Medical University Of South Carolina

NIH Research Projects · FY 2025 · 2016-07

PROJECT SUMMARY Based on genetic and cellular discoveries made in the PI lab and his collaborators, this proposal focuses on novel mechanisms that are critical for formation of heart valves. Data presented in the proposal are an evolution of our studies presented in the first round of funding and show that mutations in the DZIP1 gene cause a very common heart valve disease (i.e., mitral valve prolapse) and can be caused by errors in how valve tissue forms during development. These discoveries have led to a novel concept that cilia are involved in valve development. While the function of DZIP1 is a focus of our studies in this proposal, we will also define new mechanisms by which the cardiac valves establish a trilaminar ECM organization and how this can feed back to the cells to suppress ciliogenesis in specific regions of the valve. Our studies will provide unique opportunities to answer questions about heart-valve diseases that heretofore have been impossible to answer using even state-of-the- art biological and genetic approaches. Valvular heart disease is a serious clinical problem, affecting 5-7% of the human population. Its complications include congestive heart failure, endocarditis, atrial arrhythmias, and sudden death. There are no known non- surgical cures for this group of disease. The proposed work capitalizes on previously unrecognized genetic data collected from heart valve disease patients; studies in the mouse show that this class of genes is an important and previously unrecognized contributor to valve structural development and disease pathogenesis. The uncovering of this particular disease gene and the processes it regulates holds great potential for future remedial or therapeutic insight towards regeneration or formation of mechanically stable valve tissue that will be beneficial to valvular heart disease patients.

NIH Research Projects · FY 2025 · 2016-04

OVERALL SUMMARY/ABSTRACT The proposed renewal of this P01 builds upon the longstanding International Tobacco Control (ITC) Policy Evaluation Project, which has used cross-country comparisons and a common mediation model to evaluate the behavioral impacts of national-level tobacco control policies. The current P01 has extensively researched and documented the transitions between cigarettes and nicotine vaping products and how policies impact their use. For the renewal period, we are adding heated tobacco products, thus extending our previous two-product model to three products, but otherwise maintaining a similar team structure and research approach. The goal of this P01 renewal application is to address the question “What have different countries done to regulate tobacco products and how has this impacted tobacco use behaviors?” Our common integrated theoretical framework enables us to examine how and why policies and industry actions exert effects, as well as explore under what conditions products or policy interventions might translate into actual population-level impacts. We focus on the well-established 4 `P's' – product, price, placement, and promotion, and how public health policy and industry actions impact consumer perceptions, behavior, and ultimately health endpoints. Comparing the experiences of different countries with varying regulatory approaches is intended to inform United States public policy, based upon the best science available to maximize population health. To accomplish this, we propose to analyze policies and industry actions in different jurisdictions to answer the following three integrated questions: 1) Does the policy/industry action have an impact? (causality); 2) Under what conditions is it effective? (moderation); and 3) How is it effective? (mediation). The proposed studies assess direct and indirect or unintended effects that can affect the overall impact of a policy or action. We propose to conduct this work with four inter-related Projects, an Administrative Core, and two Shared Resource Cores, which collectively will: 1) track cohorts of adult tobacco users in 7 countries; 2) conduct repeated cross sectional surveys of youth and young adults in 3 countries; 3) utilize the Experimental Tobacco Marketplace to evaluate the effects of product availability, policy actions, and the illicit marketplace; and 4) perform statistical modeling using input from the Projects to predict consumer response. The three P01 specific aims are to: 1) understand how policies and industry actions impact consumer behavior; 2) develop scientific methods for assessing response to policies; and 3) forecast population impact of different policy approaches.

NIH Research Projects · FY 2024 · 2015-09

OVERALL – PROJECT SUMMARY / ABSTRACT Rehabilitation crucially requires interaction with the nervous system. Thus, neuromodulation (NM) is a tool uniquely able to address a large number of conditions and populations through a set of common principles that underlie an emerging neural circuit-based approach to rehabilitation and medicine. Our foundational belief is that applying NM to specific networks offers outstanding promise for advancing and improving nearly all fields of rehabilitation. While having grown over the past five years, the field of NM for rehabilitation (NM4R – the combination of NM and rehabilitation) is still nascent and is just beginning to clinically impact the practice of rehabilitation. The renewal of the National Center of Neuromodulation for Rehabilitation (NC NM4R) at the Medical University of South Carolina (MUSC) builds upon our early successes to facilitate the key steps in the discovery process that are required to develop the next generation of NM4R interventions and to use these tools to understand and study neuroplastic nervous system changes associated with rehabilitation. The center harnesses outstanding expertise in non-invasive NM, rehabilitation, operant conditioning of brain and spinal networks and animal models of NM4R. teams have formed a cohesive NM4R Community, returning to our center for multiple workshops and hands-on training experiential sessions, receiving follow-on consultations leading to pilot awards and extramural funding, and have publishing in peer-reviewed journals. The overarching goal over the new grant period is to impact multiple priorities of the NIH Research Plan for Rehabilitation (RPR) – most notably to translational science, pediatric rehabilitation and research design and methodology – by increasing rehabilitation research workforce access to NM4R approaches and supporting rigorous clinical research to translate them into effective, evidence-based rehabilitation interventions. Our Specific Aims are to: AIM 1. Increase the size and diversity of the rehabilitation research workforce with access to NM4R approaches; and AIM 2. Increase the impact of NM4R approaches. In the proposed renewal, our center will design yearly strategic activities to focus on impacting RPR priorities. Adjacent fields such as psychiatry are more advanced in applying NM tools in an emerging circuit-based medical model. NC NM4R will serve a vital purpose by infusing NM skills throughout the rehabilitation workforce and ensuring early exposure to the cutting edge of NM research for rehabilitation researchers in all domains.

