Medical University Of South Carolina

NIH Research Projects · FY 2026 · 2023-05

Project Summary: Sepsis affects more than 19 million people each year. With improved treatment strategies, more and more patients survive sepsis. The majority of these survivors develop cognitive impairment and mental health problems. However, the mechanisms that promote sepsis-associated encephalopathies (SAE) remain largely unknown, and there is a lack of SAE-targeted treatments. The long-term goals of our research program are to understand the mechanisms that lead to cerebrovascular dysfunction and cognitive impairment post sepsis and to develop novel targeted treatments for sepsis-induced cognitive impairment. To reach this goal, we characterized sepsis-induced cognitive impairment using animal models. We observed that mice exhibit hippocampus-dependent memory impairment associated with pathological neuron dysfunction. To understand the mechanisms behind cognitive impairment post sepsis, we focused on specialized cells in the brain called pericytes, which play a major role in regulating cerebral blood flow and maintaining blood brain barrier integrity. Pericytes form part of the neurovascular unit to meet the energy demands of the brain and facilitate neuro- inflammatory responses. However, the role of pericytes in sepsis-induced cognitive impairment remains unknown. Our studies demonstrated that the transcription factor friend leukemia virus integration 1 (Fli-1) regulates pericyte activation and viability. We also observed that brain pericyte numbers decreased after sepsis and that pericytes underwent apoptosis after their initial activation and production of inflammatory mediators. Pericyte loss resulted in vascular leakage and recruitment of inflammatory monocytes. We reported previously that Fli-1 governs pericyte viability through regulating caspase 1/3 expression. In our preliminary studies, we demonstrated that pericyte Fli-1 knockout mice exhibit decreased inflammatory mediator production in response to LPS. More importantly, we demonstrated that Fli-1 levels were higher in the hippocampus regions of post- mortem brain tissue from septic patients compared to controls. In this R35/MIRA application, we propose to use newly developed, unbiased approaches such as single nucleus RNA sequencing and imaging mass cytometry alongside inducible pericyte-specific Fli-1 knockout mice generated in our laboratory and novel antisense oligonucleotide Gapmers targeting Fli-1 recently developed by our group to understand the role of pericytes in vascular dysfunction and cognitive impairment post sepsis. The successful completion of the proposed studies will lead to better understanding of the mechanisms of vascular cognitive impairment post sepsis and the development of novel SAE-targeted treatments.

