Medical University Of South Carolina

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Age-related hearing loss (ARHL) is a major public health concern, as the United States population continues to age. Although hearing devices are available, they do not address the root causes of ARHL which include auditory nerve (AN) degeneration, including demyelination. There is an urgent need for novel treatment approaches that prevent or slow age-related AN degeneration. Recently, studies show that AN demyelination contributes to hearing impairments, however the exact mechanism of demyelination in the aging auditory system remains unclear. Myelin maintenance and repair is a life-long process, but the efficiency of myelin repair declines with age. The pattern recognition receptor Dectin-1 (Clec7a) has been implicated in demyelination and neurodegeneration. Preliminary data show: 1) increased macrophages/microglia in regions of demyelination in the aged human AN, 2) evidence of microglial phagocytosis of myelin in the human AN, and 3) upregulation of Dectin-1 expressing macrophages/microglia in the aged mouse AN. These data suggest that Dectin-1 may contribute to age-related macrophage/microglia dysfunction, demyelination, and AN degeneration. Although macrophages/microglia in the auditory system are well-documented, their contributions to AN degeneration are unclear. Based on previous studies and preliminary data, I propose that aging increases Dectin-1 expressing macrophages/microglia, creating a proinflammatory immune cell population that exacerbates demyelination and AN degeneration. Aim 1 will test the hypothesis that Dectin-1 expressing macrophages/microglia are proinflammatory and associated with AN demyelination in aged mice and human donors. In this aim, I will define the age-dependent changes in Dectin-1 expressing macrophages/microglia in AN demyelination using a combination of quantitative immunohistochemistry, 3D high-resolution imaging, and single nucleus RNA- sequencing. This study will evaluate inflammatory infiltration of Dectin-1 expressing macrophages/microglia in demyelinated regions of the AN in young and old CBA/CaJ mice and validate findings in human tissue. Dectin-1 expressing macrophages/microglia are predicted to express more proinflammatory markers in aged ANs in regions of demyelination. Aim 2 will test the hypothesis that reducing Dectin-1 expression will prevent myelin degeneration of the AN by decreasing microglia activation and limiting inflammation, thus preserving AN function. This study will use a global Dectin-1 knock-out mouse model to directly evaluate the effect of Dectin-1 depletion on proinflammatory macrophage/microglia activation and AN degeneration. Mice will undergo threshold and suprathreshold auditory physiology (e.g. auditory nerve responses and measures of phase locking values (PLV) to assess AN function). Dectin-1 KO mice are predicted to show less age-related AN demyelination, stronger PLV, and reduced proinflammatory activation. These studies will advance our understanding of macrophages/microglia in AN pathology and potentially reveal a new biomarker of AN degeneration.

NIH Research Projects · FY 2025 · 2025-09

Abstract Advanced Fibrosis Detection and a Predictive Diagnostic Model for Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD) in Primary Care. Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly nonalcoholic fatty liver disease [NAFLD]) affects an estimated 1 in 3 persons in the U.S., a prevalence expected to increase over the next decade. MASLD’s rising prevalence and its association with diabetes and obesity make it a chronic disease well-suited for initial management by primary care providers (PCPs). PCPs can impact MASLD care by detecting advanced fibrosis, which is the best predictor of cirrhosis, hepatocellular carcinoma, and liver-related mortality in affected patients. Recently issued guidelines from the American Association for the Study of Liver Diseases recommend the sequential use of non-invasive liver tests, the Fibrosis-4 Index (FIB-4) followed by confirmatory liver stiffness measurement (LSM) with vibration-controlled elastography (VCTE), to detect advanced fibrosis in patients with MASLD. FIB-4 is attractive in primary care due to the low-cost and broad availability of its inputs, but PCPs have little experience with FIB-4 calculation, limited comfort with its interpretation, and infrequent access to confirmatory liver stiffness testing. The guidelines provide a clinical threshold for hepatology engagement, recommending referral for patients with advanced fibrosis, while those with low-risk MASLD remain in primary care. Incorporating advanced fibrosis detection into the already overwhelming workload of PCPs requires thoughtful application of electronic health record (EHR) technologies to avoid contributing to PCP alert fatigue and burnout. Also, despite the high prevalence, MASLD is underdiagnosed in primary care due to a host of factors that include the lack of recommendations for universal screening and limitations in the performance of traditional MASLD signals for case finding, including type 2 diabetes mellitus, obesity, and abnormal liver chemistries. Iterative efforts to address the MASLD diagnostic care gap need to assist PCPs in identifying which patients need liver imaging and ensure that the signals for diagnostic testing capture MASLD with advance fibrosis, disease PCPs cannot miss. In this work, we aim to test the adoption, penetration, fidelity, sustainability, and performance of a novel, non-interruptive EHR alert for MASLD fibrosis risk assessment in a primary care network by performing a stepped wedge, cluster randomized trial in patients with known MASLD (Aim 1). We will also develop, test, and internally validate a predictive diagnostic model for identifying MASLD and MASLD with advanced fibrosis in a prospective cohort of patients with no known chronic liver disease (Aim 2). This proposal aligns with NIDDK’s scientific goal to disseminate, implement, and evaluate evidence-based care strategies in community care settings where the burden of MASLD hides in plain sight.

NIH Research Projects · FY 2025 · 2025-09

Histamine is a signaling molecule produced by host cells and bacteria, acting through four receptors (HRH1, HRH2, HRH3, HRH4), each with tissue-specific roles. HRH1 is known for its pro-inflammatory effects in the airway epithelium, but our data suggests it plays a non-inflammatory role in mucus secretion in the gut and salivary glands. Mucus is essential for oral health, influencing hydration, lubrication, and protection while affecting the oral microbiome. Disruptions in histamine signaling, such as through antihistamines or microbial changes, are linked to reduced salivation and dry mouth, suggesting a role for histamine in oral mucus secretion. HRH1, the only histamine receptor in salivary glands, is expressed on the apical and basolateral membranes of mucous acini. Our data shows that histamine stimulates mucus secretion from salivary gland organoid monolayers without eliciting pro-inflammatory responses seen in other organs, suggesting HRH1-mediated mucus release supports tissue homeostasis. This proposal aims to explore how HRH1 signaling regulates salivary gland mucus secretion and the role of microbial-derived histamine, specifically from the probiotic Limosilactobacillus reuteri. We hypothesize that bacterial histamine activates HRH1 in salivary glands, stimulating mucus secretion to support oral health. Aim 1 focuses on the signaling cascade initiated by HRH1 activation in mouse salivary gland organoids, examining PLC-IP3 pathways, intracellular calcium signaling, and transcriptional changes to understand histamine's role in mucin secretion and gene regulation. Aim 2 evaluates how L. reuteri-derived histamine impacts mucus secretion and oral health. Using wild-type and histamine- deficient L. reuteri strains, we will assess bacterial histamine’s effect on salivary gland secretion in organoid and mouse models, confirming receptor-specific effects with HRH1 antagonists. This research could inform therapeutic applications for xerostomia and other oral health issues by revealing how microbial-derived histamine and HRH1 activation influence salivary gland function. The Medical University of South Carolina (MUSC) offers a collaborative environment with resources and mentorship to support these objectives and Selene’s (the PI’s) career. Selene’s long-term goal is to specialize in host-microbe interactions, gaining expertise in techniques like cell culture, histology, and mouse models. During postdoctoral training, she aims to publish papers, improve writing, build networks, and receive mentorship from experts like Dr. Engevik and Dr. Kern, while gaining experience in grant writing and teaching to prepare for an academic career. Collectively, these experiments, the research environment, and the training plan outlined will enhance our understanding of histamine in oral health, provide insight for novel therapeutic targets to improve the oral environment, and prepare Selene for a career in science academia, aligning well with the NIDCR’s mission to train scientists and advance research that improves oral health.