NIH Research Projects · FY 2024 · 2015-07

PROJECT SUMMARY/ABSTRACT Continuation of a T32 research training program is proposed, Interdisciplinary Research Training in Otolaryngology and Communication Sciences, based in the Department of Otolaryngology-Head and Neck Surgery at the Medical University of South Carolina. Advancing the scientific foundation of otolaryngology and communication health, improving health outcomes, and developing and testing new treatments requires well- trained investigative teams with diverse skills and backgrounds in basic and clinical science. The training program continues to address these needs by supporting research opportunities in the disciplines related to otolaryngology and communication health, providing strong curricula in an integrative framework, with an interdisciplinary research culture that emphasizes mentoring, academic advancement, career development, grantsmanship, diversity outreach, responsible and ethical conduct of research, and productivity. The major components of our multifaceted program are: (1) predoctoral research training leading to PhD degrees in Biomedical Sciences or Health and Rehabilitation Science, with applications to otolaryngology/communication health; (2) research training for medical students who take the “year-out” option to extend their education with one year of research training; (3) short-term research training for health professional students with interests in otolaryngology and communication disorders (including medical, dental, pharmacy, nursing, audiology, speech-language pathology); and (4) postdoctoral research training for MD physician-scientists and PhD scientists in basic, translational, and/or clinical sciences related to otolaryngology/communication health. Each of these components is supported by highly collaborative mentors who direct active, funded research programs; interdisciplinary research collaborations and specialized training in a broad spectrum of research fields relevant to otolaryngology and communication health; and an exceptional institutional infrastructure and research culture provided by multiple departments, colleges, and universities. Mentoring expertise, technologies, and resources are thematically grouped in strategic areas of research focus: (1) basic and clinical research in otolaryngology sciences and disorders, (2) basic and clinical research in communication sciences and disorders, (3) basic and clinical neurosciences related to otolaryngology and communication health, such as development, cognition, aging, and neurobiology, and (4) biostatistics and health services research. Integrative activities include Otolaryngology and Communication Health Scholars Day, Seminars, and Journal Clubs, and didactic courses designed for our trainees. A history and record of interdepartmental collaborations and collegiality among researchers in disciplines related to otolaryngology and communication health is a key factor that led to early and ongoing success for our training program as evidenced by exceptional trainee accomplishments at all levels. Equally important is the long-standing culture of support, value, and enthusiasm for research training by the leadership of participating departments and institutions.

NIH Research Projects · FY 2025 · 2015-07

The purpose of this K24 renewal is to continue to exponentially enhance Dr. Carla Kmett Danielson's mentorship and research program in innovative approaches to risk reduction of HIV acquisition and addiction among adolescents, with a particular focus on trauma-exposed populations. Over the prior K24 funding period, Dr. Danielson, a clinical psychologist and scientist, demonstrated she is the ideal candidate for this mechanism. The impact of her protected time for expanded research and mentorship are evident through numerous achievements from over this funding period, including productive mentorship of 23 mentees (>50% from underrepresented backgrounds), awards in recognition of this mentorship, a new line of research in mHealth HIV and addiction prevention intervention, and continuous federal-funding of her innovative patient oriented research (POR) in which she has involved her mentees. Her mentees, who have included early-career faculty, post-doctoral fellows, and predoctoral psychology interns, are making significant contributions to the HIV prevention, substance abuse, and traumatic stress fields through high-impact publications and new lines of NIH-funded research. The proposed K24 award renewal will be essential for providing the time and resources necessary for the candidate to expand her research skills in virtual reality technologies for young people at high risk for HIV acquisition and addiction, sustain her mentoring program and capacity, and further stimulate the research program of her mentees (e.g., through a trainee pilot award program that was successful during the prior funding period). Innovative research proposed by Dr. Danielson under the K24 renewal involves refinement and evaluation of a virtual reality clinical tool to improve trauma-informed assessment and prevention of substance use and sexual risk behavior with at-risk young people. This will be accomplished through input and training from leading experts in the virtual reality-high risk behavior research field; an internationally known technology firm in virtual reality tool development (Virtually Better, Inc.); qualitative research; an Advisory Board of consumers and experts; and evaluation of the validity, acceptability, and feasibility of the refined virtual reality tool with high risk populations (e.g., adolescents in treatment for substance use problems and traumatic stress; young adults presenting to a high-risk HIV clinic) and health care providers. Dr. Danielson's proposed mentorship activities, current federally- funded research projects, and aims to pursue innovative, virtual reality research in the areas of HIV prevention, substance use risk reduction, and trauma among adolescents harmonize well with NIDA priorities that call for research designed to evaluate the application of new technologies for delivering adapted prevention interventions targeting substance use and prevention of HIV acquisition. The proposed research affords rich training opportunities for her mentees (with an emphasis on trainees from groups under-represented in clinical science) and will invigorate new directions in POR with young people at risk for HIV acquisition and addiction.

NIH Research Projects · FY 2025 · 2014-09

PROJECT SUMMARY Most nanoparticles for drug delivery fail in clinical trials due to insufficiency of animal models, highlighting the need for additional models to support the development of new nanoparticles. Specifically, there are limited quantitative methods to aid in the systematic design and development of nanoparticles for drug delivery to cancerous tumors. The proposed computational models can predict drug delivery to tumors, and we demonstrate model accuracy in preliminary studies. The goal of this project is to develop computational models that can simulate drug delivery to tumors in 3-D, incorporating spatial heterogeneities in tumor properties. This is achieved by employing 3-D imaging studies to derive tumor parameter maps, and then integrating those maps in the computer model. If successful, the proposed computer models will enable systemic evaluation of nanoparticles not possible with other experimental methods and may result in more efficient nanoparticle- based cancer therapies.

NIH Research Projects · FY 2025 · 2014-09

Valvuloseptal development involves a series of events during which septal structures and valves, which together are responsible for the unidirectional flow of two blood circulations through the heart, are formed. Faulty development of these structures can ultimately result in an inadequate oxygen supply to tissues throughout the body which in newborn babies can lead to “infant methemoglobinemia” better known as “blue baby syndrome”. In this project we continue our investigations into the role of the second heart field (SHF) in the pathogenesis of congenital heart disease. Specifically, we follow up on earlier published results and present new preliminary data on the role of SOX9 in the SHF and its importance in the regulation of septation. Based on data obtained during the last project period, we have designed three specific aims. In the first aim we will focus on the role of SOX9 and other SOX family members in outflow tract septation, while for the second aim we have designed experiments in which we will investigate the role of a new candidate gene, proenkephalin (PENK), in outflow tract development. Finally, in our third aim, we will, using a mouse model for Down syndrome, in which septation defects are frequently encountered, test hypotheses about the mechanisms that lead to defects in this model and might be involved in the etiology of defects in patients with Down Syndrome.