NIH Research Projects · FY 2026 · 2023-04

Sickle cell disease (SCD) is a chronic condition that affects every organ system and requires lifelong complicated treatment regimens. Adolescents and young adults (AYA) with SCD experience remarkable increases in negative outcomes (e.g., morbidity, mortality, complications, acute care utilization) following transition from pediatric to adult care. To mitigate negative outcomes, it is critical that AYA with SCD develop effective self-management behaviors prior to transition to adult care. However, AYA with SCD face challenges to self-management behavior development that are compounded by the lack of easily accessible self-management tools. Our long-term objectives are to develop a comprehensive model of self-management for AYA with SCD that incorporates mechanisms of self-management behavior development and influencing modifiable and fixed factors, along with a clinical model of care that addresses mechanisms and influencing factors and provides AYA and providers with resources to improve self- management behaviors. This R01 application to the National Institute of Nursing Research (NINR), Self-Management for Youth Living with Sickle Cell Disease (SMYLS), will advance us towards this objective by supporting: 1) effectiveness testing of our existing, theoretically founded, mHealth self-management intervention and 2) assessment of the role of patient activation on self-management behavior development. In Aim 1, we will examine the pre-post intervention differences in engagement in self- management processes, self-management behaviors, health and quality of life outcomes, and the relationships among patient activation and outcomes. In Aim 2, we will determine challenges and facilitators to adoption of the self-management intervention to inform future implementation initiatives. In the Exploratory Aim, we will identify socioenvironmental and psychosocial modifiable and fixed variables that influence outcomes. Findings from this study will determine the effectiveness of a theoretically founded, mHealth self-management intervention for AYA with SCD, identify the role of patient activation in self-management for AYA with SCD, and characterize influences on self-management behaviors. In addition, if the intervention is proven effective, findings on the challenges and facilitators to intervention adoption in this study can be applied to the next step in this research trajectory, wide-scale implementation of the intervention. Our objectives are consistent with the 2022 – 2026 National Institute of Nursing Research Draft Strategic Plan to reduce disease severity, symptoms, and progression with a focus on improving health outcomes by targeting improved self- management behaviors pre-transition to adult care to mitigate subsequent negative outcomes in AYA with SCD.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY/ABSTRACT Vascular dysfunction, such as decreases in cerebral blood flow (CBF) and disruption of the blood brain barrier (BBB) are early symptoms of Alzheimer’s disease (AD) and could contribute to AD onset and progression. In the brain, specialized cells called pericytes are integral to proper vascular function, as they play a major role in regulating CBF and maintaining BBB integrity. However, the processes that govern pericyte dysfunction and the role of pericytes in decreases of CBF in AD development have not been fully elucidated. Our previous studies have demonstrated that increases in the transcription factor Fli-1 are associated with pericyte dysfunction and viability via up-regulation of caspase-1 expression. Our preliminary data demonstrated that Fli-1 levels were higher in the hippocampus and superior temporal gyrus regions of brain tissue from AD patients compared to controls. Pericytes undergo apoptosis in the hippocampus of AD patients, and pericyte Fli-1 levels were increased in AD patients. In addition, TNF and aggregated amyloid- induced Fli-1 expression in cultured human brain pericytes. Furthermore, amyloid- induced pericyte apoptosis, as evidenced by decreased pericyte viability, increased TUNEL positive cells, and increased expression of apoptosis marker caspase-3. Knockdown of Fli-1 with antisense oligonucleotide Gapmers suppressed amyloid--induced pericyte death, apoptosis, and caspase-3 levels. Thus, increased Fli-1 levels in AD patients may lead to pericyte loss. To determine the cause- effect relationship between increased Fli-1 and AD development, we conducted studies in the 5xFAD mouse model. Fli-1 levels were higher in the hippocampus in 5xFAD mice and corresponded with spatial learning and memory impairment in Novel Object Recognition and Morris Water Maze tests. Injection of Fli-1 Gapmer into the hippocampus significantly decreased Fli-1 and inflammatory mediator levels, mitigated pericye loss and vascular leakage, suppressed adhesion molecule levels, reduced A deposition, and ameliorated spatial learning and memory impairment. These data provide the first evidence that increased Fli-1 levels contribute to AD development. We hypothesize that the transcription factor Fli-1 elevation in Alzheimer's disease leads to pericyte dysfunction and brain hypoperfusion. Three specific aims are proposed to address this hypothesis: Aim 1: Determine how Fli-1 regulates pericyte and neurovascular cell dysfunction in a mouse AD model. Aim 2: Elucidate the mechanisms by which pericyte dysfunction results in brain hypoperfusion and cognitive impairment in a mouse AD model. Aim 3: Test the therapeutic potential of intrathecal administration of Fli-1 Gapmers in mouse AD models. The successful completion of the proposed studies will result in a better understanding of the role of Fli-1 in regulating pericyte dysfunction in AD and the development of a novel treatment strategy for AD.

NIH Research Projects · FY 2026 · 2023-04

Project Summary/Abstract Deep Brain Stimulation (DBS) targeting the subthalamic nucleus (STN) is an established therapy for PD patients with motor fluctuations and dyskinesias. While STN DBS is an effective treatment for motor symptoms, it can produce unintended side effects cognition including executive function, language and attention deficits which affect quality of life and independence. Developing an individualized STN DBS approach which optimizes patient selection prior to surgery and enhances specificity when targeting neural networks is significant because it has the potential to reduce DBS induced cognitive decline. The research proposed in this K99/R00 Pathway to Independence Award will lay the groundwork needed to establish this approach by determining 1) how limited cognitive reserve prior to surgery and 2) how direct DBS interference with cognitive networks contribute to cognitive decline. Cholinergic and dopaminergic network hubs (i.e., the Nucleus Basalis of Meynert; NBM, and striatum) support cognition, however, these regions degenerate in PD and may be indirectly modulated by STN stimulation. Thus, the central objective of this proposal is to determine how vulnerability (K99) and the direct modulation (R00) of the NBM, and striatal networks contribute to cognitive decline in individuals with STN DBS. NBM/striatal vulnerability will be measured using diffusion kurtosis imaging (DKI) which reflects microstructural changes associated with the progressive degeneration of neuronal tissue. Network interference will be measured by assessing the change in NBM/striatal connectivity using combined DBS-fMRI which allows functional MRI data to be collected while simultaneously cycling stimulation. The central hypothesis of this proposal is that pre-surgical microstructural integrity (K99) and DBS induced interference (R00) of the NBM, and striatal networks will be associated with greater cognitive decline. Preliminarily data demonstrates that reduced mean kurtosis of diffusion within the NBM and striatum are associated with reduced executive function and language deficits in those with PD. In the 2-year mentored K99 phase of this proposal, I will establish the relationship between NBM/striatal microstructure and cognition (Aim 1) and cognitive decline 1-year following STN-DBS surgery (Aim 2). To accomplish these aims I will collect DKI and longitudinal neurocognitive data from 50 participants with PD planning to undergo clinical STN-DBS treatment. Additionally, I will receive training in DBS as a research tool, neurocognitive testing, combined DBS-fMRI and DKI analysis/interpretation. This will be facilitated by my mentoring team which includes DKI co-developer Dr. Jens Jensen (Primary Mentor) and DBS neurologist Dr. Gonzalo Revuelta (Co-mentor). After securing a tenure track faculty position, I will transition into the R00 phase of the award to investigate the relationship between STN-DBS modulation of the NBM/striatal networks and cognitive decline (Aim 3). This independent R00 phase will build upon my technical training and mentoring skills established during the K99 phase. Ultimately, this award will generate the pilot data necessary to apply for a R01 and establish a research program in individualized neuromodulation therapies for movement disorders.