NIH Research Projects · FY 2025 · 2025-09

Obstructive sleep-disordered breathing (SDB), defined as nocturnal respiratory disturbances ranging from snoring to severe obstructive sleep apnea, affects 8.9 million (12%) children in the US. Black children are 4-6 times more likely to have SDB, but they are less likely to undergo evaluation and to receive timely standard of care treatments, such as tonsillectomy, to address SDB. Untreated SDB is associated with significant health consequences such as behavior disorders, poor academic performance, neurocognitive deficits, and cardiovascular problems. SDB care is complex and gaps in SDB diagnosis and management are pervasive. Currently, no effective method to address non-clinical barriers in SDB care has been established. A critical need exists for a multilevel, theory-based intervention to reduce barriers to care for children with SDB. Patient navigation is an evidence-based intervention that has shown to improve referral and adherence to treatment in a variety of health conditions and is a culturally acceptable intervention to promote access to care in the setting of uneven access to care. The candidate’s foundational work informed the development of a novel, multilevel theory-based patient navigation intervention, Reach for Equity in Pediatric Obstructive Sleep Evaluation (REPOSE). In the REPOSE intervention, a centralized patient navigator a) identifies and addresses dynamic individual barriers, b) provides resources and social support for parent-child dyads, and c) facilitates bidirectional SDB care coordination between clinical teams and parents to achieve evidence-based care. In this hybrid type I effectiveness implementation study, the candidate will conduct a pilot randomized controlled trial (RCT) in which N=80 parent-child dyads will be randomized to REPOSE or usual care for SDB. We will examine the extent to which the REPOSE intervention improves rates of adherence to evidence-based guidelines among children with SDB from a broad range of socioeconomic and rural/urban status (Aim 1) and changes in barrier resolution and self-efficacy among parents (Aim 2). In addition, we will evaluate barriers and facilitators to implementation as guided by the Consolidated Framework for Implementation Research (CFIR) with a focus on social determinants of health (Aim 3). The findings of this randomized pilot trial will inform the design of a future fully powered RCT. The overall objective of this K23 proposal is to support Dr. Phayvanh Pecha as she acquires the skills necessary to become an independent health disparities investigator with a program of research focused on improving access to care for children with SDB. The current proposal includes a comprehensive Training Plan that is supported by a team of experienced and successful mentors within a rich research training environment. The training and mentorship afforded by the K23 mechanism will ensure that the candidate achieves skills in clinical trial design, implementation science, and health disparities research. The candidate’s long-term career goal is to become an independent clinical investigator and leader in testing scalable interventions aimed at promoting healthcare access and improving outcomes for children with SDB.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Rates of cannabis use and cannabis use disorder (CUD) among adults in the United States are increasing and the perception of harm associated with cannabis use continues to decline. Further, motivation to completely abstain from cannabis is low. Harm reduction strategies and their benefits have strong empirical support across other substances (alcohol, opioids, and stimulants) with validation of non-abstinence endpoints as indicators of treatment success. While preliminary evidence–some from our group—suggests that cannabis harm reduction may yield benefit in certain domains, a comprehensive, prospective, and rigorous assessment of the potential benefits of reduced cannabis consumption has not yet been conducted. The accumulating evidence base to suggest benefits to cannabis use reduction is promising; however, this literature is limited in four key ways: 1) knowledge has largely been derived from secondary analysis of trials that were not designed to evaluate the benefits of harm reduction and that did not measure cannabis use and reduction in standard delta-9- tetrahydrocannabinol (THC) units, 2) thresholds of meaningful cannabis reduction are lacking, 3) there are no consensus outcomes to demonstrate cannabis use reduction results in meaningful improvement, and 4) studies have failed to comprehensively capture patient-reported and objective improvement in functioning. The current proposal seeks to address an important gap in knowledge and is informed by our group’s data-driven metrics of clinically significant cannabis use reduction. We propose an 8-week cannabis use reduction trial for adults (ages 18+; N=176) with CUD. All participants will receive comprehensive CUD treatment, inclusive of cognitive behavioral therapy, brief motivational interviewing, and incentives for reduction. Specific aims are to assess: 1) associations between cannabis reduction and end-of-treatment cannabis-related problems, 2) improvements in objective measures of sleep and cognitive performance based on degree on cannabis use reduction, and 3) quality of life, CUD criteria count and severity, and other psychosocial improvements based on degree of cannabis use reduction. The overarching hypothesis is that participants reducing cannabis use will show significant, dose-dependent improvement across patient-reported and objective outcomes. In an exploratory aim, we also propose to capture patients’ perceptions of their areas of greatest improvement, as well as successful reduction strategies. Despite strong empirical support for harm reduction for other substances, it is currently unknown if cannabis harm reduction approaches will produce beneficial outcomes. The proposed study will fill a critical gap, as it is specifically designed to recruit those interested in cannabis reduction for a reduction-focused trial and will assess a variety of patient-reported and objective outcomes. Results will have the potential to impact CUD research and treatment by promoting a shift toward alternative, non-abstinence outcomes of treatment success.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY We propose the WINDSURFER trial to answer a signature question of emergency care; “What is the best non-invasive respiratory support (NIRS) strategy for treating acute hypoxemic respiratory failure (AHRF) in the Emergency Department (ED)?” AHRF is the syndrome of impaired breathing resulting in low blood oxygen levels, most commonly from lung or other infections, acute decompensated heart failure and chronic obstructive pulmonary disease. AHRF is a major public health problem as evidenced by its seasonal and pandemic surges and the >100,000 associated deaths each year in the United States. Aggressive treatment of AHRF at its earliest stages in the ED is essential to prevent progression to death. Non-Invasive Respiratory Support (NIRS) is an important and widely used rescue treatment for AHRF that provides effective high-level breathing support without the pitfalls and consequences of mechanical ventilation. The two forms of NIRS are: 1) Non-Invasive Positive Pressure Ventilation (NIPPV), which includes continuous positive airway pressure (CPAP) and bi-level positive airway pressure (BiPAP)], and 2) Heated High-Flow Nasal Oxygen (HFNO). NIPPV supports breathing by delivering high pressured oxygen through a tight-fitting face mask. In contrast, HFNO supports breathing by delivering high flows of heated and humidified oxygen through a specially designed nasal tube. The best NIRS strategy for AHRF is unknown. The optimal treatment for AHRF must be effective, safe, easy to deploy, comfortable for patients and effective across a spectrum of diseases and comorbidities. We propose a new clinical trial, WIN ratio analysis to Determine a strategy of non-invasive SUpport for Respiratory Failure in the EmeRgency Department (WINDSURFER), to determine the best initial NIRS strategy for patients presenting to the ED with AHRF. We will execute the trial using EDs selected from the NIH Strategies to Innovate Emergency Care Clinical Trials Network (SIREN). We will randomize adult ED patients (n=500) with AHRF to a treatment strategy of 12 hours of NIPPV or HFNO. The primary outcome is the hierarchical Major Adverse Pulmonary Events (MAPE): 1) hospital mortality, 2) ventilator-free days, and 3) NIRS hours. We will compare differences in MAPE between NIPPV and HFNO using the Win Ratio, a novel technique to assess differences in a hierarchical composite outcome. Our aims are: Aim I: Determine the effectiveness of ED NIRS strategies (NIPPV vs. HFNO) upon AHRF outcomes. We will test the hypothesis that HFNO is superior to NIPPV, as demonstrated by lower MAPE. Aim II: Evaluate the safety of ED NIRS strategies (NIPPV vs. HFNO) in AHRF. We will evaluate the risk differences between NIPPV and HFNO for the development or worsening of three specific safety outcomes: 1) pneumonia/ pneumonitis, 2) ARDS and 3) shock.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Uterine cancer incidence is rising. Much of this increase is due to a deadly form of endometrial, or uterine, cancer: uterine serous carcinomas (USC). Endometrial carcinoma is often segregated into two subtypes: type I and type II. Type I is common, less aggressive, estrogen linked, and has better prognosis. Type II tumors, which are >90% USC, make up 10% of the uterine cancer population, yet are responsible for 40% of the deaths. Almost all type II tumors are p53-mutant USCs. While characterizing our new spontaneous mouse model intended to create fallopian cancer, we serendipitously discovered that USC can originate from the fallopian tube. An observational study in humans found that fallopian tubal ligation may reduce the rate of type II endometrial cancers by 75%, but the reasons why were speculative. To better understand the human observational study, we propose mouse experimentation and human bioinformatic comparisons. In mice, we will utilize a spontaneous mouse model of fallopian cancer development, the Trp53em1Jdel_Tg(Ovgp1-Trp53*R270H-Myc). Characterization of the model has shown cancerous cells start on the fallopian tube epithelium and are later found in the uterine epithelium. Aim 1 will test murine surgical methods of removing the ovary and fallopian tube, which we predict to reduce the rates of cancer cell identification within the uterus. Aim 2 will utilize lentiviral cell barcoding at the murine fallopian tube to determine how cells move from the fallopian tube to the uterus and then metastasize throughout the abdominal cavity. Aim 3 will characterize DNA methylation patterns of human USC and compare to normal tissue patterns within the fallopian tube and uterus to define what fraction of USC clusters with which possible origin site. Taken together, this study will establish rationale of how and why prevention of human USC may be made through preventative surgeries.

