RNAi machinery, as well as a specific set of miRNAs and mRNAs, in colon epithelial cells. This interaction occurs through PLEKHA7, a member of the E- cadherin cell-cell adhesion complex. PLEKHA7 loss results in compromised epithelial integrity, decreased levels and silencing activity of a set of miRNAs, increased oncogene expression and pro-tumorigenic cell transformation. We have also found extensive dysregulation of PLEKHA7 and of the junctional RNAi machinery in colon cancer cell lines and tumor patient samples. Colon epithelial tissues undergo abnormal physical stress during fibrosis and colon cancer due to excessive ECM remodeling, which promotes disease progression. Interestingly, our preliminary data reveal that application of physical stress to colon epithelial cells through the ECM results in mis-localization of the junctional RNAi machinery. We also have preliminary evidence that disruption of the junctional RNAi results in overexpression of ECM remodeling regulators and promotes ECM remodeling and cell migration. We hypothesize that biomechanical cues from the ECM result in dysregulation of PLEKHA7 and its associated RNAi machinery at the adherens junctions, promoting oncogene expression, further ECM remodeling, and pro-tumorigenic cell behavior. We will examine our hypothesis under two specific Aims: 1) Physical cues from the ECM regulate PLEKHA7-RNAi complex formation and function at adherens junctions; 2) PLEKHA7-associated miRNAs regulate ECM remodeling and pro-tumorigenic cell behavior. This study is significant, since it investigates a novel mechanistic link between physical changes in the ECM, epithelial integrity, and colon epithelial cell behavior through a localized function of the RNAi machinery. The proposed work is innovative by introducing the concept of a mechanosensitive RNAi machinery at adherens junctions. The impact of the study is that it will advance our understanding of the underlying mechanistic causes of intestinal diseases, particularly those connecting fibrotic conditions to pro-tumorigenic cell transformation. Since this involves miRNA regulation as the focal point in the crosstalk between ECM and colon cell behavior, the study can lead to future development of RNA-based therapeutics.

NIH Research Projects · FY 2026 · 2024-04

ABSTRACT Adoptive T cell therapy (ACT) is a promising approach for treating patients with advanced malignancies. Advances in molecular biology and genetic engineering have led to the design and use of modified T cells that can recognize tumors to achieve significant tumor control upon ACT to patients. These T cells are either transduced with tumor antigen reactive T cell receptors (TCR), or chimeric antigen receptors (CARs). Yet, elimination of established tumors has not been effectively achieved, typically due to loss of T-cell effector function or failure of long-term survival. Most ACT trials use rapidly expanded T cells that are terminally differentiated and exhibit an effector memory (Tem) phenotype. These Tem phenotypes bearing cells are more susceptible to the adverse effects of the tumor microenvironment (TME). Therefore, the development of novel mechanism based therapeutic strategies that can reprogram anti-tumor T cells to maintain their metabolic fitness and effector function in a tumor microenvironment is urgently needed to enhance the therapeutic value of ACT. Our Phase I clinical trial in this proposal builds on strong in vivo pre-clinical tumor control data obtained using novel ex vivo programming conditions that merge robust phenotypes of both Th1 and Th17 cells to generate a hybrid Th1/17 cell. We have recently established that programming conditions that bring together ‘anti-tumor effector function’ of Th1 cells and ‘stemness’ of Th17 cells lead to a superior hybrid Th1/17 (and Tc/17) cell exhibiting long-term tumor control. CD19 CAR T-cell therapy (CD19-CTCT) represents an enormous scientific and clinical breakthrough for patients with CD19-positive non-Hodgkin lymphoma (NHL), however, major issues still remain regarding toxicity and with the majority of patients succumbing to disease relapse. Thus, we hypothesize that ex vivo expansion and programming of CD19-CAR-Ts to metabolically enhanced hybrid T1/17 (Th1/17 and Tc1/17) phenotype will lead to robust anti-tumor control even with fewer adoptively transferred cells. Additionally, we have used cytoplasmically truncated CD34 tag (CD34t) into the CAR T cell construct to enable a more purified CAR T-cell product via CD34 selection, which aims to improve CAR T-cell antigen reactivity, persistence, and reduces off-target toxicities. Following specific aims are proposed to establish and develop our approach for commercialization: Specific Aim 1: Define a safe dose of meCD19- CD34t-CAR-T cells while evaluating efficacy for R/R B-cell NHL and CLL/SLL. Specific Aim 2: Establish pre- and post-infusion molecular signature and its correlation to anti-tumor response. We believe that this proposal will help adopt the novel ex vivo programming conditions for generating robust anti-tumor CAR-Ts that could be used in future in clinical trials to target other malignancies.