NIH Research Projects · FY 2026 · 2023-04

OVERALL – PROJECT SUMMARY The overall goal of the Center of Biomedical Research Excellence (COBRE) in Neurodevelopment and Its Disorders (CNDD) is to enhance research capacity by enabling outstanding multidisciplinary collaborative research in neurodevelopmental disorders (NDD) at the Medical University of South Carolina (MUSC). This area is of importance to the state of South Carolina as the diagnosis rate and proportion of individuals with Autism Spectrum Disorder (ASD) who have significant cognitive impairments is estimated to be higher than those of the nation. The specific aims are to: 1) Mentor a strong cadre of early career scientists to become independently funded investigators in NDD research; 2) Establish sustainable core resources to support modern NDD research while leveraging institutional investments; and 3) Promote sustainability of the CNDD through creation of multidisciplinary research programs, rigorous evaluation, strategic improvement, and mission alignment with other Centers at MUSC and across the state of South Carolina. The Center is led by a multidisciplinary team, composed of a department chair with extensive experience in molecular neurobiology, an expert in the field of complement biology, and a clinical psychologist focused on ASD research 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 Junior Investigators (JIs) who will benefit from an innovative multiple source mentoring plan which features both internal and external mentors. We anticipate each of these JIs to transition to independent NIH funding within the first three years of the project. The CNDD also includes three Cores that will support not only the JIs but also NDD investigators throughout MUSC. Scientific cores include the: 1) Genomic and Bioinformatic Core, which will provide technical assistance, computational infrastructure, and training opportunities; 2) Mouse Behavioral Phenotyping Core, which will provide access to and training in behavioral analyses of mice; and 3) Small Animal Brain Imaging Core, which will provide access to modern brain imaging technologies that can extend the scope and impact of neurodevelopment research. Additionally, the CNDD will foster collaborations among NDD 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 expansion of research capabilities, development of JIs, and promotion of integrative, multidisciplinary NDD research programs, the proposed CNDD will substantially enhance basic, translational, and clinical research at MUSC. Together with key institutional investments across the state, the CNDD will enable the formation of a sustainable, thriving hub of world-class research in neurodevelopment and its disorders in South Carolina.

