Medical University Of South Carolina

NIH Research Projects · FY 2024 · 2020-07

In breast cancer, collagen re-alignment is predictive of subtype, outcome and recurrence with limited data on contribution to racial disparities. For African-American (AA) women, breast cancer mortality is higher than any other race/ethnicity, in spite of having lower incidence rates. A disproportionate number of African-American women are affected by aggressive metastatic triple negative breast cancer (TNBC) without significant knowledge of mechanisms driving this ancestry-dependent difference. Collagen processing is a primary feature of TNBC tumors with increases in tumor adjacent collagen deposition, altered tumor-stroma ratios, and re-alignment of collagen fibers at tumor borders leading to metastasis. However, a knowledge gap exists on understanding ancestry-dependent translational and post-translational mechanisms of the collagen structure in any breast cancer type progression. Our preliminary data reports, for the first time, that post-translational regulation of the collagen triple helical structure by hydroxylated prolines (HYP) is a defining mechanism of racial disparities in normal and TNBC tissue. Consequently, this proposal focuses on identifying ancestry-dependent translational and post-translational mechanisms of collagen re-alignment that can ultimately be used to predict and potentially prevent breast cancer metastasis in AA women. In Aim 1, we will define ancestry dependent post-translational HYP regulation of collagen sequences from low grade to invasive triple negative breast cancers. Novel technological platforms will be combined to measure collagen sequences from the tissue microenvironment with measurement of collagen fiber changes and immune infiltrate. In Aim 2, we will identify HYP post-translational regulation of collagen sequence variants in ancestry-mapped normal breast tissue stratified by density, socioeconomic status, marital status, contraceptive use, and risk factors of smoking and alcohol. We will further determine if collagen sequence variants can be used as a companion scoring metric for prediction of breast cancer risk. In Aim 3, ancestry-defined normal and metastatic human breast cells will be used to precisely trace ancestry dependent collagen processing and oncogenic signaling influenced by collagen sequence variants. This study will increase our understanding of racial disparities in metastatic collagen re-alignment, working to generate better ancestry-dependent biomarkers for earlier detection of breast cancer and limit mortality due to breast cancer in minority populations.

NIH Research Projects · FY 2024 · 2020-07

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is one of the deadliest forms of cancer. Poor survival rates are largely due to the late stage at which PDAC is diagnosed and a lack of effective therapies. The long-term goal of this research program is to discover new therapeutic approaches and drug combinations for the treatment of PDAC and other incurable cancers. Previous studies by our group identified a new class of protein disulfide isomerase (PDI) inhibitor with activity in a variety of solid and hematological cancer types including PDAC. PDIs are emerging oncology targets that play a critical role in the proper folding of newly synthesized proteins. PDIs are overexpressed in a variety of tumor types and are attractive oncology targets. In an unbiased screen of FDA-approved oncology drugs, we found this new class of drug could dramatically enhance the activity of histone deacetylase (HDAC) inhibitors with the strongest synergy being observed in PDAC models. The specific objectives of this study are: (1) to uncover the molecular mechanism responsible for the remarkable synergy between PDI and HDAC inhibitors in PDAC, (2) to resolve binding of novel PDI inhibitors to their target using X-ray crystallography, and (3) to demonstrate the preclinical anti-cancer activity of lead PDI inhibitors as single agents and in combination with HDAC inhibitors in genetically engineered mouse models (GEMMs) of PDAC. These aims are built on clear rationale from the existing literature and strong preliminary data. This work is innovative because we investigate the activity and mechanism of a new drug candidate and new treatment combination for the treatment of PDAC, a cancer in desperate need of new therapies. It is our expectation that this work will deliver a new drug candidate and combination treatment regimen for the treatment of PDAC, provide insight into the druggability of an emerging cancer drug target in PDI, and uncover molecular mechanisms that enhance the activity of HDAC inhibitors.

NIH Research Projects · FY 2024 · 2020-07

ABSTRACT Drug addiction, including cocaine-abuse disorder, represents a major public health issue, characterized by compulsive drug seeking and increased propensity to relapse after abstinence. Relapse to cocaine seeking is triggered by environmental cues strongly associated with the rewarding effects of the drug itself. The neuronal encoding of cocaine-associated cues at a single-cell level remains unclear, limiting our understanding of how cocaine-paired cues trigger drug seeking behavior. Via its constituent dopamine D1- and D2- receptor expressing medium spiny projection neurons (MSNs), the nucleus accumbens core (NAcore) plays a key role in encoding cue-reward associations and triggering relapse to cocaine seeking behavior. The NAcore integrates multiple cortical and allocortical inputs. In particular, the activation of afferent glutamatergic projections from the prelimbic cortex (PL) are necessary for cue-induced reinstatement of cocaine seeking. Using chemogenetic and optogenetic manipulations on D1- and D2-MSNs, previous studies have shown opposite roles of these neuronal subtypes on cue-induced reinstatement of cocaine seeking in rodent models of self-administration. Therefore, I hypothesize that cocaine seeking during context/cue-reinstatement and refraining from seeking during extinction training are associated with temporally and spatially distinct neuronal ensembles of D1- and D2-MSNs that are differentially modulated by PL-NAcore projections. I will address this hypothesis by quantifying Ca2+ activity in D1-MSNs (Aim 1) and D2-MSNs (Aim 2) during cocaine-seeking and extinction, with and without inhibiting PL- efferents to NAcore. To investigate the functional role of D1- and D2-MSNs during cocaine seeking, we will record single-cell Ca2+ dynamics from D1- and D2-MSNs using a head-mounted miniature microscope and virally expressed Cre-dependent Ca2+ indicator (GCaMP6f) in D1- and D2-cre transgenic mice while undergoing cocaine self-administration, extinction training and cue-induced reinstatement, We will further inhibit PL-NAcore projections during drug seeking tests (post abstinence and during cue-induced reinstatement) using virally expressed inhibitory Gi-DREADDs. Recorded Ca2+ dynamics will be analyzed using advanced statistical models and clustered to isolate the neuronal ensembles associated with context/cue-induced drug seeking and refraining from seeking during extinction. The information obtained from this research will isolate neuronal ensembles that encode cocaine-seeking, as well as the mechanism(s) by which PL-NAcore projections affect these ensembles to regulate cue-induced reinstatement. This fellowship will train me in experimental design, scientific writing, and cutting-edge techniques to understand the brain circuits underlying drug addiction, including viral transfection and micro-endoscopic analysis of Ca2+ activity in transgenic mice trained to self-administer and reinstate to drug- associated cues and contexts.