NIH Research Projects · FY 2025 · 2014-08

PROJECT SUMMARY The Medical University of South Carolina/Hollings Cancer Center (MUSC/HCC) aims to expand and enhance the NCORP trial portfolio by accruing from other medically overlooked groups into NCORP studies, share expertise and experience on broadening recruitment and retention and leveraging local knowledge within the NCORP community, and contribute to the development and implementation of cancer care and cancer delivery research. During the current project period, the MUSC NCORP-MU, which is comprised of three MUSC/HCC sub-affiliates and community oncology primary affiliates, has made significant contributions to the NCORP program through the effective and efficient accrual of historically overlooked patient populations and leadership that has shaped the scientific agenda for clinical trials, disproportional cancer health outcomes, and cancer care delivery research. These accomplishments were made possible through a highly invested and transdisciplinary investigative team consisting of David T. Marshall, MD (Radiation Oncology). Craig Lockhart, MD, MHS, (Medical Oncology), Marvella E. Ford, PhD (Public Health Sciences), and Evan Graboyes, MD, MPH (Otolaryngology and Public Health Sciences). The multi-PI team works hand-in hand with the clinical research operational leaders at the MUSC/HCC and local clinical investigative team at the NCORP affiliate location to establish and manage a robust clinical research operation to add value to NCORP. This leadership team has also worked collaboratively with other committed clinical and cancer control researchers, oncology care providers, cancer patients, and survivors in our catchment areas to advance all types of cancer research through the NCORP research bases. The MUSC NCORP-MU aims to improve fairness and access to clinical research in medically overlooked groups in order to enhance the quality of cancer care delivery and reduce differences in cancer health outcomes within South Carolina and communities across the US.

NIH Research Projects · FY 2024 · 2014-06

PROJECT SUMMARY / ABSTRACT The Organizing Concept of the parent Phase II COBRE in Stroke Recovery is that better understanding of the experience-dependent nature of neural plasticity allows us to investigate and exploit inherent neural recovery processes, develop and translate novel mechanism-based interventional strategies, and ultimately improve the function and quality of life of individuals recovering from stroke. And Overall Specific Aim 2 focuses on strengthening innovative scientific cores that support/advance stroke recovery research – such as the Brain Stimulation Core. Transcranial focused ultrasound (tFUS) offers unprecedented spatial resolution and depth of focus versus other methods of non-invasive brain stimulation - such as transcranial magnetic stimulation (TMS), transcranial electrical stimulation (tES), or deep brain stimulation (DBS) - and has been shown to be a safe and effective method of delivering precise ultrasonic energy to the brain without causing tissue damage or lasting neurological effects. The existing technology used by COBRE investigators has significant limitations. In direct alignment with the Organizing Concept and Overall Specific Aim above, we propose to acquire the first-in-class, state-of-the art transcranial focused ultrasound (tFUS) targeting, navigation, and sonication platform for administration of noninvasive deep brain stimulation (the NeuroFUS Pro Neuronavigated tFUS System). This platform will serve a pioneering suite of equipment designed to advance novel interventions for post stroke motor recovery, cognitive impairment, depression, and pain using the emerging new technology of ultrasound. This proprietary cutting-edge system incorporates technology that 1) allows for the advancement of focused ultrasound interventions in a stroke population, 2) enables precision administration with sub-centimeter spatial resolution of individual brain targets relevant to stroke recovery, 3) variable penetration depths ranging from 20- 80mm allowing for whole brain targets for cortical or subcortical sonication, 4) optimize sonication parameters and compare the calculated exposure and dose parameters based on individual skull and brain anatomy, and 5) administer tFUS using individual MRI targeting to conduct mechanistic and behavioral experiments that can rapidly advance this area of research. Taken together, this advanced focused ultrasound platform promises to make a large leap in the area of post-stroke rehabilitation by enabling access to previously inaccessible stroke- related brain areas. It will allow us to create new potential treatments for stroke recovery and allow us to further strengthen our research program through additional NIH funding opportunities. Such opportunities are a cornerstone of our COBRE sustainability plan to continue to thrive after Phase III.

NIH Research Projects · FY 2026 · 2014-04

Project Summary / Abstract Abstract Stroke is a disabling and often fatal disease that affects all ages, but mostly in the elderly. Stroke incidence is expected to rise in the US as its population ages. Therefore, its impact on public health and health resources utilization will continue to be significant. The National Institute of Neurological Disorders and Stroke (NINDS) has identified a need for a network of stroke clinical trial centers in order to prioritize and efficiently design and conduct exploratory (Phase II) clinical trials and confirmatory (Phase III) clinical trials to identify and advance stroke treatments. The NIH Stroke Net is a multidisciplinary stroke research infrastructure that includes a National Clinical Coordinating Center, a National Data Management Center (NDMC), 24 Regional Coordinating Centers, and the NINDS. Its mission is to develop and test new therapies for stroke treatment, recovery, and prevention that can decrease the global burden of stroke. The NDMC’s role is to establish a collaborative relationship with all parties involved in the Network and provide efficient and standardized central data management that yields high-quality data and statistical support in the planning and execution of the stroke trials. To this end, the Data Coordination Unit (DCU) at the Medical University of South Carolina has developed a web-based comprehensive integrated electronic data capture and clinical trials management system, WebDCU™, that enables data entry from the participating clinical sites with extensive data quality control and that provides the necessary tools to efficiently manage operational activities for concurrent multiple trials, while ensuring compliance with the NINDS Common Data Elements and FDA guidance and regulations. Using the WebDCU system, we have developed, implemented, and maintained a central database that streamlines and maximizes efficiency in the management of data collection, processing, and monitoring of clinical, biomarker and neuroimaging data. In addition, the WebDCU™ incorporates a trial management information system that provides full support for all study operational activities in the Stroke Net. In collaboration with the study Principal Investigator and other parties of the Stroke Net, the NDMC biostatisticians: contribute to the innovative and efficient protocol development (including study design and case report forms development); statistically monitor study progress; generate reports for the DSMB and the study teams; conduct interim and final analysis; disseminate study results via presentations and publications; and create public use data sets for data sharing when a study is completed.