NIH Research Projects · FY 2025 · 2023-03

PROJECT SUMMARY Speech recognition difficulties are common for older adults and those with age-related hearing loss (ARHL), particularly in complex environments. Maladaptive hyperexcitability in the central auditory system, a form of central gain, is known to occur with age and hearing loss and may contribute to altered temporal processing and subsequent speech-in-noise (SIN) deficits. Studies of central gain in humans often focus on cortical hyperactivity, yet research suggests that subcortical hyperactivity, notably exaggerated encoding of sound onsets and low-frequency amplitude modulation envelopes (like those common in speech), may be present in the auditory midbrain of older and hearing-impaired adults and exert a larger influence on SIN difficulties than previously thought. However, we currently lack a clear understanding of the contexts in which subcortical hyperactivity exists in age and ARHL and how it relates to behavior. This complicates long-term efforts to develop pharmaceutical and behavioral interventions to ameliorate SIN deficits. The overarching goal of the proposed research is to characterize how hypersensitivities to stimulus onsets and modulation envelopes localized to the auditory midbrain are (1) more prevalent for older than younger adults, (2) related to inferior colliculus structure, (3) predicted by hearing loss in older adults (independently of age), and (4) associated with SIN deficits. Experiments use an innovative combination of electrophysiology, structural neuroimaging, and source localization to characterize neural responses arising from subcortical generator sites (e.g. inferior colliculus) in both quiet and noise. To quantify hyperresponsivities in the midbrain relative to the periphery, inferior colliculus responses are normalized auditory nerve responses. Aim 1 examines whether hyperactivity is more prevalent in older adults relative to younger adults, whether diminished cochlear compression associated with ARHL leads to enhanced envelope encoding in quiet, and assesses how midbrain microstructural characteristics that have been associated with GABAergic changes (e.g. longitudinal relaxation time, R1) relate to hypersensitivity and potentially mediate age effects. Aim 2 examines how midbrain hypersensitivity predicts behavior, testing the hypothesis that greater hypersensitivity benefits perception in quiet (e.g., better amplitude modulation (AM) discrimination in quiet) but not perception in noise (e.g., poorer performance on SIN tests, poorer AM discrimination in noise). Results can advance our understanding of the contexts in which envelope and sound onset hyperresponsivities are present in the subcortical auditory system, how best to quantify it, and whether it alternately benefits or impedes perception. Findings will inform future studies of subcortical neural hyperactivity and not only improve our understanding of SIN difficulties of older adults, but also determine the extent to which clinical interventions need to consider declines in subcortical structure and function. With the aging (and hearing-impaired) population growing yearly, this research has high

NIH Research Projects · FY 2026 · 2023-03

Glaucoma, a leading cause of blindness worldwide, is characterized by progressive loss of retinal ganglion cells (RGCs), an excavated appearance of the optic nerve, and vision loss. The etiology of glaucoma is complex, involving biomechanical stress, pro-inflammatory cytokines, deprivation of neurotrophic factors, and epigenetic changes. Currently, there is no clinical treatment to rescue RGCs in glaucoma patients. Therefore, effective neuroprotective strategies and agents are needed to rescue RGCs. Epigenetic modification is an emerging and promising novel approach to modulate cellular function in neurodegenerative diseases, however, its role in glaucoma remains poorly defined. Our laboratory has demonstrated that sustained activation of δ-opioid receptor by SNC-121 for 7-days offered significant long-term (42-days) RGC neuroprotection in a chronic rat glaucoma model. This long-term neuroprotective response supports the idea that opioids induce epigenetic changes in the retina allowing RGCs to maintain their functional integrity under conditions that normally lead to progressive RGCs loss. Pain management studies have shown that epigenetic changes are associated with opioid-induced tolerance and dependence that develops following chronic opioid-administration. We provided preliminary data showing that epigenetic regulators such as class I and IIb histone deacetylases, DNA methyltransferases (DNMTs) activities and expression, and genome wide DNA methylation were significantly increased in response to ocular hypertension-induced injury. Additionally, RNA Seq, PCR array, immunohistochemistry, and ATAC Seq data provide significant leads that cytokines, pro-apoptotic pathways, transcriptional factors, neurotrophins, and chromatin structure are significantly affected by ocular hypertension injury and δ-opioids treatment. We also have shown that transcription start sites (TSS) of numerous genes in “CpG” Island were differentially affected by δ-opioids. Based on our Preliminary Data, we hypothesize that “Activation of δ-opioid receptors induces hyperacetylation and hypomethylation that attenuates RGCs death in glaucoma”. To test this hypothesis, we propose the following two Specific Aims. Specific Aim 1. Determine the crucial roles of class I and IIb histone deacetylases (HDACs) in RGC death in ocular hypertensive animals. Specific Aim 2. Determine the role of DNA methylation in δ-opioid-mediated RGC neuroprotection in ocular hypertensive animals. The outcome of the proposed studies will not only have a positive impact on the understanding of mechanisms underlying the opioid-mediated RGC neuroprotection, but will also identify novel and innovative targets for glaucoma therapy.