NIH Research Projects · FY 2025 · 2020-06

Project Summary Mitral valve prolapse (MVP) affects a significant portion of the population (1 in 40 individuals), yet its potential severity has been underestimated. Recent findings indicate that a substantial number of MVP patients develop left ventricular (LV) fibrosis, a serious complication. However, current surgical guidelines often delay intervention until patients exhibit symptoms of LV dysfunction, leading to poorer outcomes and increased mortality rates. Our research has unveiled MVP as a condition that impacts both the heart valve and the ventricle, highlighting the need for routine monitoring of LV function and consideration of cardioverter defibrillator implantation in MVP patients. This project aims to delve deeper into the mechanisms underlying MVP-related fibrosis. By investigating how MVP induces regionalized fibrosis, particularly in areas where tension forces are heightened, we aim to uncover the role of increased tension as a driver of LV fibrosis in MVP. This multidimensional approach will provide insights at the molecular, cellular, and tissue levels, contributing to a better understanding of MVP pathology.

NIH Research Projects · FY 2025 · 2020-04

Overall The overall objective of the Medical University of South Carolina Digestive Disease Research Core Center (MUSC DDRCC) is to provide researchers focused on our thematic continuum with core resources, collaborative exchange, and other opportunities to further their scientific success in a thriving and interactive community. Closely linked to the Overall Component is dedicated leadership and a highly effective Administrative Core that directs the strategic direction of the Center and ensures focus on our vision and goals. Our vision is to establish and sustain the DDRCC as the driving force for digestive and liver diseases research at MUSC and in our entire state. With this vision comes our major goal, which is to create an enhanced infrastructure to support digestive and liver disease research capacity and for our Center to provide meaningful value to our Members. Our central theme is focused on the continuum of organ injury, inflammation, and fibrosis - leading to disease. This continuum is highly relevant for the vast majority of digestive and liver diseases. Our specific aims are integrated with the goal of serving our Members and are as follows: 1) Support and foster collaboration among digestive and liver disease researchers. Our leadership emphasizes collegiality and collaboration, and we will provide multiple avenues for Center Members to function in this manner. We will continue to foster this philosophy by supporting the career development newly recruited junior investigators as well as Members. Our supportive and attractive environment will continue to enhance our collaborative culture. 2) We will develop sustainable scientific core resources to support digestive and liver disease studies while leveraging institutional investments. DDRCC Cores include: a) A Cell Models Core; b) An Advanced Imaging Core; c) A Proteomics Core; and d) a new Bioanalytical and Biospecimen core offering biostatistics and bioinformatics support as well as a biorepository. Finally, we will 3) Promote the long-term success and sustainability of the DDRCC. We believe the key to our long term success is to build not only a superb infrastructure though emphasizing collaboration amongst our members, and by providing access to high performing Biomedical Research Cores, but to build Center membership through mentorship. The Center is made up of 36 Full Members focused specifically on our theme, representing growth of over 30% during the last 4 years and an additional 24 Associate Members. Finally, we will aggressively assess in an ongoing manner the success of all of our Cores, and the Enrichment and P&F Program. In aggregate, the MUSC DDRCC has made an enormous impact on our institutional and local community, addressing critical questions with consequential impact to the patients and communities we serve.

NIH Research Projects · FY 2025 · 2020-04

Overall – Project Summary The overall goal of the Center of Biomedical Research Excellence (COBRE) in Digestive & Liver Disease (CDLD) is to enable outstanding multidisciplinary collaborative research in digestive and liver diseases at the Medical University of South Carolina. These diseases are of importance to the state of South Carolina because of the tremendous, disparate burden they have upon the state’s citizens. The specific aims are to: 1) Mentor, train, recruit and retain a cadre of early career scientists to become independently funded investigators in digestive and liver disease research; 2) Develop sustainable scientific core resources to support digestive and liver disease studies while leveraging institutional investments; and 3) Promote the long-term viability and success of the CDLD through development of multidisciplinary basic science research programs, rigorous evaluation, ongoing improvement strategies, and mission alignment with other centers at MUSC. The Center is led by a multidisciplinary team of leadership within the MUSC College of Medicine, coalescing resources to achieve their overarching objective of building a critical mass of funded investigators that will allow MUSC to compete for future external peer-reviewed programmatic grant support. This application highlights four of our most outstanding Research Project Leaders (RPLs) who will benefit from an innovative multiple source mentoring plan which features both internal and external mentors. Based on the success of our Phase 1 RPLs, we anticipate Phase 2 RPLs to transition to independent NIH funding within the first three years of the project. The CDLD also includes three Cores that support not only the RPLs but also digestive and liver disease investigators throughout the medical center. Scientific cores include the: 1) Cell Models Core, which will generate advanced cell models of digestive and liver diseases; 2) Animal Models of Digestive Disease Core, which will provide access to and training in essential animal models; and 3) Advanced Imaging Core, delivering sophisticated equipment, technologies and expertise required for successful, state-of-the-art cell and tissue-based imaging and analysis. Additionally, the CDLD will continue to foster collaborations among digestive and liver disease researchers by promoting interdisciplinary scientific exchange through our enrichment activities and build research capabilities through our Pilot Project Program. With NIH and institutional support, the CDLD will attain our long-term goal of integrating basic, translational and clinical research as a sustainable, multidisciplinary, programmatic center.

NIH Research Projects · FY 2025 · 2020-03

PROJECT SUMMARY Prior research has demonstrated a consistently strong inverse association between statin drug use and risk of developing lethal prostate cancer, and a stronger protective effect with a longer duration of use. Further, in men with clinically localized prostate cancer, statins are associated with a reduced risk of progression to metastasis and dying from prostate cancer. For statins to have clinical utility as chemopreventive and therapeutic (adjuvant) agents, additional characterization of the mechanisms through which statins interact with the tumor microenvironment is needed. Yes-associated protein (YAP) is a transcriptional regulator highly expressed in regulatory T lymphocytes (Tregs). Statin drugs have been shown to inhibit YAP nuclear translocation (via YAP phosphorylation) required for Foxp3-meditated Treg immunosuppressive function. Thus, we propose to investigate the association between statin drugs and YAP-mediated Treg dysfunction, a novel immune-modulatory mechanism through which statins may impede development and progression of lethal prostate cancer in the following specific aims. For Aim 1 (K99 phase) we will create a new tissue microarray set including statin users and nonusers at the time of prostatectomy matched on clinical pathological characteristics. We will evaluate whether the proportion of Tregs with phosphorylated YAP in the cytoplasm of Tregs differs between statin users and nonusers, and if the prostate immune cell profile differs among statin users and nonusers. For Aim 2 (R00 phase), we will conduct a proof-of-principle randomized trial investigating the effect of statins on YAP-mediated Treg dysfunction in men diagnosed with prostate cancer scheduled to receive prostatectomy. This proof-of-principle trial will also provide a controlled environment to assess the effect of a single type of statin and dosing schedule to overcome heterogeneity in the type of statin drugs and dose in the observational study purposed in Aim 1. Potential biases, such as confounding by indication, will be minimized through the use of randomization. We will leverage the tremendous expertise in the biology and measurement of the immune cell profile present in prostate cancer tissue and our established, well characterized prostate cancer cohorts with associated archived tissue at JHU. The translational value of this work lies in the ability to characterize the effect of statin drugs on a novel immunemodulatory mechanism, which may be relevant in the setting of immune-based therapy for prostate cancer. This research plan is complemented by a training plan that builds on the applicant’s background in cancer epidemiology and research synthesis methods and includes new training in 1) contributing an epidemiologic perspective in multidisciplinary team science collaborations; 2) conducting tissue-biomarker validation studies; and 3) clinical trial design and implementation. The combined research and training plans will prepare the applicant for a successful independent research career focused the translation of cancer biomarkers into improved population health outcomes.