NIH Research Projects · FY 2026 · 2013-01

Abstract This renewal application from the Medical University of South Carolina (MUSC) requests support for the continuation of the NIDA Mentored Clinical Scientists Development Program in Drug Abuse and Addiction (NIDA K12) at MUSC. Established in 2012, the overall objective of the NIDA K12 program is to provide an intensive program of mentored clinical research training and career development activities to promote the research independence of Scholars in substance use disorders. The substantial expertise in addiction research at MUSC ensures our ability to mentor individuals in the early stages of their research careers to contribute significantly to the understanding and treatment of substance use disorders. During the previous funding periods, a strong mentoring and career development infrastructure has been established, and participating Scholars have had significant success in obtaining independent federal funding. This application requests support to build on these programmatic successes by making innovative changes to strengthen the K12 program, including increasing opportunities for Scholar training in leadership development and scientific writing, providing innovative and timely didactic training in clinical research and entrepreneurship, broadening our mentorship pool to provide expertise in telehealth, opioid use disorders, and health disparities, and leveraging the newly developed MUSC Regional Health Network to expand addiction research throughout South Carolina. The program will support three Scholar positions. Scholars will remain in the program for typically two to four years, depending on their level of training and experience at entry and the time needed to obtain independent funding. Scholars will be junior faculty members recruited from internal and external candidate pools. In keeping with the mission of NIDA, emphasis during the renewal funding period will continue to be placed on attracting and training clinical researchers, building on MUSC’s strong track record of preparing highly trained scientists to address the Nation’s critical health care needs in drug abuse and addiction.

NIH Research Projects · FY 2025 · 2012-12

ABSTRACT Systemic sclerosis (SSc; Scleroderma) is a connective tissue disease of unknown etiology that is associated with significant morbidity and mortality. It has long been presumed that SSc likely results from environmental triggers, although these environmental insults have not been identified. The gold standard for assessing the role of environmental and inherited genetic effects on the development of a disease is the study of twins. A cross sectional study of twins with SSc we conducted several years ago showed a comparable concordance for disease of approximately 5% in monozygotic (MZ) and dizygotic (DZ) twins. We propose to conduct a follow-up study of the twin cohort to determine longitudinal concordance for disease, ANA status, and autoantibody presence. Since epigenetic regulation has emerged as an important mechanism mediating gene expression and the manifestation of a disease phenotype, we will also compare the DNA methylation profile of twins longitudinally. One of the factors we recently implicated in dermal fibrosis in SSc is estrogen. Our findings show that estrogen levels are elevated in Caucasian patients with diffuse cutaneous (dc)SSc and identified clinical features of disease associated with elevated estrogen levels. Since dcSSc is more severe in African Americans (AA), we now propose to measure estrogen levels in post-menopausal AA women and men of similar age with dcSSc and identify correlates with clinical features of the disease. Our findings will significantly advance our understanding of disease pathogenesis in SSc, propel progress in the field, and importantly provide new avenues for research for mentees to facilitate their research and allow them to establish their own independent research programs. These mentees will be integral participants in my program throughout the award period. I will mentor junior physician investigators in the assessment of SSc in patients and the absence of disease in healthy twins, evaluation of Raynaud phenomenon, detection of autoantibodies, obtaining informed consent, banking and use of clinical samples, examination of DNA methylation profiles, measurement of estrogen, and identification of associations with clinical variables. The mentoring goals of this application also include mentoring junior clinician investigators in patient-oriented research, grantsmanship, manuscript writing, responsible conduct of research, entrepreneurship and innovation, and career development. My reputation as an excellent mentor coupled with the collaborative and supportive environment at the Medical University of South Carolina, the resources available at the institution and via the CTSA, and the resources of the Division of Rheumatology P30 CCCR, provide the perfect environment for attracting and training successful clinician investigators. My ultimate goal is to ensure a pipeline of well-trained clinical investigators who will continue the mission of treating patients and identifying the cause and cure for Scleroderma and related diseases.

NIH Research Projects · FY 2026 · 2012-07

PROJECT SUMMARY/ABSTRACT This renewal application seeks support for our well-established research education program in substance use disorders to support undergraduate students pursuing short-term summer research experiences at the Medical University of South Carolina (MUSC). The goal is to develop the next generation of independent researchers who can progressively enhance existing therapies and develop novel approaches to substance use disorders. The specific aims are to: 1) Foster interest in these talented and highly motivated students to pursue careers in biomedical research in the areas of addiction research by providing a forum where accomplished investigators can be mentors sharing their enthusiasm and expertise; 2) Leverage existing research training programs at MUSC to complement and expand the overall experience of the students; 3) Provide a forum where students not only acquire the basics of how to address research problems, but also learn cutting edge research techniques, research ethics, and presentation of research data; 4) Contribute to enhancing the students' overall science literacy by nurturing an appreciation of the nature of science and acquisition of socioscientific skills and values.; and 5) Implement a comprehensive evaluation plan that measures the degree to which the program is achieving its objectives. Each year, fourteen undergraduate students will have the opportunity to conduct biomedical research projects under the guidance of faculty mentors based primarily in the Department of Neuroscience. The ten-week summer research projects conducted by the students will culminate in a formal scientific presentation. Additional activities include a lecture series on focused topics; a research ethics component; formal and informal discussions on the meaning of scientific literacy, professional development and career opportunities; and social functions. The participating faculty constitutes a highly collaborative, interdisciplinary team of laboratory-based researchers. Training opportunities are thematically organized around three areas of research: neurobiological basis of cocaine relapse; neurobiology of methamphetamine and opioid dependence; and stress and substance use disorders. The program builds upon and leverages (1) MUSC's strong and continued commitment to research training; (2) its excellent reputation in providing meaningful research experiences for talented undergraduate students; (3) An established record of successfully recruiting trainees from undergraduate institutions both with and without strong research programs in substance use disorders., and (4) its effective program management. This R25 program will teach and promote the integration of clinical and basic science knowledge, with an emphasis on acquiring research skills in the basic neurobiology of substance use.

NIH Research Projects · FY 2026 · 2011-08

Abstract Aggressive tumors that are metastatic and intrinsically resistant to conventional therapies represent a critical issue mediating the morbidity and mortality of most, if not all tumors, including breast cancer. It is postulated that targeting the epithelial-mesenchymal transition (EMT) and the ensuing formation of cancer stem cells (CSCs) is likely to represent a means of reducing the rate at which primary breast cancers spawn metastatic derivatives. In the context of cancer, cells having undergone an EMT have enhanced tumor-initiating ability, are capable of generating mammospheres, exhibit cell-surface markers and gene expression profiles similar to both normal mammary (MaSC) and breast cancer (BCSC) stem cells and become more resistant to chemotherapeutics. We have recently demonstrated a role for TGFβ-induced EMT in the formation of tumor initiating cells (TICs), through a signaling pathway involving the RNA binding protein hnRNP E1 (E1). Herein, our data demonstrates that this TGFβ/E1/ signaling pathway leads to the induction of an embryonic lncRNA known as Platr18 (pluripotent associated transcript 18). We show that this lncRNA is not expressed in normal epithelium or other adult somatic tissues but is highly induced by the TGFβ/E1 axis and in cells having undergone an EMT or during cancer progression. The scientific premise of the proposal is that the TGFβ- mediated EMT program induces the generation of TICs and tumor progression through TGFβ/E1 signaling and reactivation of silenced Platr18. Its goals are to delineate the molecular mechanism(s) of Platr18 function and determine its role in modulating T-cell mediated immunity through VSIG-3 & tumor innervation through Sema4F.