NIH Research Projects · FY 2025 · 2025-09

Abstract Cancer will rarely be cured through pharmacologic targeting of single genes. Tumors evolve in response to selection pressure. Precision oncology often targets a single gene product, and that gene simply becomes mutated once the drug is administered. Although individual genes may mutate, tumor biology is nonetheless constrained to dysregulating specific pathways for each cancer type. We have previously created cutting-edge bioinformatic tools to better understand which constrained pathways are acting as tumor suppressors and oncogenes, due to collaborative gene dysregulation at the molecular pathway level. Aneuploidy is a major cause of molecular pathway changes in cancer and unfortunately each aneuploid event alters both predicted driver genes and unknown passenger genes. Investigation of causal aneuploid changes in a tumor remains difficult, if not impossible, to study with current cell biology and genetic tools. However, we have discovered a unique, commonly suppressed (70% of high-grade serous ovarian cancers have a monoallelic loss, correlating with average reduced expression), pathway which is amenable to well-controlled basic science experimentation: the cadmium response pathway. It is composed of 11 highly homologous metallothionein genes arrayed on a single chromosomal locus. Metallothioneins sequester the bulk of intracellular Zn2+ and environmental genotoxic Cd2+ ions. The loss of the metallothionein locus is associated with chromosome instability and occurs early in tumor formation. Our in vitro assays show controlled metallothionein suppression results in elevated DNA damage. However, the role of metallothioneins as tumor suppressors and as regulators of cancer cellular and molecular biology is largely unknown. This project will establish specific tumor suppressor phenotypes of metallothioneins in ovarian cancer and determine if this aneuploid pathway will serve as a representative example of how multi- genic vulnerabilities can better enable next-generation cancer therapies. We will (1) characterize in vivo the effects of metallothionein gene loss in spontaneous tumor formation in ovarian cancer, (2) develop controlled models of gene suppression enabling suppression of all 11 genes, including by a synthetic dead-Cas9-based transcription factor, (3) determine which cadmium-dependent and cadmium-independent metallothionein- regulated molecular pathways convey tumor suppressor functions, and (4) discover drug classes which best selectively kill low-metallothionein cells. Genetic tools created by this project will enable causal investigation of entire molecular pathways for future projects. Taken together, this innovative research program will directly test how an uncharacterized aneuploid-suppressed pathway contributes to oncogenesis and remains a pharmacologically targetable vulnerability throughout tumor development.