NIH Research Projects · FY 2024 · 2019-09

7. Project Summary/Abstract . Cardiac arrest is a common and devastating emergency of the heart and the brain. More than 380,000 patients suffer out of hospital cardiac arrest (OHCA) each year in the US. Improvements in cardiac resuscitation (the early links in the “chain of survival” for patients with OHCA) are tempered by our limited ability to resuscitate and protect the brain from global cerebral ischemia. Neurological death and disability are common outcomes in survivors of cardiac arrest. Therapeutic cooling of comatose patients resuscitated from shockable rhythms may markedly increase the rate of good neurological outcome, but poor outcomes still occur in as many as 50%, and the benefit of cooling in those resuscitated from asystole and pulseless electrical activity has not been evaluated in a randomized study. Even in patients with shockable rhythms, prior trials showing efficacy have been questioned. Therapeutic cooling is already a guideline-recommended and commonly used treatment in comatose survivors of cardiac arrest, but because of limited data, the optimal duration and patient selection criteria remain unknown and cooling devices are not FDA approved for this indication. Preclinical data and mechanistic studies strongly suggest that durations of hypothermia longer than those typically used may minimize brain injury. This study will determine if identifying an optimal duration of therapeutic hypothermia can improve outcomes, and if development of a duration response curve can substantiate efficacy in a wider patient population of cardiac arrest survivors. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having good outcome. The overarching goal of this project is to identify clinical strategies that will increase the number of patients with good neurological recovery from cardiac arrest. The results of this trial will be immediately significant, impacting both clinical practice and regulatory evaluation. The trial uses innovative adaptive dose finding methods that allow exploration of a wide range of potential durations and efficiently allocate subjects where they will be most informative. The study methods also include innovative approaches to traditional outcome assessment and innovative outcome assessment tools, including the NIH Toolbox. The study will be conducted in the NIH SIREN Emergency Clinical Trials infrastructure. SIREN leverages existing resources to achieve economies of scale, maintain talented rapidly responding teams to screen and enroll subjects in the emergency department setting, and to continue clinical investigations through the ICU stay and beyond with proven performance.

NIH Research Projects · FY 2025 · 2019-07

The experimental toolkit available to contemporary scientists is extraordinary, permitting rapid experimentation with previously unknown precision and innovation. In essence, however, the principles that underlie scientific inquiry remain unchanged. Our PhD training program in Cellular, Biochemical and Molecular Sciences seeks to blend these foundational principles with state-of-the-art research and the opportunity to develop a breadth of skills and explore a diversity of career options. We will select 6 trainees from the cohort of students who enter our PhD program through a common portal, and will support them during their 1st and 2nd years (in total, 12 trainees/year). Our 49 training faculty, representing multiple departments and disciplines, are part of a cohesive scientific community that offers a strong mentoring environment. Central to our new training program is the commitment to educate a diverse population of students to conduct science in a rigorous, reproducible, creative and ethical manner. Our curriculum will emphasize the ability to think critically, to build and test models and hypotheses, and to understand the essential principles of experimental design. Biomedical science is an empirical discipline, and our students must understand the strengths and limitations of contemporary and classical methodologies. The ability to critically analyze data is essential, as is competency with quantitative methods and statistical analysis. We want to ensure that our trainees can work effectively in diverse groups and are skilled at communicating with a variety of audiences. In addition to coursework and a deep immersion in a research laboratory, our trainees will participate in two (out of four) enrichment tracks focused on Communication, Community Engagement and Advocacy, Education, and Innovation and Entrepreneurship. In the Communication track, students will have the opportunity to hone their skills in written, verbal and graphic presentations for expert, non-expert and lay audiences. In the Community Engagement and Advocacy track, trainees will work with students in nearby elementary schools, children's museums and city-wide events to foster their enthusiasm for, and appreciation of, science. Engagement in science policy and advocacy in regional and national contexts will also be featured. Trainees participating in the Education track will be educated in “teaching techniques”, will participate in teaching externships at local universities and give guest lectures at regional HBCUs. Trainees in the Innovation and Entrepreneurship track will earn a certificate by taking an online course and participating in local and regional pitch competitions, and will participate in brief externships in local biotechnology companies and the MUSC Foundation for Research Development. For at least two of these tracks, Digital Badges will also be offered. As they pursue their dissertation research, our studies will participate in a variety of career development activities that introduce them to a breadth of future opportunities within and beyond academe. They will be truly prepared to make important contributions within the changing landscape of contemporary biomedical science.

NIH Research Projects · FY 2025 · 2019-07

PROJECT SUMMARY This is a renewal application of a T32 postdoctoral research training program in basic research, translational research, clinical research, clinical trials and health service research, and telehealth research relevant to improving lung health within the southeastern United States. The goal of the Pulmonary Focused Foundations in Innovation and Scholarship (PuFFInS) Training Program is to recruit, train and ensure that the next generation of investigators have the skillsets needed to improve the healthcare and outcomes for individuals with lung diseases with particular emphasis on lung cancer prevention, screening and implementation, critical care, and rare lung diseases, including pulmonary fibrosis, sarcoidosis and cystic fibrosis. Our interactive and interdisciplinary PuFFInS Training Program brings together a spectrum of well- funded investigators across the Medical University of South Carolina, including clinician researchers, epidemiologists, and cell biologists. The training program is structured to help trainees obtain the necessary competencies and expertise for sustained careers in pulmonary medicine in a flexible framework that accommodates a diverse range of prior education/experience. PuFFInS trainees may matriculate into one of two research tracks with a foundation in innovation and entrepreneurship: a Clinical Science Research Track focused on clinical trials, health service research, and telehealth research, and a Basic Science Research Track. Training will be outlined in each Fellow’s Individualized Development Plan and guided by their selection of a Primary Mentor in a pulmonary-related research area and Secondary Mentor to provide a complimentary interdisciplinary scientific approach or clinical area of expertise. PuFFInS trainees will also benefit from core and selective training options that include formal course work, workshops, training in the responsible conduct of research, and retreats. The application requests support for 4 PuFFInS trainees per year. PuFFInS trainees will be on the research training grant for two years. The Program Steering Committee will review and approve the selection and annual re-appointment of PuFFInS trainees based on specified criteria and evaluation data. A multi-year assessment plan will be used to: 1) assess each trainee’s performance and experience in the program and subsequent development and productivity; 2) assess the effectiveness of the mentors and mentee-mentor relationships; 3) enable program leadership to determine if the objectives of the program are being achieved; and 4) inform strategic direction for future program development.