NIH Research Projects · FY 2024 · 2010-09

PROJECT SUMMARY The consumption and abuse of alcohol during adolescence is a serious public health problem. In this age group, alcohol is often consumed in large quantities within repeated binge-like episodes that result in high levels of intoxication. In addition to legal ramifications and concerns with physical safety, these patterns of alcohol consumption appear to adversely impact continued brain and behavioral maturation during the transition from adolescence to adulthood. The prefrontal cortex (PFC) controls higher-order cognitive functions such as working-memory and behavioral flexibility. Adolescence represents a critical period of refinement of PFC neurocircuitry that supports maturation of executive cognitive functioning. This research component of the NADIA consortium will test the overarching hypothesis that AIE-induced deficits in cognitive control in adulthood are associated with alterations in DA neurotransmission in the PFC. This hypothesis is based upon previous studies demonstrating AIE-induced deficits in PFC-mediated behaviors and alterations in expression and function of prefrontal DA. The proposed studies are designed to establish a direct link between AIE-induced altered DA signaling and behavioral impairments, and further test the hypothesis that epigenetic alterations in gene expression are a primary mechanism underlying AIE-induced cognitive deficits. The proposed studies involve the following four specific aims: Aim 1 will test the hypothesis that alterations in activity of DA D1 receptor-expressing neurons in the mPFC contribute to AIE-induced deficits in behavioral flexibility. Aim 2 will test the hypothesis that DNA hypermethylation in the mPFC underlies AIE-induced cognitive deficits. Aim 3 will test the hypothesis that normalization of DNA hypermethylation will reverse AIE-induced alterations in structural plasticity in the mPFC. Aim 4 will test the hypothesis that AIE disrupts the in-growth of VTA-DA axons from the nucleus accumbens to the mPFC. These studies involve an innovative and multidisciplinary set of experiments that utilize state-of-the-art methodologies and procedures. Together, these studies will yield novel and exciting new findings and will significantly advance our understanding of the effect of adolescent alcohol exposure on cognitive function and behavioral control in the adult, and identify novel therapeutic approaches for treatment.

NIH Research Projects · FY 2026 · 2010-04

ABSTRACT The long-term goals of this research are to elucidate the molecular mechanisms underlying noise-induced hearing loss (NIHL) and to propose rational therapeutic interventions for prevention. Based on our previous findings and consistent with findings in other systems, we will test the hypothesis that prolonged activation of AMPKα (T172) by calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) and liver kinase B1 (LKB1) or reactive oxygen species (ROS) triggers outer hair cell (OHC) death. We further propose that activated CaMKK2 facilitates translocation of nuclear factor of activated T-cells (NFAT) into OHC nuclei, causing release of cytokine genes. Finally, we will use siRNA and pharmacological compounds to block multiple death pathways for potential synergistic protection against NIHL. We will employ a comprehensive experimental approach including in-vivo studies with adult mice to define the underlying molecular mechanisms using short hairpin RNA (shRNA) via virus transfection, single cell RNA-seq (scRNA-seq) with gene set enrichment analysis (GSEA), and fluorescence in-situ hybridization with RNAscope. These studies investigating innovative therapeutic strategies are designed to identify novel avenues for the prevention of NIHL, benefiting the quality of life of affected individuals and reducing healthcare costs. In addition, the data generated by this proposal will make a significant contribution to our understanding of a broad range of inner ear disorders since similarities have been shown in the molecular events associated with noise-induced, drug-induced, and age-related hearing loss.

NIH Research Projects · FY 2025 · 2009-04

The Hollings Cancer Center (HCC) at the Medical University of South Carolina (MUSC) is the only National Cancer Institute (NCI)-designated Cancer Center in the State of South Carolina (SC), serving 5.2M residents. SC’s Catchment Area is notable for its high levels of poverty, smoking (18%), and significant health challenges across the population. The mission of HCC under the new leadership of Raymond N. DuBois, MD, PhD, is to reduce the cancer burden in the state through the provision of cancer screening, care, training/education, community outreach, and conducting transformative research that spans the bench, bedside, and population. HCC includes 130 cancer scientists from six colleges and 21 departments, 35 of which were recruited since the last review. Supported by $25.7M (directs) in extramural cancer research funding, including $14M from the NCI, a 69% increase, this application seeks support for three Research Programs that promote multidisciplinary collaborations: Cancer Biology and Immunology (newly configured), Cancer Prevention and Control, and Developmental Cancer Therapeutics, supported by six Shared Resources that advance member science and productivity. HCC members have generated 1,245 peer-reviewed publications since 2018, with 21% in journals with an Impact Factor >10 and with high rates of intra-programmatic, inter-programmatic, and inter-institutional collaboration. With a newly implemented translational pipeline, HCC-led investigator-initiated clinical trials more than tripled during the last year alone. During the past year, HCC recruited 1,142 patients to interventional studies and 983 patients to non-interventional studies, with 24% of participants classified as minority groups and 12% residing in rural communities (RUCC ≥ 4). Other major accomplishments since the prior review includes two new NCI P01s, one in pancreatic cancer-induced cachexia and one in tobacco control, 16 new MPI R01s, a tripling of state funding to HCC, and a leading role in pediatric CAR-T therapy in the state. This progress has been enhanced for over two decades by progressive, HCC-led outreach, community engagement, and cancer education services. The center developed the state’s only comprehensive cancer education pipeline for learners across the entire education continuum, from high school through early professional career development, and has made significant contributions to affect public policy to impact cancer burden, literally around the world. In summary, HCC requests funds to support years 16-20 of the MUSC Cancer Center Support Grant (CCSG); CCSG funding will support Community Outreach and Engagement, Cancer Research Training and Education Coordination, Clinical Protocol and Data Management, Protocol Review and Monitoring, Leadership, Planning and Evaluation, Administration, Shared Resources, and Developmental Funds. HCC’s future plan is to merit NCI Comprehensive status at the following CCSG review.