NIH Research Projects · FY 2026 · 2025-09

PROJECT SUMMARY/ABSTRACT The proposed K23 Award will support Dr. Stephanie Aghamoosa, PhD in launching an independent program of research developing non-pharmacological interventions for the secondary prevention of dementia. Dr. Aghamoosa is a clinical neuropsychologist whose long-term career goal is to become a federally-funded investigator conducting large-scale clinical trials of non-pharmacological interventions that are clinically scalable, widely applicable to patients, and that produce long-lasting cognitive and functional benefits. Need for this research is significant and consistent with NIA’s Strategic Goal of identifying interventions to delay the progression of cognitive decline. To achieve her career goal, Dr. Aghamoosa proposes to obtain advanced training that builds upon her clinical specializations in health psychology and neuropsychology and foundational research experiences focused on aging, Mild Cognitive Impairment (MCI), and Alzheimer’s disease (AD). The proposed K23 training, development, and research activities will address remaining gaps, ensuring that Dr. Aghamoosa has the skills and knowledge necessary to accomplish her Career Development Goals which are to: 1) Become an expert in non-pharmacological interventions to improve cognition in MICI/AD, 2) Obtain advanced training in clinical trial methodology for MCI/AD, 3) Become proficient in advanced statistical techniques for clinical trials that incorporate digital health technology, and 4) Establish herself as an independent NIH-funded investigator. Dr. Aghamoosa is an Assistant Professor in the Department of Health Sciences and Research at the Medical University of South Carolina. She will be supported by an exceptional mentorship team of experts in the areas relevant to her career goals and proposed research project: clinical trials in MCI/AD (Benitez, Primary Mentor), cognitive rehabilitation interventions (Twamley, Co-Primary Mentor), non-invasive brain stimulation (McTeague), longitudinal analysis of clinical trial data (Nietert), and digital health technology for assessment of real-world function (Moore). Dr. Aghamoosa’s K23 research project builds upon her involvement in her Primary Mentor’s ongoing work demonstrating cognitive enhancement from non-invasive intermittent theta burst stimulation (iTBS) in people with MCI. In this K23 application, Dr. Aghamoosa proposes a new and distinct line of work aimed at maximizing treatment outcomes through combining iTBS with computerized cognitive training (CCT). The proposed Phase I clinical trial will randomize 50 people with MCI to iTBS+CCT or iTBS+shamCCT to: Aim 1: Establish the feasibility and acceptability of combining iTBS with CCT in MCI. Aim 2: Determine the preliminary effect sizes of combining iTBS with CCT in MCI. Exploratory Aim: Identify potential mediators and moderators of treatment response. These activities will prepare Dr. Aghamoosa to successfully lead a program of high impact, rigorously designed clinical trials of non-pharmacological interventions for MCI.

NIH Research Projects · FY 2026 · 2025-08

Project Summary Pulmonary arterial hypertension (PAH) is a lethal disease with a median survival of only 5-7 years. Pathophysiologically, PAH is a progressive vasculopathy of the precapillary pulmonary vessels that increases pulmonary arterial pressures and pulmonary vascular resistance while reducing pulmonary arterial compliance. The changes in the pulmonary vasculature augment the work load of the right ventricle, which ultimately results in right ventricular dysfunction (RVD). The presence of RVD is the greatest risk factor for death in PAH; however, no current PAH therapies actually target the RV directly. In this proposal, we will investigate the hypothesis that GP130 activation in RV cardiomyocytes promotes cardiomyocyte dysfunction via microtubule remodeling which causes t-tubule derangements and mitochondrial metabolic dysfunction. We will use state- of-the-art approaches to probe the molecular and physiological effects of GP130 antagonism on right ventricular function in porcine RV failure.

NIH Research Projects · FY 2025 · 2025-08

Progressive Pulmonary Fibrosis (PPF) is a serious illness where individuals experience declining physical function, constraints of supplemental oxygen, social isolation, impaired quality of life, and shortened lifespan. Caregivers (CGs) experience high levels of stress and a great sense of fear of the unknown. Loneliness is impactful for both. Individuals with PPF and their caregivers report being poorly informed about the serious nature of the illness and not being referred for educational and symptom-modifying interventions: i.e., palliative care (PC). National guidelines recommend that PC be offered to patients who are diagnosed with serious life-limiting illnesses. PC addresses symptom burden and can assist patients and families/caregivers through the processes of Advanced Care Planning (ACP) for end-of-life (EOL). Patients with unfavorable non-medical factors are even more deprived of access to this key component of comprehensive care and face unnecessary suffering. To address the major gap and answer critically important questions that remain, the PI developed “SUPPORT-T”, an innovative digital health platform adapted from an evidence-based, multi-component, PC intervention “A Program of SUPPORT™” (Symptom management, Understanding of disease, Pulmonary rehabilitation, PC, Oxygen therapy, Research participation, and Transplantation). To reach individuals with PPF, we intend to recruit from two sites; the rural setting will be across South Carolina, and the urban setting will be Mount Sinai in New York City, NY. Community partners will be engaged to alert “hard to reach” patients. “SUPPORT-T” will be delivered: 1) via a digital application over 9 weeks by a nurse interventionist and 2) with virtual quarterly support group participation for one year. Our central hypothesis is that SUPPORT-T is feasible, acceptable, and (because of community outreach and networking) accessible to the broadest population of PPF patients, especially those in rural or urban settings who have limited access to PC. The PI and her study team are uniquely poised to test this hypothesis and generate critically needed data.