NIH Research Projects · FY 2025 · 2019-07

PROJECT SUMMARY/ABSTRACT This proposal is in response to PAR-21-138: Method to Extend Research in Time (MERIT) Award Extension Request, which includes a 2-year MERIT extension request to support new data collection focused on cannabis-tobacco co-use and the implications of cannabis use on tobacco cessation outcomes. This MERIT proposal represents a timely and logical extension of the NCI-funded parent MERIT award (R37 CA237245, PI McClure) entitled, “Determining the impact of cannabis use and severity on tobacco cessation outcomes: A prospective tobacco treatment trial.” The overall goal of the funded parent R37 MERIT award was to conduct a prospective tobacco treatment study evaluating the impact of cannabis co-use on tobacco cessation outcomes, focused specifically on those smoking cigarettes. In the parent study, participants who co-use cigarettes and cannabis are being oversampled 2:1 to cigarette-only participants. The parent study is designed to evaluate how cannabis use may serve as a barrier to successful tobacco cessation and how cannabis use changes during a tobacco cessation attempt. Several important observations have emerged during the course of the parent award as well as in the tobacco-cannabis co-use literature more broadly, prompting the proposed 2-year MERIT extension. Specifically, the use of e-cigarettes (vaped nicotine products; electronic nicotine delivery systems [ENDS]) has increased among youth and adults in the United States (US). These trends in non-combustible forms of tobacco use have been observed in the parent R37 award. Within the parent study, we are excluding a large number of interested callers due to their use of e-cigarettes primarily or in combination with cigarettes at a frequency that is exclusionary. While the parent study is focused on combustible tobacco use (cigarette smoking), which is the most harmful of tobacco products, the ubiquity of e-cigarettes cannot be ignored, particularly as it relates to cessation and the underlying relationship with cannabis co-use. Therefore, this 2-year MERIT extension proposes to enroll a third group of adults (ages 18-40; N=70) who are using e-cigarettes daily or near daily (co-use of cigarettes is allowable; <10 days out of the past 30) and are also using cannabis. We will leverage the methods, measures, and procedures being used as part of the parent R37 to complete this e- cigarette cessation trial with a focus on a co-use population to extend the generalizability of study findings. The sample of e-cigarette-cannabis co-use participants is the main difference in this MERIT extension. This 2-year MERIT extension will allow for the exploration of e-cigarette and cannabis co-use characteristics and the impact of cannabis co-use on e-cigarette cessation. New data collection proposed here falls within the scope of the parent grant and represents an important extension of the original aims. The inclusion of those using tobacco through both cigarettes and e-cigarettes will allow for the evaluation of cannabis co-use on tobacco/nicotine cessation and changes in the relationship between substances during a quit attempt.

NIH Research Projects · FY 2025 · 2019-06

: Two major hurdles must be overcome to cure type 1 diabetes (T1D): (i) the autoimmune response and (ii) the destruction of insulin-secreting islets/β cells. Immunotherapies, including improved immune regulation using ex vivo expanded regulatory T-cells (Tregs) or low-dose interleukin-2 (IL-2), may suppress autoimmunity. However, immunomodulation is not expected to directly stimulate regeneration of β cells. On the other hand, mesenchymal stromal/stem cells (MSCs) possess both immunomodulatory and regenerative properties and represent a promising new intervention for autoimmune diseases. MSCs are an accepted therapeutic for wound healing in plastic surgery applications and are being tested in clinical trials for treating autoimmune and inflammatory diseases, ischemia-reperfusion injuries, diabetes, and other diseases. Our group and others found that after infusion into spontaneous non-obese diabetic (NOD) mice, MSCs migrated into the injured pancreas, reduced hyperglycemia, and attenuated Th1 immune responses concomitant with the expansion/proliferation of Tregs. Most importantly, MSC infusion increased mRNA expression of IL-2 and TGF-β receptors in pancreatic Treg cells in NOD mice. A pilot clinical trial in Sweden showed that a single infusion of autologous bone marrow-derived MSCs preserved insulin secretion in adult patients with new-onset T1D. This study has yet to be systemically tested in patients in the United States, and no mechanistic studies have been reported that explain the observed benefits. MSCs derived from umbilical cord (UC-MSCs) show greater cell yield, a less invasive harvesting procedure with associated reduced morbidity, and stronger immunosuppressive and regenerative potential and are a popular source for cell therapy. Based on the above principles and the successful patient enrollment in our one-year R01 grant, we propose a renewal of a randomized, double-blind, placebo-controlled, single-center clinical trial to determine the efficacy of UC-MSC therapy in patients with new-onset T1D. Our working hypothesis is that systemic administration of MSCs freshly expanded ex vivo reduces the progression of diabetes and preserves insulin secretion through restoring normal function of the immune system and preservation/improvement of pancreatic β cells in patients with T1D. We will test this hypothesis by determining the safety and efficacy of MSC therapy in patients with new-onset T1D when added to standard-of-care. MSCs may constitute an important therapeutic advancement for T1D.

NIH Research Projects · FY 2025 · 2019-03

Project Summary Mammalian heart development does not end with birth; major changes occur in the early postnatal heart that lay the foundation for subsequent physiology and pathology. A critical transition occurs shortly after birth in the outcome of cardiomyocyte (CM) cell cycle: in the embryo, CMs complete cell cycle and divide (proliferate), whereas postnatally, most CMs interrupt cell cycle after S-phase DNA replication but before cytokinesis and become polyploid. The same events in the normal postnatal heart are reiterated in the injured adult heart: CMs are induced by injury to enter cell cycle and then mostly interrupt rather than complete it, resulting in failure to replace lost CMs. A critical gap in knowledge relates to the mechanisms that cause postnatal CMs to interrupt or complete cell cycle; for a process that is so fundamental to both embryonic heart growth and postnatal heart regeneration, it is surprising how little is known of the cellular and molecular features that underlie these events. In this project renewal, we propose to explore two novel pathways that influence mammalian CM cell cycle completion, ploidy and regeneration. Both Aims of this project relate to oxygen or reactive oxygen, which rise in the postnatal period. Both Aims invoke signaling mechanisms (rather than nonspecific damage or toxicity) that transmit oxygenation into the physiological outcome of cell cycle interruption and CM polyploidy. Aim 1 builds on our prior discovery of Tnni3k, which is a CM-specific kinase. Tnni3k activity promotes CM polyploidy, whereas absence of Tnni3k activity improves CM cell cycle completion. We discovered that Tnni3k is hyperactivated by peroxiredoxin mediated oxidation. The studies proposed use a range of cell and animal models to expand on this insight in normal heart biology and in heart regeneration. Aim 2 involves FIH1, which we newly identified as a regulator of CM polyploidy. FIH1 is an oxygen-dependent asparagine hydroxylase, and through a genetic strategy described in the proposal, we also identified Pik3r4 as a candidate substrate of FIH1 action. Pik3r4 is a component of the midbody machinery that initiates abscission, the terminal step of cytokinesis and the step at which most mouse CMs fail when becoming polyploid. The proposed analyses define this interaction and its consequences in normal heart biology and in heart regeneration. Our earlier insights established a relationship between CM ploidy, proliferation and regeneration. The studies in this application seek to extend this understanding to its underlying mechanistic components.