NIH Research Projects · FY 2025 · 2006-07

This is a competing renewal application for our T32, Training in Craniofacial and Oral Health Research (T-COHR), an integrated research training program based in the College of Dental Medicine at the Medical University of South Carolina (MUSC). The overarching objective of T-COHR is to foster the development of clinician scientists and scientists focused on oral, dental, and craniofacial research. To accomplish this goal, T-COHR offers mentored, interdisciplinary research training opportunities in oral health, craniofacial biology and bioengineering. T-COHR provides strong curriculum and thematic research experiences in an integrative framework that emphasizes mentoring, scientific advancement, academic career development, workforce diversity, team science, grantsmanship, and productivity. For this renewal period, we are requesting (i) continued support for the Dental Scientist Training Program (DSTP) which is a consolidated DMD/PhD degree pathway (2 slots); (ii) continued support for predoctoral research training leading to the PhD degree in biomedical sciences or bioengineering with applications to oral/craniofacial health (4 slots); and (iii) continued support for postdoctoral research training for dentist scientists and/or non-clinician PhD scientists in basic, translational or bioengineering sciences important to dental, oral or craniofacial health (4 slots). The planned duration of trainee appointment is up to 3 years. T-COHR is an integral part of the Center for Oral Health Research (COHR), a University Center of Research Excellence in the College of Dental Medicine that engages faculty and trainees in other disciplines and departments in the Colleges of Medicine, Graduate Studies, Pharmacy and Dental Medicine at MUSC, the Department of Bioengineering at Clemson University, and the NCI-designated Hollings Cancer Center at MUSC. With 32 program faculty members, mentoring and training activities are thematically grouped into 4 strategic areas of research focus: (i) molecular and cellular biology of oral infectious diseases, (ii) oral pharyngeal cancer biology and cancer immunology, (iii) bioengineering/biomechanics of the oral and craniofacial complex, and (iv) craniofacial growth and development. T-COHR benefits from excellent administrative support and institutional commitments that have provided continued support to the COHR. An integrated multi-year evaluation plan will be used to measure the extent to which T-COHR goals and objectives are met. T-COHR trainees are critical thinkers skilled at rigorous experimental design and data analysis, are equipped to be scientists in society working productively in interdisciplinary and diverse teams, and are able to communicate to a breadth of audiences. Our aim is to develop the next generation of independent dental, oral, and craniofacial researchers who can better understand disease and thus develop novel therapies.

NIH Research Projects · FY 2026 · 2006-05

5R25DA020537-19 The Drug Abuse Research Training program (DART; R25DA020537; MPIs: Back & Brady), which was established in 2006 with support from NIDA, is an intensive research training program at the Medical University of South Carolina (MUSC). The main impetus for the DART program is the continued shortage of well-trained clinical researchers, particularly physicians, prepared to conduct rigorous patient-oriented research focused on substance use disorders (SUD). The primary objective of the DART program, therefore, is to increase the number of physician-scientists committed to pursuing clinical research careers in the field of SUD. To accomplish this, we designed and successfully implemented a two-year research track within the General Psychiatry residency program, which allows selected residents to spend approximately 50% time during PGY3 and PGY4 in a well-coordinated research education curriculum that includes mentored clinical research and core research training activities. The DART program received the annual Award for Creativity in Psychiatric Education from the American College of Psychiatrists for its innovative approach to promoting physician-scientist training, namely: (1) access to research mentors; (2) support for research time during residency; and (3) financial support, such as funding for pilot projects and travel to present research at scientific conferences. A secondary objective of the DART program is to reach potential clinician-scientists earlier on in their career trajectories to expose them to cutting-edge clinical and translational SUD-related research. To accomplish this, we created the DART Summer Research Fellowship, which provides medical, graduate, and select undergraduate students the opportunity to work alongside dedicated researchers and participate in a set of structured enrichment activities for 10 weeks. Thus far, 281 trainees (61 residents and 220 summer research fellows) have participated in the DART program with a 99.6% retention rate. Program evaluation data demonstrate that DART trainees evidence high levels of research participation and productivity, and the majority of program graduates continue to engage in research activities following participation in the DART program. DART trainees have received numerous local and national awards for their research, teaching and clinical excellence and have, thus far, generated 708 manuscripts and 633 conference presentations. DART is supported by an Advisory Board comprised of highly accomplished researchers and leaders in the field of addiction from 14 different U.S. institutions. Members of the Advisory Board contribute by providing seminars, mentorship, and one-on-one career advice to trainees. The multidisciplinary leadership team, strong partnerships with campus-wide initiatives, and a cadre of federally-funded SUD faculty mentors ensures a rich and vibrant training program.