NIH Research Projects · FY 2025 · 2025-08

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by episodic flares, significant morbidity, and higher mortality. Since >1 million Americans have SLE, the economic impact is $50 billion/year, with the most disease burden on women of non-white ancestry. Few effective treatments exist for SLE, largely because etiology is incompletely understood, but the disease is likely to occur in genetically susceptible individuals upon environmental triggers. Patients with childhood-onset SLE (cSLE) have more severe and aggressive disease than those with adult-onset. While genetic investigations of cSLE could yield important insights to SLE pathogenesis, most studies have focused on adult-onset SLE patients. We studied two African American families, each having two sons affected with cSLE, using whole exome sequencing. In each family, a private loss-of-function (LOF) variant of SAT1 co-segregated with the SLE disease status of the affected sibling, exhibiting an X-linked recessive pattern. SAT1, encoding the spermidine/spermine-N1- acetyltransferase (SSAT1), a rate-limiting enzyme in polyamine catabolism, was not known as a genetic association with SLE. We showed disease causation of the frameshift LOF variant in CRISPR/Cas9-edited (knock in, KI) C57BL/6 (B6) mice. Young hemizygous male and homozygous female mice spontaneously develop lupus-like characteristics, highlighting potential monogenic contribution in multiplex families with cSLE, an understudied resource. Here we propose to 1) apply whole genome sequencing on 30 SLE multiplex, 62 simplex families, and an additional 35 cSLE patients enriched for early disease onset (< 10-year-old), familial aggregation, and non-European ancestry, to define polygenic risk scores of each individual and to identify novel, ultra-rare, pathogenic coding and non-coding variants; (2) test the evolutionally conserved, pathogenic coding variant candidates for their ability to induce either spontaneous or apoptotic cell-induced lupus in conditional KI mice on B6 mouse background and to assess differentially expressed genes and pathways that are altered in diseased tissues and cell types; and (3) test the functional consequences of pathogenic coding variants from Aim 2 and predicted non-coding candidate risk alleles in differentiated human immune cells derived from genome-edited induced pluripotent stem cells (iPSCs). Our proposed studies are likely to discover novel monogenic lupus variants and validate causality of new and/ or prior monogenic lupus-associated variants in isogenic non-autoimmune mice and iPSCs, which will gain insights into disease causal pathways and pave the way for the new development of targeted therapies in disease management of patients affected with SLE.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT This project will be conducted in the context of the Alzheimer’s Clinical Trials Consortium (ACTC), which is a consulting group of over 100 sites (with 30 leading clinical sites in the Steering Committee) dedicated to Alzheimer’s disease (AD) research and the infrastructures supported by the National Institute on Aging (NIA). The Life’s end Benefits of CannaBidiol and TetrahYdrocannabinol (LiBBY) Study is the first phase 2, multicenter, randomized, double-blind, parallel-group, placebo-controlled,12-week study to evaluate the efficacy and tolerability of an oral combination of two cannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD), in hospice care eligible patients with agitation and Alzheimer’s disease (AD) or other types of dementia (HAD). We here propose to continue the LiBBY Study beyond the initial 12 weeks with an open label extension (OLE) study design. Although the double-blind, placebo-controlled study will offer important information about the efficacy of the THC/CBD combination in this population, other relevant clinical questions still need to be answered. Specifically, 1. do participants treated with THC and CBD maintain their level of response with prolonged exposure and do participants treated with placebo respond to the THC/CBD oral combination during the OLE study?, 2. does treatment with THC and CBD have an impact on lifespan and site of care with prolonged exposure?, 3. does treatment with THC and CBD impact quality of life with prolonged exposure?, and 4. does treatment with THC and CBD have an impact on caregiver burden with prolonged exposure? Furthermore, despite the fact that our approach may be controversial, the investigators feel strongly that for humanitarian reasons, active treatment should be offered to all individuals in the study including those receiving placebo in the double-blind, placebo-controlled study. To that end, since the double-blind, placebo- controlled study is ongoing, the Alzheimer’s Therapeutic Research Institute (ATRI) has agreed to provide bridge funding to allow individuals currently in the double-blind, placebo-controlled study to proceed to the OLE study until LiBBY OLE is funded. To address the questions stated above, we propose to conduct a 12-week, OLE study to be offered to participants who complete the double-blind, placebo-controlled LiBBY Study.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY People with HIV (PWH) have a disproportionately high anal cancer risk. As a result of the recent success of the national Anal Cancer–HSIL Outcomes Research (ANCHOR), several health organizations and specialty societies have developed anal cancer screening guidelines for PWH and have prioritized implementation of the screening guidelines. However, from patients’ perspective, the provision of anal cancer screening can be complex due to a lack of understanding of the screening modalities and algorithms and the potential benefits versus side effects. Furthermore, limited knowledge about the screening algorithms, provider beliefs, and limited availability of screening resources may restrain HIV healthcare providers from adequately discussing screening options with PWH. These patient- and provider-related constraints may further limit opportunities for PWH to make informed decisions about screening participation. To address this knowledge gap, the proposed project will obtain patient and provider perspectives to understand the decisional needs for anal cancer screening and create anal cancer screening communication intervention for healthcare providers to facilitate effective screening communication with PWH. The K99 phase of this project will include two aims: 1) Determine decisional needs (knowledge deficits, sources of decisional conflicts, values, expectations, and resources) for anal cancer screening among PWH, and 2) Examine the perspectives of HIV care providers on current anal cancer screening practices and barriers and facilitators to anal cancer screening implementation in HIV clinics. The R00 phase of the project will include the development of a screening communication intervention for healthcare providers and pre-testing the intervention to evaluate its acceptability, feasibility, complexity, fidelity, and usability. This K99/R00 award will not only create the first communication intervention designed for anal cancer screening, but it will also equip Dr. Garg with the necessary skills and training to complete the proposed research and transition to research independence. She will advance her training in four key areas: 1) qualitative and mixed methods design and analysis, 2) intervention designing, 3) intervention mapping and implementation science, and 4) professional skills development. She will complete her training and the proposed research with the full support of her mentors (Drs. Ashish Deshmukh, Katherine Sterba, and Eric Meissner). At the end of her R00 phase, Dr. Garg will submit an R01 application to test the effectiveness of the communication intervention in a hybrid effectiveness- implementation trial. This K99/R00 plan will enable Dr. Garg to achieve her goal of pursuing high-impact research in this crucial and understudied area of anal cancer screening implementation in PWH and equip her for a successful transition as an independent investigator, with emphasis on health disparities, early detection, and implementation science.