NIH Research Projects · FY 2024 · 2018-09

Post-stroke cognitive impairment (PSCI) is a leading VCID with no treatments. While it is known that proper cerebrovascular function is critical for brain health, our poor understanding of the cellular/molecular mechanisms that promote the onset and progression of cognitive decline at the vascular unit (VU)/neuron interface limited the identification of therapeutic targets. Inadequate inclusion of vascular risk factors, biological sex and long- term stroke care practices into the recovery research prevented the development of comprehensive preventive and therapeutic strategies for PSCI. The goal of this proposal is to address these gaps in knowledge by advancing our understanding of the role of the endothelin (ET) system beyond its extensively studied contractile effects to the regulation of the VU (endothelial cell-pericyte-astrocyte) integrity using preclinical models of hypertension, PSCI and rehabilitation. Brain ET-1 levels correlate with the degree of hypoperfusion and the severity of dementia. Yet, how and to what extent the ET system contributes to PSCI is not known. In contrast to the detrimental effects of ETA receptor (ETAR) signaling, the encouraging results of a recently completed Phase III trial showed that the stimulation of ETBR improves functional outcomes. We have evidence that prevention of cognitive decline is associated with preserved VU integrity; integration of enriched care (EnCare) with social/physical activities to our stroke care paradigm attenuates PSCI in male SHRs; this is associated with the prevention of stroke-induced increases in the expression of VU ETAR, brain microvascular endothelial cells (BMVECs), which were previously thought to have only ETBR, also possess ETAR, and ETAR signaling promotes BMVEC and pericyte degeneration (senescence, endothelial mesenchymal transition-EndMT, and transition of pericytes to a microglia-like phenotype). We hypothesize that dysregulation of microvascular ETAR/ETBR balance contributes to profound progressive PSCI in hypertension by promoting degeneration of the VU which disrupts vaso-neuronal coupling. A corollary to this hypothesis is that modulation of the ET signaling via ETAR blockade or ETBR stimulation will improve the functional and structural integrity of the VU and prevent PSCI. Aim 1 will determine the relationship of post-stroke changes in the ET system with the development of PSCI. Mechanistic Aim 2 will determine endothelial yin-yang (ETAR-ETBR) mechanisms contributing to the regulation of VU phenotypes and vasotrophic (un)coupling by defining the impact of modulation of the ETAR or ETBR signaling on autocrine/paracrine regulation of senescence and phenotypes of VU cells in and targeted eETAR silencing on VU integrity and PSCI. Translational Aim 3 will determine the most effective approaches to stimulate protective ETR signaling by defining the impact of intranasal or systemic administration of ETAR antagonist BQ123 or ETBR agonist IRL-1620 alone and in combination with EnCare on the development and progression of cognitive and psychological deficits and fluid/imaging biomarkers in PSCI.

NIH Research Projects · FY 2025 · 2018-08

SUMMARY Metastasis is a significant cause of mortality for patients with triple-negative breast cancer (TNBC), with a median overall survival of less than one year. The introduction of immunotherapy has revolutionized the systemic treatment of metastatic cancer. However, there are underlying resistance mechanisms that limit response to immunotherapy in TNBCs. Increased PD-L1 cell surface expression is associated with improved response to α- PD-L1 or α-PD-1 therapies. One potential mechanism by which tumor cells acquire resistance to immunotherapy is by reducing PD-L1 expression in the cell membrane. Furthermore, recent reports have demonstrated that internalized (non-membranous) PD-L1 participates in oncogenic/pro-metastatic signaling within cancer cells without much mechanistic understanding. It is known that lipid metabolism and signaling alterations play a role in cancer cell migration/invasion and tumor metastasis, including reductions of bioactive sphingolipid ceramide that mediates pro-apoptotic and anti-proliferative signaling. We recently showed that reductions in ceramide synthase 4 (CerS4)-generated long-chain C18-C20-ceramides induce TNBC migration and metastasis by activating the TGF-β/Sonic hedgehog (Shh) signaling axis. However, the regulatory components of this mechanism remain unknown. Based on our published and unpublished preliminary data, this application is designed to test a novel overall hypothesis that the reduction of CerS4-generated ceramide signaling enhances PD-L1 internalization, induces pro-metastatic signaling and facilitates resistance to immunotherapy in TNBC. There are two Specific Aims proposed: Aim 1 is designed to define the mechanism by which reduced CerS4/ceramide signaling regulates PD-L1 internalization and its intracellular metastatic signaling. Aim 2 is designed to determine how CerS4/ceramide signaling regulates the PD-L1/Caprin-1 complex to control TNBC metastasis and resistance to immunotherapy. Overall, this application describes a novel resistance mechanism to immunotherapy and intracellular PD-L1-dependent pro-metastatic signaling driven by lipid/ceramide metabolism alterations. Combination therapies targeting this signaling network could reduce the metastatic burden and improve metastatic TNBC response to immunotherapy, collectively addressing clinically unmet needs in this application.

NIH Research Projects · FY 2026 · 2018-08

Project Summary The burden of stroke disproportionately impacts the Southeast United States- a region known as the “Stroke Belt”. Outreach to populations in this region for stroke education, prevention, acute treatment, rehabilitation, and participation in clinical research, remains a challenge. In order to change the disproportionate stroke burden of this region, a highly functional clinical and research multicenter infrastructure to engage populations at high risk for stroke is critical. In this application, investigators in the Southeast Collaborative Alliance for Stroke Trials (SE-CoAST) are committed to continuing to serve as a Regional Coordinating Center (RCC) in Stroke Net. SE-CoAST is now an expanded, robust collaboration between 5 tertiary care medical centers situated in the heart of the Stroke Belt: the Medical University of South Carolina along the South Carolina (SC) coast, the University of South Carolina at Columbia (Prisma Health Richland) in the Midlands of SC, the University of South Carolina at Greenville (Prisma Health Upstate) in the Upstate of SC, the Augusta University Medical Center in eastern Georgia, and Guilford Neurological Associates (Moses Cone Health) in western North Carolina. The greatest strength of this expanded network is our established partnerships in research and stroke care delivery, which has resulted in SE-CoAST emerging as one of the top recruiting Stroke Net RCCs overall. SE-CoAST has also been the #1 recruiting RCC in the Stroke Belt and the #1 recruiting RCC of Black subjects. SE-CoAST Investigators continue to make significant contributions to national Stroke Net activities, serving on Stroke Net national committees and in leadership roles for Stroke Net clinical trials. Additionally, the SE-CoAST training core has a proven track record of successful faculty development of a diverse group of Stroke Net Scholars. Over the next 5 years, the goals of SE-CoAST are: 1) to leverage the SE-CoAST organization to accelerate trial start-up and increase recruitment and retention in Stroke Net trials while continuing to ensure high-quality data collection; 2) to make impactful contributions to the leadership of Stroke Net activities nationally; 3) Provide a fertile learning environment that includes strong mentorship and support to enhance the career development of our Stroke Net scholars. Our commitment to enrolling a diverse population of subjects from a highly stroke-prone region and the experience and leadership of our expanded multicenter team makes SE- CoAST a highly successful and valuable member of Stroke Net.