NIH Research Projects · FY 2026 · 2024-03

SUMMARY/ABSTRACT Smoking cessation is difficult, despite the demonstrated efficacy of several pharmacotherapeutic agents and cognitive behavioral therapies. This may be due to imbalanced neuronal circuits, including elevated functional connectivity in the drive-reward circuit (medial orbital frontal cortex [mOFC] to nucleus accumbens [NAc]) and decreased functional connectivity in the executive control circuit (dorsolateral prefrontal cortex[ DLPFC] to NAc). Repetitive transcranial magnetic stimulation (rTMS) is a new class of therapeutics that has already displayed remarkable potential for producing novel, non-pharmacological interventions for neuropsychiatric disorders. Previous studies have reported that rTMS decreased cue craving, reduced cigarette consumption, and increased smoking quit rate in tobacco use disorders(TUDs). However, the treatment parameters and exact mechanism for rTMS increasing smoking quit rate need further refinement. The goal of this UG3/UH3 application is to develop a circuit-based precision rTMS therapy for smoking cessation further. In the 2-year UG3 phase, we will recruit 45 TUDs. Participants will undergo a baseline cue-exposure fMRI and a resisting-to smoke fMRI session. Participants will be randomized into three groups: 1) Sham rTMS over the left mOFC or the left DLPFC. 2) Active, inhibitory low-frequency rTMS (LF-rTMS) over the left mOFC (1 Hz, 900 pulses, E- field modeling, 15 minutes, smoking cue exposure fMRI-guided target). Or 3) Active, high-frequency rTMS (HF- rTMS) over the left DLPFC (10 Hz, 3000 pulses, E-field modeling,15 minutes, resisting-to-smoke fMRI guided target). Fifteen sessions of rTMS will be completed over three weeks, after which we will acquire fMRI scans. Go/No-Go: To move on the UH3 phase, the UG3 must demonstrate (1) daily 1-Hz TMS over the left mOFC shows a different clinical effect in the reduction of cigarette consumption by 3 or more cigarette per day, compared to daily 10-Hz over the left DLPFC (2) compared to sham, one of the active site/frequency combinations shows relative clinical improvement (reduces cigarette consumption by 5 cigarettes per day) and significant brain connectivity changes (p < 0.05) (decreases the connection between NAc and mOFC, and increases the connection between DLPFC and NAc). In the 3-year UH3 phase, we will test the therapeutic effects of 4 weeks of active rTMS (1 Hz rTMS over the left mOFC or 10 Hz over the left DLPFC by the UG3 phase) vs sham rTMS in 64 TUDs and follow participant outcomes for 4 months post-treatment. We will also test the imbalanced function of drive-reward and executive control before and after 4 weeks of treatments to compare the imbalanced function between groups.