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Pediatric brain tumors are the leading cause of cancer-related deaths in children, with medulloblastoma (MB) being the most common type. Despite advances in MB treatment, tumors recur in approximately 30% of children. Virtually none of the patients with recurrent MB survive beyond one year, highlighting the need to better understand the mechanisms underlying treatment failure. In addition to changes in the mutational landscape at relapse, inherent tumor heterogeneity hinders the success of current therapeutic approaches for MB patients. In line with this concept, our data suggest that small populations of astrocyte and oligodendrocyte progenitor cells underlie the relapse of Sonic Hedgehog (SHH) subgroup MB when exposed to compounds acting on SHH signaling, as well as to chemotherapy. Despite their likely involvement in treatment failure and MB relapse, the signaling mechanisms allowing these glia-committed progenitor cells to propagate remain elusive. Here, we propose to uncover the mechanisms enabling these cells to expand in response to therapies, with the specific goal of identifying potential drug targets. Furthermore, we will assess the effectiveness of combining compounds that block bulk MB growth with those that control the propagation of glia-committed progenitor cells. Our studies will establish the mechanistic foundation for the development of future therapeutic approaches to enhance the efficacy of compounds attenuating MB growth, ultimately aiming to secure long-term remission.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Cancer remains a leading cause of mortality globally, particularly among aging populations. While adoptive T cell transfer therapy (ACT) has shown promise in treating hematological malignancies, its efficacy against solid tumors is hindered by tumor-induced immunosuppression. A significant contributor to the failure of ACT is the exhaustion and dysfunction of T cells upon exposure to the hypoxic and lipid-rich tumor microenvironment (TME). Peroxisomes, organelles involved in regulating fatty acids and reactive oxygen species, have been implicated in cellular functions, yet their role in anti-tumor T cell responses within the TME remains poorly understood. Our preliminary data shows a reduction in peroxisome levels and antioxidant enzyme catalase in T cells exposed to the TME, correlating with increased exhaustion markers, suggesting peroxisome deficiency may be limiting T cells ability to overcome TME oxidative stress. The overarching goal of this study is to elucidate the impact of peroxisome biogenesis on adaptive immune responses, particularly within the TME and anti-tumor immunity. We hypothesize that T cells with enhanced peroxisome capacity will exhibit increased antioxidant defenses and improved interactions with other organelles, thereby enhancing their resistance to lipid-mediated stress and persistence within the immunosuppressive TME. This hypothesis will be tested through two integrative specific aims. Specific Aim 1 aims to delineate the mechanisms by which peroxisome capacity influences T cell exhaustion, lipid accumulation, and organelle interactions. We anticipate that T cells with elevated peroxisome levels will demonstrate enhanced anti-tumor activity through regulation of catalase and lipid intermediates, and by maintaining interactions with key organelles to mitigate oxidative stress and lipid peroxidation. Specific Aim 2 seeks to establish optimal in vivo conditions for promoting peroxisome capacity to generate exhaustive-resistant anti-tumor T cells. We expect that enhancing peroxisome capacity will improve T cell persistence and mitigate exhaustion in the TME. This will be investigated through ACT experiments using melanoma and Burkitt lymphoma models, employing strategies to augment peroxisome quantity and catalase levels. The findings from this study will provide novel insights into the role of peroxisomes in modulating T cell function and anti-tumor immunity. By uncovering mechanisms to enhance ACT efficacy through peroxisome manipulation, this research holds translational potential for improving cancer immunotherapy strategies beyond ACT, including immune checkpoint blockade therapy.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Formaldehyde is a class I carcinogen and is present in the environment and generated endogenously by cells. Formaldehyde has been shown to form DNA-base adducts and DNA-protein crosslinks, both of which contribute to formaldehyde-induced genomic toxicity. My preliminary data using an inducible single-stranded DNA (ssDNA) system in yeast has shown that formaldehyde preferentially mutagenizes ssDNA and that this mutagenesis is dependent on translesion synthesis and DNA-protein crosslink repair. Currently, it is unknown which sources of endogenous ssDNA act as targets for formaldehyde-induced mutagenesis. Without this knowledge, it is impossible to know which individuals are at elevated risk for formaldehyde-induced carcinogenesis. One of the major sources of ssDNA is at replication forks. While ssDNA production at replication forks is typically tightly regulated, several human disorders cause fork dysregulation and ssDNA accumulation. Therefore, my central hypothesis is that ssDNA generated at dysregulated replication forks is a preferential substrate for formaldehyde- induced mutagenesis. Aim 1 will employ a sensitive mutational reporter in yeast to investigate dysregulated replication forks as substrates for formaldehyde-induced mutagenesis. This will be done via replicative polymerase knockdown and manipulation of the replication fork protection complex. In aim 2, I will investigate replication-associated ssDNA as a preferred formaldehyde substrate in human HepG2-aldh2-/-. Replication stress will be induced with hydroxyurea and cells will be treated with formaldehyde to determine a formaldehyde- induced mutational signature in human cells. Additionally, cells will be treated with the translesion synthesis inhibitor JH-RE-06 (REV1) or the DNA-protein crosslink repair inhibitor 1,10-Phenanthroline (SPRTN) to determine the roles of these pathways on formaldehyde mutagenesis in human cells. Using this combination of yeast reporter systems and human cells, I will investigate replication forks as preferential targets for formaldehyde-induced mutagenesis. The findings of this work will be significant because it will identify individuals who are “at-risk” for formaldehyde-induced carcinogenesis and establish a formaldehyde-specific mutational signature in human cells that can be used to track long-term environmental exposures to formaldehyde. This research will be performed at the Medical University of South Carolina under the mentorship of Dr. Natalie Saini and Dr. David Long. The Department of Biochemistry and Molecular Biology and the Hollings Cancer Center both have well established and effective programs for student training. Being the only Ph.D. student in the Saini lab, I have gotten an extremely personalized and hands on training experience, and Dr. Long contributes significant mentorship experience to my training plan. This proposal outlines the experimental and professional development goals for my training as I prepare for a career as an independent principal investigator at a research-focused institution.