NIH Research Projects · FY 2025 · 2018-08

Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality. How ethanol (EtOH) damages the liver remains poorly understood, and therapies are lacking or unproven. A better understanding of the mechanisms by which the liver handles, processes, and responds to EtOH is needed to develop strategies to avoid and treat the dangerous hepatic ramifications of alcohol, particularly fibrosis and cirrhosis. EtOH consumption produces a swift increase in alcohol metabolism (SIAM) that is associated with a commensurate increase of mitochondrial respiration. Our work reveals reversible hepatic mitochondrial depolarization (mtDepo), increased mitophagic burden, and release of mitochondrial DNA (mtDNA) in mice after EtOH treatment, that precedes hepatic steatohepatitis and fibrosis. Here, we build on these findings to characterize the signals, pathways, and mechanisms of 1) onset and recovery from EtOH-induced mtDepo, 2) mtDepo- induced mitophagy, and 3) stellate cell activation and fibrosis downstream of mtDepo. Overall, we hypothesize that mtDepo is an adaptive response stimulating more rapid mitochondrial NADH oxidation to supply NAD+ required for EtOH metabolism, but chronically, mtDepo becomes maladaptive, causing disordered mitophagy and release of mitochondrial damage-associated molecular patterns (mtDAMPs) like mtDNA, leading ultimately to hepatic end stage liver disease. In Specific Aim 1, we will characterize the mechanisms of onset and recovery of EtOH-induced mtDepo, specifically the role of opening and closing of different proton leak pathways in inducing mtDepo and of mitochondrial biogenesis to restore functional mitochondria after EtOH is metabolically eliminated. In Specific Aim 2, we will characterize the manner of mitophagy after EtOH treatment. Specifically, we will determine if mitophagy initiated by EtOH-induced mtDepo involves the classical PINK1/Parkin ubiquitination pathway, is triggered by mitochondrial swelling leading to inner membrane herniation through a ruptured outer membrane with release of mtDNA as observed in preliminary work, or both. In Specific Aim 3, we will determine pathways by which mtDAMPs (like mtDNA) (possibly in synergism with acetaldehyde generated from hepatic EtOH metabolism) elicit a profibrogenic response in stellate cells with particular attention of the role of mtDNA-sensing toll-like receptor-9 (TLR9) whose deficiency decreases alcohol-induced liver injury. Together, these aims will increase our understanding of mechanisms underlying both the onset and recovery from mtDepo and how mtDepo-induced dysregulated mitophagy leads to mtDAMP release causing stellate cell activation and ultimately hepatic fibrosis. The findings of this project will allow development of new mechanism-based therapeutics to treat and prevent alcoholic liver disease.

NIH Research Projects · FY 2026 · 2018-01

Project Summary Despite extensive research, effective therapies for Alzheimer's disease (AD) are still unavailable. One important contributing factor for this is a lack of sensitive tools for assessing AD pathology progression at its earliest stages when interventions are most likely to succeed. Both positron emission tomography and anatomical magnetic resonance imaging (MRI) have been applied for this purpose in many prior AD studies, but the information they provide is limited. In particular, they are insensitive to brain tissue microstructure and functional connectivity, which are known to be altered by AD pathology. Therefore, alternative imaging methods with sensitivity to microstructure and function could help in monitoring response to potential therapeutic interventions as well as support studies of the underlying causes of AD, which are still not fully understood. For quantifying brain microstructure, diffusion MRI (dMRI) is the pre-eminent noninvasive imaging modality, while for brain functional connectivity, resting-state functional MRI (rs-fMRI) is the leading approach. In our first funding period, we have shown, for the 3xTg-AD mouse model of the AD pathology, that a specific dMRI method called diffusional kurtosis imaging (DKI) is able to detect microstructural brain abnormalities as early as 2 months of age, which precedes the deposition of amyloid plaques and neurofibrillary tangles, the two classic histological markers of AD. In addition, DKI measures are found to be extremely sensitive to further changes in microstructure occurring throughout the progression of AD pathology up to 21 months of age. In Aim 1 of this renewal application, we propose to extend this work by determining the ability of DKI to monitor, from 2 to 18 months of age, the response of AD pathology to a promising drug treatment known as neurotrophic factor peptide mimetic (P021), which is known to inhibit neurodegeneration and prevent the deposition of amyloid plaques and neurofibrillary tangles in 3xTg-AD mice. The goal is to demonstrate the utility of both standard DKI and a novel extension known as double-pulsed DKI as tools for monitoring therapy response in AD. Since DKI is easily implemented on clinical MRI scanners, translation to human drug trials would be straightforward. In Aim 2, we will acquire rs-fMRI data in this same mouse model to determine the ability of rs- fMRI to monitor response to P021 treatment. In Aim 3, both our DKI and rs-fMRI data will be correlated with biochemical, morphological, and behavioral measures in order to investigate the biological significance of the observed imaging changes. The successful completion of this project will support the application of DKI and rs-fMRI as valuable imaging tools for the assessment of AD drug therapies and for improving our understanding of the mechanisms underlying AD.