NIH Research Projects · FY 2025 · 2005-07

SUMMARY Head and neck squamous cell carcinoma (HNSCC) includes mucosal squamous cell carcinomas of the oral cavity, pharynx, and larynx. It represents over 65,000 new cancer cases, with 14,500 cancer-related deaths in the United States annually. Previous studies demonstrated that ~75% of HNSCC tumors contain decreased ceramide synthase 1 (CerS1)-generated C18-ceramide, a bioactive sphingolipid with anti-proliferative signaling functions. Lower ceramide levels are associated with advanced disease stage and poor survival in HNSCC patients with defective mitophagy. Our preliminary data showed that the reconstitution of C18-ceramide synthesis in mitochondria by CerS1 restored mitophagy and HNSCC tumor suppression. Recently, we discovered that instead of trafficking C18-ceramide, its metabolic enzyme, CerS1, is transported from the endoplasmic reticulum (ER) to damaged mitochondria, a paradigm-shifting mechanism, to induce mitophagy in response to cisplatin, rapamycin or sodium selenite (SoSe)-mediated stress signaling. A previously unidentified 17 kDA protein catalyzes this process. We coined its name as p17/PERMIT (protein ER-mitochondrial transporter). However, mechanisms that regulate CerS1-p17/PERMIT and subsequent ceramide-dependent mitophagy and cell death in HNSCC remain unknown. Accordingly, to restore ceramide accumulation in mitochondria, we developed a novel ceramide analog drug, LCL768. This ceramide analog contains C18-ceramide, conjugated with selenium and pyridinium moieties, which target C18-ceramide selectively to HNSCC cell mitochondria, leading to mitophagy induction. Thus, our preliminary data suggested to us the novel hypothesis that mitochondrial trafficking of CerS1 by p17/PERMIT mediates ceramide-dependent mitophagy, leading to HNSCC tumor suppression in response to cancer therapeutics and stress signaling. As a corollary, we also hypothesize that LCL768 reconstitutes mitochondrial ceramide and mitophagy in HNSCC with defective mitochondrial CerS1- p17/PERMIT trafficking. To test these hypotheses, we propose three Specific Aims: 1) Determine the mechanism whereby p17/PERMIT-mediated trafficking of CerS1 to mitochondria induces C18-ceramide generation and mitophagy. 2) Define the mechanisms by which mitochondrial CerS1/C18-ceramide mediates mitophagy via Drp1 activation. 3) Identify the therapeutic mechanisms and efficacy of mitochondria-targeted ceramide-analog drug, LCL768, in HNSCC tumor suppression. Our research team, which includes both basic and clinical scientists, is uniquely positioned to execute studies proposed in this application based on our complementary expertise in the fields of sphingolipid metabolism, mitochondrial damage signaling, mechanisms of cancer cell death, and HNSCC therapy. In addition to ceramide analogs (such as LCL768), we propose experiments here using clinically available therapeutic drugs, such as SoSe, rapamycin and cisplatin in patient-derived 2D HNSCC organoids and PDX tumors, which can readily be translated into the clinic to induce ceramide-dependent mitophagy and tumor suppression in HNSCC.

NIH Research Projects · FY 2025 · 2005-07

ABSTRACT This renewal application seeks support for our well-established T32 postdoctoral research training program in basic, translational and clinical investigations of rheumatic and autoimmune diseases and the significant health disparities associated with these diseases. The Research Training Program in Inflammatory and Fibrosing Diseases is centered in the Rheumatology Division at the Medical University of South Carolina. The program's ultimate goal is to improve the healthcare and outcomes for individuals with rheumatic diseases in the southeastern United States. Our training program emphasizes the interrelationship between inflammation and fibrosis and how these biologic processes impact end organ function such as renal disease in lupus and lung disease in scleroderma. The participating faculty members have particular strengths and existing collaborations in areas of health outcomes and community-based research, epidemiology of rheumatic diseases, health disparities, gene/environment interactions, innate immunity and adoptive immunotherapy, lupus nephritis, signaling pathways leading to fibrosis, matrix proteins, scleroderma lung disease, and disease biomarkers. Trainees matriculate to 1 of 3 research tracks: Bench Research Track for Clinicians, Clinical Investigator Track including a Master of Science in Clinical Research degree, and Translational Research Track for Non-Clinicians. The program's structure helps trainees gain critical skills for sustained careers in academic medicine in a flexible framework that accommodates a diverse range of prior education/experience and multiple modes of investigation focused on the programmatic theme. Established in 2005, with NIAMS T32 support for 3 cycles (2005-2021), this program has graduated 21 postdoctoral fellows to date: 19 females, 2 males including 4 underrepresented minority (URM) fellows; 9 MD, 2 MD/PhD, 10 PhD. Collectively, they published 135 peer-reviewed publications (89 first authored) based on their research training. Currently, 13 remain in academic research, 3 in clinical practice, 3 in industry research, and 1 in the nonprofit sector. We propose 16 Primary Mentors and 6 Emerging Mentors of which 3 are URMs. For the coming year, 3 fellows will be appointed: 1 female PhD and two female rheumatology fellows (1 Med/Peds fellow). The current application requests continued support for 3 fellowship positions. Fellows will be on the research training grant for 2 years with an option for a 3rd year if justified based on productivity and potential. Application numbers for our fellowship program have doubled over the last 5 years due to increased interest in rheumatology as well as national recognition of our program's excellence. The Program Steering Committee will review and approve the selection and annual re-appointment based on specific criteria, evaluation data and slot availability with input from the External Advisory Committee. In this renewal, our research areas have expanded into other rheumatic diseases and into other fields of research (microbiome, community interventions, oral health, regenerative medicine and cellular therapies).

NIH Research Projects · FY 2026 · 2003-03

PROJECT SUMMARY Stress is known to be a significant factor in triggering relapse, promoting heavy alcohol (ethanol) consumption, and producing adaptations that reduce behavioral flexibility, thereby compromising control over alcohol drinking and elevating susceptibility to relapse. Unfortunately, mechanisms and neurocircuitry underlying the complex interaction between stress and alcohol drinking are not well understood. As part of the INIAstress Consortium, we developed a mouse model in which repeated brief forced swim stress (FSS) exposure interacts with chronic intermittent ethanol (CIE) exposure to selectively enhance alcohol drinking in dependent (CIE-exposed) mice. During the current funding period we established a role for the pro-stress neuropeptide dynorphin/kappa opioid receptor (DYN/KOR) system in stress-enhanced alcohol drinking. At the same time, we used operant conditioning procedures to demonstrate that the anti-stress neuropeptide oxytocin (OT) reduced alcohol self- administration and stress-induced relapse-like behavior. This research project focuses on the role of DYN/KOR and OT systems within stress-relevant circuits in models demonstrating the ability of stress to interact with chronic alcohol in promoting escalation of alcohol drinking, enhanced relapse-like behavior, and impaired behavioral flexibility. The project will employ two stressors (forced swim stress (FSS) and predator odor (TMT) exposure), two models of stress-alcohol interactions (CIE-FSS Drinking and stress (TMT)-induced operant alcohol relapse seeking/drinking), and two measures of behavioral (in)flexibility (alcohol-biased choice behavior and persistence of alcohol drinking despite aversion). Building on our previous work demonstrating an important role for DYN/KOR activity in the central amygdala (CeA) and pilot data showing strong DYN input to the CeA from the insular cortex (a stress and alcohol sensitive cortical area), studies will examine the role of DYN/KOR signaling in insular cortical (IC) projections to the CeA (IC-CeADYN pathway). Other pilot data suggest that the stress-buffering effects of OT may be mediated by signaling in the CeA. Thus, studies will examine OT activity in hypothalamic (PVN) projections to the CeA (PVN-CeAOT pathway). Further, studies will examine the potential unique interactive effects of the DYN/KOR and OT systems in the PVN on behavioral consequences of stress-alcohol interactions. The general experimental strategy will entail utilizing transgenic mice and pharmacological, chemogenetic, and CRISPR/Cas9 approaches to target manipulation of these neuropeptides in specific neurons within these specific neurocircuits. Collectively, these studies focus on adaptations in pro-stress (DYN/KOR) and anti-stress (OT) systems within stress-relevant neurocircuits using different stressors and different drinking models, thereby directly interfacing with the overall thematic framework of the consortium. The ultimate goal is to gain new knowledge that will inform development of more effective interventions for treating stress-related excessive alcohol drinking and relapse.