NIH Research Projects · FY 2025 · 2025-08

Project Summary After spinal cord injury (SCI), the excitability and connectivity of cerebral cortex – spinal cord (corticospinal) pathway diminish, often resulting in weak voluntary activation of muscles and impaired motor control. Yet, such corticospinal impairments are reversible at least partially, and an intervention that improves corticospinal excitability for the affected muscles may enhance motor function recovery. At present, no interventions that target corticospinal pathways for treating motor dysfunction are readily available to people with SCI. Operant conditioning of the motor evoked potential (MEP) to transcranial magnetic stimulation (TMS) to induce targeted plasticity in the corticospinal pathway may become one of those interventions. Indeed, in lower limb, people with SCI can increase corticospinal excitability through operant up-conditioning and can improve walking. Supported by those findings, our core hypothesis is that MEP operant conditioning can increase the corticospinal excitability for the targeted muscle and improve its activation and motor functions in which it participates. Regaining arm/hand function is one of the top priorities of individuals with tetraplegia and often most challenging. Through mass practice and conventional therapy, functions can be restored partially, but it is likely through compensation rather than induction of relevant corticospinal plasticity. In such cases, corticospinal recruitment of motoneurons and resulting muscle activation could remain impaired and continue to limit function recovery. Abnormal motoneuron recruitment and motor unit firing hinder effective production of motor functions. Thus, to enhance upper limb motor rehabilitation beyond what conventional therapy has achieved, a method to improve corticospinal recruitment of a targeted pool of motoneurons would be needed. Here, we hypothesize that wrist extensor MEP up-conditioning can improve forearm motor functions in people with cervical SCI by increasing the corticospinal excitability and improving corticospinal recruitment of wrist extensor motoneurons. Towards testing this hypothesis, this R21 project aims: (1) to demonstrate that the wrist extensor MEP becomes larger through operant up-conditioning in people with chronic incomplete cervical SCI, Extensor Carpi Radialis (ECR) MEP is up-conditioned in individuals with weak wrist extension due to chronic cervical incomplete SCI; (2) to obtain preliminary data for the functional effects of MEP up-conditioning in people with chronic incomplete cervical SCI, multiple functional tests will be performed before and after conditioning intervention; and (3) to examine whether corticospinal recruitment of wrist extensor motoneurons changes with MEP up-conditioning, motor unit firing is studied using high-density surface EMG (HDsEMG) before and after conditioning intervention. This R21 is the first step in understanding how MEP conditioning may improve upper limb functions and corticospinal recruitment of motor units in cervical SCI. Since upper limb functions have tremendous impact on the health, independence, and quality of life in people with tetraplegia, improving them is of critical importance.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Smoking rates among people living with HIV (PLWH) are approximately 40-50%, over triple the rate in the general United States population. The health effects of smoking on PLWH are significant, with PLWH losing more years of life to smoking than to HIV-related morbidities. Because smoking is often not addressed in the context of HIV care, few PLWH are offered evidence-based cessation treatment. Pharmacists are in a unique position to offer tobacco treatment to PLWH as many clinics funded by the federal Ryan White HIV/AIDS Program have a pharmacist on staff. As such, capitalizing on pharmacists’ roles in a comprehensive approach to HIV care, their scope of practice could be expanded to offer tobacco treatment counseling and pharmacotherapy. The ENHANCE-TTS (ENgaging pHarmacists to AdvANCE Tobacco Treatment Service delivery) program seeks to increase tobacco treatment counseling in HIV care settings through a novel program with tools, training, and facilitation support for systems change. Clinical pharmacists will be trained as Tobacco Treatment Specialists and the training will follow with technical assistance and coaching to support the implementation of new practices. This hybrid type II effectiveness-implementation study will use a stepped wedge design in 6 clinics in South Carolina. We will evaluate the effects of ENHANCE-TTS on pharmacists’ tobacco treatment care delivery adoption (pharmacotherapy prescriptions, tobacco treatment counseling codes) (Aim 1) and evaluate the acceptability, feasibility, fidelity, implementation cost, and penetration of the approach (Aim 2). Aims 1 and 2 will also characterize barriers and facilitators to implementation outcomes guided by the Consolidated Framework for Implementation Research (CFIR). Finally, in Aim 3, we will evaluate the effects of ENHANCE-TTS on patient- level tobacco treatment outcomes among PLWH using biochemically-confirmed 7-day point prevalence abstinence outcomes at 3- and 6- months following the initial counseling appointment in a subsample of patients (N=156) who received tobacco treatment from the clinical pharmacists. This study will examine a novel program with tools, training, and facilitation support for systems change within HIV care settings to deliver tobacco treatment to PLWH. Integrating effectiveness and implementation results will help define best practices for pharmacist training and engaging clinic teams for practice change to ultimately provide high-quality evidence- based tobacco treatment interventions to PLWH.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY This proposal is requesting funds to acquire a Thermo Scientific Orbitrap Astral Mass Spectrometer for the Mass Spectrometry Facility & Proteomics Center at the Medical University of South Carolina in Charleston, South Carolina. This instrument will support NIH-funded research in areas of cancer, immunotherapy, cardiovascular disease, liver and digestive disease, neurological disease, and addiction. Acquisition of this equipment will provide state-of-the-art research capabilities for our investigators and meet the growing demand for ultra- sensitive quantitative proteomic experiments for limited sample amounts and post-translational modifications of low abundance. This high resolution and accurate mass instrument with Quadrupole, Orbitrap, and Astral mass analyzers exhibits 4-5x faster data acquisition rates than our current instruments improving the sensitivity, quantitative resolution, and reproducibility of measurements. This new advance in technology will speed the discovery of mechanisms underlying disease onset and progression and yield insights into the response to therapeutics. The requested instrumentation is to be housed in the Mass Spectrometry Facility, a University Shared Research Resource Facility, to provide LC-MS/MS based proteomic capabilities to investigators at the Medical University of South Carolina and academic institutions in South Carolina.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 pathway has induced dramatic and durable clinical responses in melanoma and other cancers. Despite the success of ICB, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking. TANK-binding kinase 1 (TBK1) is a versatile innate immune protein kinase nominated as a candidate immune evasion gene in a number of pooled genetic screens. Using genetic and pharmacologic tools across multiple experimental model systems, we have confirmed a role for TANK-binding kinase 1 (TBK1) as an immune evasion gene. Targeting TBK1 enhances response to ICB by lowering the cytotoxicity threshold to effector cytokines (TNFa/IFNg) secreted by immune cells. Tumor cells lacking TBK1 are primed to undergo RIPK1-dependent cell death in response to TNFa/IFNg. Beyond its effect on cancer cells, targeting TBK1 in immune cells appears to augment this effect as TBK1 inhibition +/- PD-1 blockade not only promoted accumulation of effector/progenitor exhausted CD8 T cells and M1-like macrophages, but was sufficient to enhance production of inflammatory cytokines (e.g., IFNg, TNFa) from these cells. Taken together, our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy and raise important questions about the function of TBK1 in cancer cells versus immune cells in tumor immunity. In this proposal, we aim to confirm and extend these initial observations and resolve the cell type specific roles of TBK1 in tumor immunity. In Aim 1, we will determine the cancer cell-specific roles and regulation of TBK1 in resistance to cancer immunotherapy, by defining the downstream substrates of TBK1 in the setting of ICB resistance and defining upstream the mechanism(s) of TBK1 regulation promoting immune evasion. In Aim 2, we define the T cell-specific role of TBK1 in anti-tumor immunity by examining the effect of conditional deletion of TBK1 in CD8+ T cells. We will use CD8+ T cell specific TBK1 conditional knockout mouse models to define the effect of TBK1 deletion in T cells on the efficacy of ICB and profile of tumor-infiltrating immune cells, and CD8+ T cell effector function/dysfunction. In Aim 3, we will dissect the role of TBK1 in regulating intratumoral myeloid cells. Using myeloid-specific TBK1 conditional knockout mouse models, we will define the effect of myeloid-specific TBK1 deletion on the efficacy of ICB and the landscape of tumor infiltrating immune cells, as well as the effector function of macrophages and other myeloid cell populations.

NIH Research Projects · FY 2025 · 2025-07

Summary Alzheimer's Disease (AD), the primary cause of cognitive decline, is intricately linked to impaired mitophagy, the recycling of damaged mitochondria. This complex pathology may be driven by specific amyloid precursor protein (APP) processing pathways that interfere with mitophagy, which could subsequently promote Tau hyperphosphorylation and amyloid plaque accumulation. Ceramides, bioactive lipids synthesized by ceramide synthase 1 (CerS1), have emerged as crucial regulators in mitophagy and mitochondrial homeostasis. Their role, though pivotal, is not fully delineated. These lipids are known to influence mitophagy through specific signaling pathways, possibly involving receptors such as CERT1, which mediates ceramide transport and distribution, thus affecting mitochondrial health and function. Although ceramides are often criticized for being elevated in AD and associated with negative outcomes, our research proposes a nuanced perspective, suggesting that it is not the overall abundance but rather a disruption of ceramide homeostasis, specifically decreased ceramides at the mitochondrial membrane, that may be driving the cell's increased ceramide production in an effort to upregulate mitophagy. Regardless, the dysregulation in ceramide levels contributes to neuronal death and AD progression by disrupting these pathways, yet the intricate details of these mechanisms remain to be elucidated. A novel ceramide analog, LCL768, has been synthesized and shows promise in counteracting the detrimental effects of mitochondrial APP accumulation. Preliminary findings suggest that LCL768 may independently modulate ceramide signaling, enhancing the association between mitochondria and autophagosomes and thereby potentially restoring effective mitophagy. The exact molecular action of LCL768 in AD is under investigation, with hypotheses focusing on its interaction with ceramide pathways and mitochondrial membranes, influencing the mitophagic process and neuronal survival. Our research will employ a range of experimental techniques to investigate these mechanisms. Aim 1 will utilize genetic ablation in CerS1 knockout cell and mouse models, alongside molecular assays to assess mitochondrial function and AD progression markers. Imaging techniques, such as fluorescence microscopy, will be used to visualize mitophagy. Aim 2 involves pharmacological intervention with LCL768 in Sh-Sy5y neurons and 3xTg AD mice, using behavioral tests to gauge AD symptom alleviation and cellular assays to measure mitophagy enhancement. Expected outcomes from this study include a deeper understanding of ceramide-mediated mitophagy in AD and the potential regulatory role of CerS1. Demonstrating LCL768's efficacy in restoring mitophagy and mitigating AD symptoms could offer a novel therapeutic avenue. The insights gained could impact our understanding of AD pathogenesis, highlighting new targets for intervention and innovative treatments aimed at preserving mitochondrial health and neuronal function, ultimately reducing AD morbidity.