NIH Research Projects · FY 2025 · 2017-09

The mission of the Core Center for Clinical Research (CCCR) at the Medical University of South Carolina is to advance knowledge in clinical care and health outcomes for patients who have, or are at risk of developing, systemic lupus erythematosus, vasculitis, scleroderma, and related rheumatic diseases. The center is built on a solid framework of collaborative leadership in rheumatology, biostatistics, public health sciences, and clinical research infrastructure, with a strong history of successful patient recruitment and research productivity. We will retain and expand our leadership and core resources, which include three key components: Administrative, Methodologic, and Clinical and Community Resource Cores. The CCCR will impact the field by: a) providing well-phenotyped research samples to an expanding pool of investigators at MUSC and external institutions to define mechanisms of rheumatic disease pathogenesis and progression; b) enhancing use of the electronic health record (EHR) to identify, phenotype, and recruit patients efficiently for clinical research; c) developing novel tools for clinical and translational studies and investigations of gene-gene and gene-environment interactions; and d) disseminating research findings and promoting research participation. Our center will offer unique resources and methodologies that complement other CCCRs and serve the broader research community. Specific aims are: 1. Foster translational, clinical, and outcomes research focused on patients with lupus, vasculitis, and scleroderma; 2. Develop innovative tools for streamlined EHR-based recruitment and cohort expansion and reduce administrative burden on investigators. 3. Serve as a centralized resource for information dissemination to patients, healthcare providers, the public, research professionals, other CCCRs, and agencies; 4. Provide well-characterized longitudinal samples and clinical data to support investigation into biologic mechanisms underlying risk and disease variation; 5. Deliver statistical and methodological guidance while developing and applying novel analytic methods, including educational support for trainees and junior investigators; 6. Operate a robust pilot project program with methodological support and structured mentorship to promote the success of junior investigators. Key strengths include strong institutional support, integration with MUSC’s CTSA, and strategic collaboration with national organizations such as the Lupus Foundation of America, public- private partnerships, and relevant federal health agencies. *

NIH Research Projects · FY 2026 · 2017-09

PROJECT SUMMARY Although the most significant risk factor for developing Alzheimer’s disease (AD) is advanced age, the changes in tissue microstructure that signal the shift from normal aging to AD are not well understood. Thus, in response to PAR-22-093, NOT-AG-21-039: Understanding AD in the Context of the Aging Brain, we seek to elucidate the changes in white matter microstructure in preclinical AD using advanced diffusion MRI methods developed by our group. During the 1st funding period of this grant, we established a longitudinal cohort of 165 cognitively unimpaired participants ages 45-85 who completed extensive clinical procedures (i.e. MRI, amyloid PET, neuropsychological testing, questionnaires), with an exceptional 92% retention rate at 2-year follow-up, including 14% of participants who have developed incident mild cognitive impairment (MCI) thus far. We showed that in participants with preclinical AD, late-myelinating white matter tracts demonstrate signs of myelin repair/gliosis as evidenced by greater diffusion restriction. We also observed that greater diffusion restriction in the hippocampus significantly predicts incident MCI over and above age, a finding we did not observe with other AD neuroimaging biomarkers of amyloid pathology, neurodegeneration, and white matter lesions. These results have significant implications for disease monitoring and treatment development for the very earliest stages of AD, but further work is needed to refine these methods and determine how they indicate both aging and disease progression over time. Thus, during the 2nd funding period, we seek to continue studying this cohort longitudinally every 2 years, to enhance the cohort’s inclusivity and sample size, and to add new, complementary MRI biomarkers of myelin/gliosis to test our inferences. Our overall objective is to delineate the natural history of white matter changes from normal aging to preclinical AD and to MCI/dementia, illuminating what aspects of myelin/gliosis drive changes in diffusivity, where these preferentially occur, and when in the course of disease these take place. We will continue leveraging our interdisciplinary group’s expertise in diffusion MRI (Diffusional Kurtosis Imaging, Fiber Ball Imaging) and biophysical modeling, adding new experts on T1-based myelin water imaging and 1H- Magnetic Resonance Spectroscopy to assay myelin dynamics/gliosis. We hypothesize that advanced diffusion MRI methods can indicate myelin repair/gliosis in the preclinical stage prior to myelin breakdown and axonal loss in the symptomatic stage, a trajectory that is distinct from normal, homeostatic processes such as myelin remodeling/maintenance. Thus, we aim to: Characterize longitudinal changes in white matter microstructure in aging and AD (Aim 1); Quantify microscopic axonal fiber organization in aging and AD (Aim 2); Determine the associations between diffusion MRI-derived microstructural parameters and complementary measures of myelin/gliosis in aging and AD (Aim 3). This work will have the greatest overall impact in providing the critical translational support for trials that target mechanisms such as innate immunity/inflammation and glial senescence, which are very promising yet grossly underexplored in AD especially for the asymptomatic stage.

NIH Research Projects · FY 2025 · 2017-08

Project Summary Cancer is a leading cause of death in the United States and worldwide. This innovative multi-PI project in its 6th year has established a novel approach to the challenge of discovering strategies to control cancer. Oncogenic activation of the RAS family of GTPases occurs in ~30% of cancers making it the most frequently mutated oncogene in human cancers. Despite impressive progress in our understanding of the biochemistry of RAS and its role in tumorigenesis over the past 3 decades and the excitement of the first approved drug that directly targets a particular oncogenic RAS mutant, development of effective therapeutics targeting RAS remains a grand challenge. We have pioneered the use of monobody technology to define previously unrecognized vulnerabilities in RAS. Monobodies are small synthetic binding proteins that achieve levels of affinity and selectivity for their target similar to antibodies and can be used as tool biologics in biochemical, structural, cellular and in vivo studies. In the current project period, we have developed and used two monobodies, NS1 and R15, to gain new insights into RAS function and vulnerabilities. NS1 revealed the importance of the α4-α5 interface implicated in RAS dimerization. R15 revealed the feasibility of targeting the nucleotide-free (apo) state of a subset of oncogenic RAS mutants, despite the conventional wisdom that one cannot effectively compete against tightly bound nucleotides in RAS. Furthermore, we have established the feasibility of developing monobodies that noncovalently and selectively inhibit oncogenic RAS mutants and of selectively degrading RAS mutants using monobody-VHL fusions. Building on these successes and strong preliminary data, the next phase of this project aims to accomplish the following: 1, We will utilize NS1, R15 and additional monobodies as highly selective perturbants to address important mechanistic questions in RAS biology, including roles of dimerization/self- association in RAS effector activation, roles of wild-type KRAS in heterozygous KRAS mutant cells, and roles of KRAS4A in tumorigenesis. 2, We will establish cell lines and mouse models using genetically encoded monobodies to determine how specific modes of RAS inhibition affect tumorigenesis in vivo driven by oncogenic RAS mutants. 3, We will develop monobodies with new specificity profiles to expand the scope of our project, specifically those selective to NRAS, KRAS4A, and common RAS mutations. Results from this project will advance our mechanistic understanding of RAS function at the biochemical, cellular and in vivo levels and inform the development of therapeutics directly targeting RAS. Furthermore, uniquely powerful tools developed in this project will empower the entire RAS community.