NIH Research Projects · FY 2026 · 2024-03

Patients are living longer with metastatic lung cancer (i.e., metavivors) due to therapeutic advances, but face significant challenges. Most metavivors will ultimately die of cancer and must navigate the duality of living while dying. Unsurprisingly, metavivors endorse high psychological distress (e.g., anxiety, depression, illness non- acceptance), high symptom burden (e.g., fatigue, dyspnea, pain), and poor quality of life. Psychosocial interventions can improve outcomes, but existing paradigms are not designed to help metavivors navigate the emotional turbulence of living with metastatic disease. Dialectical Behavioral Therapy (DBT) Skills Training is an evidence-based treatment that teaches patients transdiagnostic, easy-to-use skills to both accept things as they are (mindfulness, distress tolerance) and change things within their control (emotion regulation, interpersonal effectiveness) to better navigate life challenges. However, DBT Skills Training has rarely been applied in patients with chronic illness. We adapted DBT Skills Training (e.g., intervention dose, delivery, content) for patients living with metastatic lung cancer to create LiveWell, an 8-session Skills Training protocol delivered one-on-one via videoconference. Building on preliminary data and aligned with the ORBIT model for behavioral intervention development, the first phase of this study (K99, Aim 1, 1 year) aims to iteratively refine LiveWell using 1) qualitative exit interview data from a proof-of-concept study, 2) an advisory board of interested parties, 3) the Dynamic Sustainability Framework from implementation science, and 4) user testing (n=10). The K99 phase will produce a standardized protocol and procedures for the R00. The second, independent phase of the study (R00, Aim 2, 3 years) will be a Phase IIB randomized pilot trial to test study feasibility, acceptability and outcome patterns suggesting the efficacy of LiveWell compared to Enhanced Usual Care (EUC). Lung cancer metavivors (n=80, >20% non-White) receiving care at NCI-designated centers (N=2 sites) and endorsing distress >3/10 will be randomized to LiveWell or EUC. We hypothesize that: 1) LiveWell and EUC protocols and procedures will show evidence of feasibility (accrual N=80/20 months, >80% adherence to interventions and assessments, <20% attrition) and acceptability (>3/5 satisfaction study procedures, >3 mean intervention satisfaction LiveWell)), and 2) LiveWell will improve quality of life (primary outcome) and reduce psychological distress (depression, anxiety, illness acceptance) and symptom burden (fatigue, dyspnea, pain) (secondary outcomes) from baseline to post-treatment compared to EUC. We will explore emotion regulation as a mechanism of change. The objective of this Early K99/R00 is to provide Dr. Hyland with limited additional mentored training, then facilitate her transition to an independent investigator working to develop, test, and implement novel psychosocial interventions for cancer metavivors. Findings from this study will inform an R01 submission to conduct a Phase III efficacy trial of LiveWell. If successful, LiveWell will improve metavivor quality of life and provide a promising psychosocial intervention paradigm for other metavivors and patients with chronic illness.

NIH Research Projects · FY 2026 · 2024-03

This K24 Midcareer Investigator Award will provide Dr. Lindsay Squeglia with protected time to conduct research in adolescent alcohol use disorder treatment development, mentor junior clinical investigators in adolescent alcohol research, and continue her own career development in patient-oriented alcohol use research initiatives. The research aims of this grant are focused on utilizing inflammation markers, neuroimaging, and neurocognitive assessment to test a potential pharmacological agent to treat adolescent alcohol use disorder. This study will provide a strong training platform for junior investigators interested in patient-oriented alcohol research to gain experience in clinical trial methods, adolescent substance use assessment, alcohol and inflammation biomarkers, neuroimaging, neurocognitive assessment, pharmacotherapy development, and statistical analysis. It will also provide a platform for Dr. Squeglia to develop a new direction for her patient-oriented research by incorporating peripheral measures of inflammation and central measures of neuronal health, which could provide additional venues for identifying both treatment efficacy markers and candidate treatments for adolescent alcohol use disorder. She will utilize her network of national and international collaborators to provide networking opportunities for mentees and broad dissemination of research findings. Career goals will focus on areas critical to growth and development as a mentor and leader and will help ensure continued success with independent funding in neuroscience-informed alcohol use disorder treatment development. Goals will be achieved through hands-on research experiences guided by experts in the field; coursework; seminars, workshops, and conferences; and leading publications with trainees and expert colleagues in the field. In sum, this award will provide a platform for training the next generation of adolescent alcohol use researchers and expand the reach of adolescent alcohol use treatment research.