NIH Research Projects · FY 2025 · 2025-07

Opioid-related overdose is the leading cause of maternal mortality, despite availability of lifesaving treatments. Opioid agonist medications, such as buprenorphine, effectively treat opioid use disorder (OUD) and prevent overdose. Yet, over half of pregnant women who receive buprenorphine discontinue in the postpartum year. Multiple challenges hinder buprenorphine engagement among pregnant and postpartum women (PPW). No known intervention directly targets buprenorphine retention in PPW and such an intervention is urgently needed. Dr. Witcraft’s pilot data, including feedback from PPW with OUD, informed the development of an intervention explicitly designed to enhance buprenorphine retention in PPW: EMPWR (EMpowering Pregnant Women Receiving medications for OUD). The complementary research and training plans proposed in this K23 application will advance Dr. Witcraft towards her long-term goal to develop adaptable, scalable, and sustainable interventions to reduce opioid-related overdoses among PPW. The overall objective of this research project is to evaluate feasibility and implementation of EMPWR into routine practice, and to preliminarily characterize clinical outcomes. This objective will be achieved through two specific aims: (1) evaluate feasibility of EMPWR and (2) measure EMPWR implementation outcomes. Under the first aim, a randomized controlled feasibility trial of EMPWR vs. medication monitoring (N=30) with a hybrid type I effectiveness-implementation approach will be conducted with baseline (prenatal), 3-, and 6-month postpartum assessments. For the second aim, implementation outcomes will be assessed via mixed methods, including synthesis of qualitative interviews guided by the Consolidated Framework for Implementation Research (CFIR) determinant framework, and quantitative signals for implementation outcomes evaluated with the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) evaluative framework. The research plan directly corresponds with Dr. Witcraft’s training goals in: 1) implementation science; 2) clinical trial methodology; 3) buprenorphine retention barriers; 4) clinical trial, longitudinal, and mixed methods data analysis; and 5) advancement of grantsmanship and scientific skills. Several activities will ensure training goals are met, including mentorship from nationally recognized experts across each of the training domains, participation in didactic and applied training activities, and application of skills through the research project. Dr. Witcraft’s faculty appointment is at the Medical University of South Carolina, which has an excellent research environment and robust facilities and resources that are ideally suited for mentored career development in substance use disorder research. This K23 award would allow Dr. Witcraft to establish expertise in each of these intersecting research areas, represents a clear progression from previous training, and serves as the next logical step in her research. This award would equip her with a range of critical skills necessary to achieve a high-impact and federally funded research portfolio, and lead to a follow-on R01 multisite hybrid effectiveness-implementation trial of EMPWR in varied practice settings.

NIH Research Projects · FY 2025 · 2025-07

Abstract Systemic lupus erythematosus (SLE) is one of the most common autoimmune disorders, predominantly affecting women of childbearing age. Up to half of all lupus patients develop lupus nephritis (LN), a severe kidney disease characterized by persistent glomerular inflammation and associated with poor health outcomes. Although urinalysis tests for proteinuria or hematuria are utilized for patient monitoring, their lack of specificity often reveals significant and irreversible glomerular damage only after its onset. Additionally, conventional markers such as urinary protein/creatinine ratio (UPrUCr) fail to accurately reflect treatment response, prompting the need for repeated biopsies to monitor disease progression. Currently, kidney biopsies serve as the primary method for diagnosing LN and evaluating treatment effectiveness. The goal of this proposal is to identify more sensitive and less invasive clinical biomarkers for monitoring LN progression and assessing treatment response. The glycocalyx, comprised of glycoproteins and other molecules, plays a pivotal role in the glomerular filtration barrier within the glomeruli, which is damaged in LN. Utilizing mass spectrometry-based techniques, our laboratory can identify specific glycomic patterns in tissues and biofluids, offering a complementary approach to existing clinical tests for LN detection and monitoring. Given the severity of the pathology in LN the central hypothesis of this proposal is that glycosylation changes can be detected in urine earlier than conventional markers, and these unique glycomic signatures can differentiate LN from controls and serve as a noninvasive predictor of treatment response. In Aim 1, I will evaluate the precision of the distinct glycomic signatures in identifying LN compared to controls (Aim 1A) and ascertain the efficacy of these unique glycomic profiles in enhancing the differentiation between complete responders (CR) and non-responders (NR) (Aim 1B). In Aim 2, I will focus on determining the spatial localization of N-glycans within the kidney (Aim 2A) and identifying their protein carriers (Aim 2B) using an independent LN cohort with matched serum, urine, and kidney biopsy samples. Ultimately, this proposal seeks to deepen our understanding of LN pathophysiology, evaluate the predictive potential of glycomic signatures for disease severity and treatment response in patients, and introduce a less invasive urine-based approach that can complement current clinical methods to enhance patient care and outcomes.

NIH Research Projects · FY 2025 · 2025-07

This application requests support for the South Carolina Clinical and Translational Research (SCTR) Predoctoral Training Program (T32) at the Medical University of South Carolina (MUSC) to provide a 2-year comprehensive training experience in clinical and translational science (CTS) supporting four predoctoral trainees at a time. The mission of our program is to train a multidisciplinary cadre of translational scientists to become domain experts skilled in the application of clinical and translational science (CTS) principles and individuals who will increase the efficiency and efficacy of translation while conducting clinically relevant research to address the Nation’s biomedical, behavioral, and clinical research needs. We will accomplish this through four main objectives: 1) optimize our interdisciplinary training program by providing novel didactic, experiential, and research experiences such that predoctoral trainees will be prepared to think both independently and interdependently as integral members of translational science teams; 2) implement innovative practical experiences focused on translational science that emphasize team building, entrepreneurship, and near-peer mentoring; 3) augment the trainee’s translational research skills by leveraging institutional strengths in CTS research; and 4) promote a comprehensive approach to recruit and develop a pool of CTS professionals across a range of scientific disciplines. We will leverage the availability of mentors from multiple scientific backgrounds who are domain experts and boundary crossers, follow a curriculum that encourages trainees to be team players, emphasizes the importance and roadmap of translating discoveries from the bench to the clinic through the principles of CTS, become systems thinkers, skilled communications, innovators and team players who contribute to boundary-crossing teams that are addressing barriers in translational science affecting their own disciplines and other disciplines. The program utilizes rigorous training encompassing a combination of didactic courses, practical experiences, and team science experiences. We accomplish this via training opportunities such as a Team Science in Clinical Research course, unique Translational Research Journal Club, participation in a translational medicine seminar series, attendance at the annual ACTS national meeting, and internship opportunities with a resident science writer on Science Communication. The program is designed to promote interactions with other SCTR hub programs, including K12 scholars. The program will appoint 4 predoctoral trainees for two years. Graduates of this program will become rigorous innovative domain experts and part of a community of clinical and translational science teams who are poised to leverage team science to advance strategies that improve health.