NIH Research Projects · FY 2026 · 2017-07

Abstract Adolescent Brain Cognitive Development (ABCD) is the largest long-term study of brain development and child health in the United States. The ABCD Research Consortium consists of 21 research sites across the country, a Coordinating Center, and a Data Analysis and Informatics Resource Center. In its first five years, under RFA-DA-15-015, ABCD enrolled a diverse sample of 11,878 9-10 year olds from across the consortium, and will track their biological and behavioral development through adolescence into young adulthood. All participants received a comprehensive baseline assessment, including state-of-the-art brain imaging, neuropsychological testing, bioassays, careful assessment of substance use, mental health, physical health, and culture and environment. A similar detailed assessment recurs every 2 years. Interim in-person annual interviews and mid-year telephone or mobile app assessments provide refined temporal resolution of developmental changes and life events that occur over time with minimal burden to participating youth and parents. Intensive efforts are made to keep the vast majority of participants involved with the study through adolescence and beyond, and retention rates thus far are very high. Neuroimaging has expanded our understanding of brain development from childhood into adulthood. Using this and other cutting-edge technologies, ABCD can determine how different kinds of youth experiences (such as sports, school involvement, extracurricular activities, videogames, social media, unhealthy sleep patterns, and vaping) interact with each other and with a child's changing biology to affect brain development and social, behavioral, academic, health, and other outcomes. Data, securely and privately shared with the scientific community, will enable investigators to: (1) describe individual developmental pathways in terms of neural, cognitive, emotional, and academic functioning, and influencing factors; (2) develop national standards of healthy brain development; (3) investigate the roles and interaction of genes and the environment on development; (4) examine how physical activity, sleep, screen time, sports injuries (including traumatic brain injuries), and other experiences influence brain development; (5) determine and replicate factors that influence mental health from childhood to young adulthood; (6) characterize relationships between mental health and substance use; and (7) specify how use of substances such as cannabis, alcohol, tobacco, and caffeine affects developmental outcomes, and how neural, cognitive, emotional, and environmental factors influence the risk for adolescent substance use.

NIH Research Projects · FY 2025 · 2016-09

TRANSFORM SC – (Trials and ReseArch NetworkS FOR More) South Carolina is a statewide consortium of pediatric providers who collectively can reach virtually all children in the state of South Carolina. This consortium has all the critical elements for a center to be a successful collaborator in the IDeA States Clinical Trials Network (ISPCTN): adequate patient volume, creation and retention of an established clinical research infrastructure, a track record of outstanding subject enrollment, dedication to team-based science, and proven ability to recruit rural children. These elements have allowed the South Carolina clinical site to be a highly successful and administratively active participant in the first 2 funding cycles of the ISPCTN. Furthermore, South Carolina investigators have participated in many leadership roles for the ISPCTN including Chair of the Publications and Presentations Committee (Atz), Network PI of a Junior Investigator Study (MacGeorge), chair of ECHO clinical focus working groups (Atz- pre, peri, postnatal outcomes). South Carolina sites are represented in 8 of 9 of the prior and current ISPCTN clinical trials. The combined resources of patient volume, research infrastructure and dedication have enabled TRANSFORM SC to be among the top subject enrollers with robust participant retention in the ISPCTN.

NIH Research Projects · FY 2025 · 2016-09

Project Summary BRCA1 is an established tumor suppressor that plays a critical role in the development of both sporadic and hereditary breast and ovarian cancer. Considered a “master regulator” of genome integrity, BRCA1 has been linked to nearly all aspects of chromatin biology. Loss of BRCA1 is embryonic lethal and leads to cellular defects in stress signaling, DNA repair, cell cycle progression, apoptosis, chromatin condensation, and gene expression. Each of these processes involves dynamic changes in chromatin architecture that regulate spatial and temporal access to genomic DNA. Although implicated in various mechanisms of chromatin modification and remodeling, a mechanistic understanding of BRCA1’s role in regulating chromatin dynamics has been difficult to establish due to the global consequences of its dysfunction. Recently, we established a cell-free system that supports transcription of naturally chromatinized plasmid substrates in Xenopus egg extract. Transcriptional activity in extract is tightly coupled to changes in chromatin modification and structure, providing a powerful tool to study how regulation of chromatin dynamics controls gene expression. By coupling this system with established approaches used to elucidate mechanisms of DNA replication and DNA repair, we are now poised to examine the interplay between these fundamental processes. Indeed, BRCA1’s role as a sensor for genomic stress places it at the center of genome utilization, maintenance, and repair. In this proposal, we seek to understand how BRCA1 and other chromatin regulators control access to DNA in response to different cellular events. Together, these studies will provide new mechanistic insight into the complexities of chromatin signaling that remain an essential, but poorly understood regulator of genome integrity.

NIH Research Projects · FY 2025 · 2016-07

PROJECT SUMMARY/ABSTRACT This first renewal application seeks continued National Cancer Institute (NCI) support for a successful ‘Integrative Training in Oncogenic Signaling’ (ITOS) Program developed to train postdoctoral fellows by a select group of cancer scientists affiliated with the Hollings Cancer Center (HCC) at the Medical University of South Carolina (MUSC). The programtakes place in an active and growing medical center with state -of-the-art facilities,a vibrant NCI-designated cancer center, and an active Office of Postdoctoral Affairs. Led by a Program Directorship team with an exceptionally strong cancer research and leadership background, the ITOS Program selects and supports the placement of trainees in experienced, well-funded, productive laboratories led by the Program Faculty who reside in an interactive, multi-departmental research environment with extensive resources. Each trainee has a primary mentor and one/two secondary mentors with complementary expertise to ensure distinct and valuable perspectives that enhances the overall cancer-relatedresearch training experience. The objectives of the ITOS Programremain unchanged, seeking to provideproactive mentoring, oversight and research training in cutting-edge methodology; to develop useful academic and essential career development skills; to foster collaborative, interdisciplinary interactions with faculty and other trainees; and, to provide exposure to current cancer research discoveries and how these are being translated into novel approaches to prevent, diagnosis, and treat cancer. The ITOS Program has seven essential programmatic components: 1) 33 member Program Faculty who share common cancer research interests and provide essential mentoring for trainees; 2) one to two year experiences in designated Program Faculty laboratories; 3) an ITOS Program Research Club providing an engaging community forum for the trainees and Program Faculty to discuss work in progress as well as the latest discoveries; 4) shared research resource workshops and tailored training in cutting-edge biotechnologies; 5) interdisciplinary engagement with trainees in HCC-sponsored thematic research retreats, symposia, work in progress meetings, and seminars; 6) career development workshops and courses that equip trainees for independent success; and, 7) opportunities to network nationally at a minimum of two professional conferences each year. In its fourth year, the ITOS Program has graduated 9 fellows; 1MD, 1MD/PhD, 7 PhDs. Trainees from diverse backgrounds, 58% female and 30.8% underrepresented racial/ethnic minorities, whom have all successfully transitioned to positions in academia or industry. Based on the capabilities, capacity, trajectory of MUSC for cancer-related training, and the successful accomplishments achieved during its initial funding period, the ITOS Program is requesting the support for seven postdoctoral trainees each year, representing an increase of two trainee positions. In summary, our ITOS Program offers distinct experiences and opportunities only afforded to the selected ITOS Fellows, and the program, led by an outstanding cadre of Program Faculty, is anticipated to remain highly attractive to emerging junior investigators locally and nationally.