NIH Research Projects · FY 2025 · 2024-02

Many cancers exhibit aberrant overexpression of developmental lineage-specific transcription factors. In this project we investigate the potential of exploiting oncogenic overexpressed transcription factors to force cancer cells to produce anti-cancer therapies using a gene therapy strategy. We will design synthetic promoters specifically responsive to transcription factors of interest in different cancers to use in therapeutic vectors as drivers of cancer therapies. As a proof-of-concept, the project will begin with the lineage-specific transcription factor ‘X’ in the context of lung cancer. In lung adenocarcinoma the highly expressed homeobox protein ‘X’ is regularly used as a clinical marker and has been shown to be an oncogenic driver and fundamental to carcinogenesis. The investigation will extend to other lineage-specific transcription factors in different types of cancer, including prostate, breast, melanoma, brain, liver, head and neck, gastric, ovarian, kidney, cervical, pancreas, and Ewing sarcoma. The goal of our proposed aims is to develop a novel science for controlling spatial precision of drug delivery by exploiting a cancer’s transcription factor lineage-addiction to drive production of therapeutics locally. Our preliminary results indicate cancer-specific transgene expression after systemic therapy administration. In our first aim, we propose to study the effect of our gene therapy on cancer growth in a humanized murine model with therapeutic payloads safely used systemically in the clinic. In our second aim, we propose to develop a pipeline for unbiased discovery and validation of synthetic promoters specifically responsive to transcription factors of interest; work that will move beyond proof-of-concept experiments to designing gene therapy strategies for the range of human cancers with transcription factor-mediated growth dependencies.

NIH Research Projects · FY 2026 · 2024-02

Increased resistance to sinusoidal blood flow is an important component of early as well as advanced portal hypertension. This results from an imbalance in intrahepatic vasoconstrictor and vasodilator molecules, the latter including nitric oxide (NO). Our laboratory has been on the cutting edge of advances in understanding the molecular basis for the imbalance in NO that occurs after liver injury. Seminal among our discoveries is that there is a (dramatic and remarkable) reduction in endothelial NO synthase (eNOS) dependent NO release by sinusoidal endothelial cells (SECs) after liver injury. Further, this “endothelialopathy” is a critical feature of portal hypertension, especially early in disease. Our focus has been on understanding the mechanism underlying this defect. Preliminary data presented in the current application has identified highly novel post-translational defects in eNOS in SECs after liver injury, including reduced phosphorylation of eNOS caused by abnormalities in molecules that form a macromolecular regulatory complex that controls eNOS function (including the following G protein coupled receptor (GPCR) regulatory proteins: β-arrestins, GIT1 and now β-PIX). Additionally, many of these partners are regulated during liver injury. In the current project, we will test the highly focused and innovative central hypothesis that the GIT1/β-PIX complex and its partners play a fundamental role in regulating eNOS function. Therefore, overarching goals of this new project are twofold. First, we wish to uncover fundamental basic mechanisms that regulate eNOS function. Secondly, with a future objective being to translate our work to humans with liver disease, we wish to validate the importance of the proposed signaling pathways in vivo. Therefore, our specific aims are as follows: We will (1) determine how β-PIX, as a GIT1 binding partner, exerts a dual role in post-translational regulation of eNOS activity in normal versus injured SECs, and (2) we will characterize the function of the GIT1/β-PIX complex partner, paxillin, in regulating eNOS function through interaction with β-PIX and GIT1 after liver injury. The proposed experiments will uncover novel mechanistic aspects of eNOS function and as such have fundamental therapeutic implications not only for patients with liver disease and portal hypertension, but also for those with other vascular disorders.