NIH Research Projects · FY 2025 · 2002-09

The MUSC Specialized Center of Research Excellence (SCORE) on Sex Differences in substance use disorders and the relationship between stress and relapse has been highly productive for 20 years. In addition to coalescing a multidisciplinary group of investigators across different disciplines working closely together to explore sex differences in substance use disorders and the relationship between stress and drug use, the MUSC SCORE has provided a fertile training ground for new investigators and attracted senior investigators to apply their skills to sex-differences research. During the proposed renewal period, we will continue to reach across the MUSC campus, state of South Carolina, and nationwide through cross-SCORE collaborations and other initiatives focused on dissemination of research findings to improve health outcomes. The science within our research group also will grow with four tightly integrated research projects. To address critical public health needs, the proposed research projects will investigate sex differences in cannabis use disorders across the lifespan, focusing on populations (emerging adults, postpartum women, and older adults) with recent rapid increases in cannabis use and potential vulnerability to sex disparate harms of cannabis. The specific aims of this SCORE are to support and enhance translational scientific collaborations among the investigators conducting primary and pilot research projects, catalyze further growth of interdisciplinary sex-based research on the MUSC campus, continue foundational research training for Early Career Investigators dedicated to sex -differences translational research, and promote strategic partnerships to enhance the translation and dissemination of SCORE findings and other relevant research to improve health outcomes.

NIH Research Projects · FY 2026 · 2000-09

The Southern Consortium Node (SCN), an integral part of the NIDA-funded Clinical Trials Network (CTN) Consortium since 2000, has demonstrated the capacity, expertise, and flexibility to respond to the evolving CTN mission, leading and contributing to cutting-edge clinical research in real-world settings with outstanding performance metrics. During the renewal period, the specific aims include sustaining and growing collaborative relationships with a broad array of geographically-dispersed clinical programs, including robust connections with a variety of healthcare entities in South Carolina and surrounding states (Alabama, Tennessee, Georgia), MUSC Regional Health Network, Telehealth Center of Excellence and the newly formed South Carolina Center of Excellence in Addiction. The SCN will also continue strategic collaborations with community-based organizations, policy-makers, and individuals with lived experience through the Policy Advisory Committee to advise and inform SCN activities. Using state-of-the-art research methodologies and technical innovations, the SCN will continue to develop and conduct clinical trials focused on the substance use disorder (SUD) continuum (prevention, treatment, and recovery) using implementation science to ensure public health impact. The SCN will also work across a number of ongoing research training initiatives using the CTN as a training platform to increase, strengthen, and broaden the SUD research workforce. These strong relationships, complemented and enhanced by our statewide CTSA infrastructure, provide a research capacity that extends far beyond our academic home and will enhance SCN efforts to provide accessible pathways for broad community engagement in clinical trials, better understand the impact of individual and regional development and support on SUDs, and facilitate impactful dissemination and implementation efforts. In sum, the SCN has the experience, creativity and the collaborative and innovative spirit required to meet new challenges and to lead and participate in CTN initiatives. The multidisciplinary SCN team includes expertise in addiction psychiatry, clinical research informatics (including advanced data analytics and healthcare technologies), comorbidity, polysubstance use, adolescent substance use, prevention, recovery, integration of addiction medicine in a variety of healthcare settings, remote clinical trial methods, training/education, dissemination & implementation, and public health policy. The SCN research agenda addresses critical opportunities across the SUD continuum and across the translational research continuum ensuring that our agenda drives research questions with substantial public health significance.

NIH Research Projects · FY 2024 · 1999-07

PROJECT SUMMARY / ABSTRACT This application requests continued support of the Medical Scientist Training Program at the Medical University of South Carolina. The major goal is to train the next generation of physician-scientists who will choose a career that will conduct research that integrates both the basic and clinical sciences to improve human health and treat diseases. The program was originally founded in 1980 and has steadily grown to its current size of 56 students, with 32% females and 11% underrepresented minorities. Of these 136 alumni, 6 are Professors, 3 holding endowed chairs, 10 associate professors, 21 assistant professors, 6 conduct research in industry, 1 is at the NIH, 2 are at the VA, 8 are clinical faculty (instructor-assistant professor), 27 in private practice, 52 still in training, 1 unknown and 2 deceased. Our 2018 applicant pool is the largest ever with 208 applications. Over the past 5 years (2013-2018) the average number of applicants has been 189/yr, compared to the previous 5-yr average of 152/yr, which is a 24% increase. This increase in our trainee candidate pool reflects a combination of MUSC’s exceptional research environment, our MSTP students’ outstanding accomplishments, and the program’s national recruitment efforts, which includes personal contacts and a recruitment letter with brochure sent to students who took the MCAT and received a score of >514 or better. The growth in the quality and quantity of our applicants provides the basis for the requested 10 positions per year. Our program in the medical school is changing to an integrated flex curriculum. In this curriculum, the first two years will be condensed into 18 months, with frequent short vacations. The new preclerkship (FLEX) curriculum will increase flexibility for graduate students to re-enter into medical school. In addition to rigorous basic science research training and medical school, trainees gain experiences in translational research via the Translational Sciences Clinic, a month in the Research Nexus and the Translational Medicine Seminar series. The objectives for the next phase are to: 1) continue the rigorous research training in areas of biomedical research by collaborative and highly accomplished faculty with exceptional records of training and research, 2) offer a training program that challenges students to think independently and critically, 3) conduct the training in a challenging, interactive environment that embraces basic, clinical and translational sciences, 4) utilize individualized development plans to enhance the training experience, 5) continue the rigorous and formal evaluation of the program that uses both quantitative and qualitative data to ensure the most rigorous, effective and efficient training, and 6) institute entrepreneurship training.