NIH Research Projects · FY 2025 · 2023-02

Hepatocellular Carcinoma (HCC) is the 5th most common cause of cancer-related death with an estimated 32,000 annual deaths in the United States. Current measures to combat the disease are insufficient and there is an unmet need translating pre-clinical model findings to patients. Recently, though, a study modeled HCC in mice using hydrodynamic tail vein injections with the Sleeping Beauty transposon system (referred hereafter as the “transposon system”). Here, tumors that develop are 69% genetically similar to patient HCCs driven by mutant ꞵ-catenin and the tyrosine kinase receptor MET (B+M). I found that including IQGAP1, a scaffold protein known to orchestrate and promote oncogenic signals, accelerates B+M HCC development and causes enhanced tumor growth and severity. Importantly, I found increasing IQGAP1 expression promotes YAP1 signaling and drives the expression of NUAK2 kinase, a druggable YAP1 target gene recently linked to HCC oncogenesis. These findings indicate that targeting the IQGAP1-YAP1 network in the liver could be a possible direction for future therapies. I aim to better understand how IQGAP1 regulates the molecular mechanisms in HCC, and my central hypothesis is that IQGAP1 drives HCC oncogenesis and its incorporation into a humanized HCC system will improve HCC disease modeling. I will test this hypothesis in 2 specific aims: Aim 1 will establish a humanized model of HCC and determine if IQGAP1 exacerbates disease pathology. Aim 2 will validate the utility of the humanized HCC model by targeting oncogenic Hippo signaling driven by IQGAP1 overexpression. Overall, this proposal aims to explain IQGAP1’s mechanistic role in HCC biology. The IQGAP1-YAP1 relationship provides a novel direction for personalized medicine in HCC. In addition, elevated NUAK2 expression resulting from IQGAP1 mediated YAP1 activity is a mechanism novel to my work. Better understanding this mechanism will provide greater insight to activated YAP1 in HCCs. In addition, my proposed humanized HCC model is intended to accelerate pre-clinical findings and open the door to potential personalized therapeutic approaches to benefit patients. I plan to pursue this work during my independent career and the University of Pittsburgh provides a suitable environment for me to carry out my designed studies. HCC is a significant public health concern and I am committed to a career studying the disease. With full support from my collaborators, I am confident that I will be able to complete the proposed research. My proposal builds on my current expertise and the protected time provided by the K22 mechanism will enable me to gain experience in techniques that will inevitably support my independence.

NIH Research Projects · FY 2026 · 2023-01

Emergency care often determines the patient outcome as it is critical to make accurate, timely diagnoses and interventions during the early stages of the injury or disease. The Strategies to Innovate Emergency Care Clinical Trials Network (SIREN) was created by the NIH to enable the investigation of different emergency care treatments spanning across organ systems and diseases without duplication of effort, thereby minimizing start- up costs and promoting economies of scale. The purpose of the Data Coordinating Center (DCC) for SIREN is to provide a comprehensive data management and statistical infrastructure to support the network’s goal of conducting high quality clinical trials that will improve outcomes for patients with neurologic, cardiac, respiratory, hematologic and trauma emergency events. This renewal application, in response to RFA-NS-22-013, describes the features, functions and coordination we will continue to provide as the DCC for the SIREN Network. The DCC’s role is to establish a collaborative relationship with all parties involved in the Network and provide efficient and standardized central data management that yields high quality data, provide statistical support in the planning and execution of the clinical trials, prepare and disseminate trial reports for the various stakeholders and facilitate data sharing. To this end, the Data Coordination Unit (DCU) at the Medical University of South Carolina has developed a web-based comprehensive integrated data and project management system, WebDCU™, that enables distributed data entry from the participating clinical sites with extensive data quality control. The DCU also provides the necessary tools to efficiently manage operational activities across multiple trials, while ensuring compliance with FDA regulations and guidelines. Using the WebDCU system, we have developed, implemented and maintained a central database that streamlines and maximizes efficiency in the management of data collection, processing, and monitoring of clinical data. In addition, the WebDCU™ incorporates trial management information that provides full support for all study operational activities in SIREN. In collaboration with the individual study Principal Investigator and our partners of SIREN (CCC, Hubs, Governance Committees), the DCU will continue to: contribute to the innovative and efficient protocol development (including study design and case report form development); oversee data quality; generate reports for the DSMB, regulatory parties and the study teams; conduct interim and final analysis and dissemination of study results via presentations and publications; and create public use datasets for data sharing. SIREN initiated 5 large, simple multicenter trials over the previous 5 year grant period and will initiate at least 4 more in the next grant period. The network aims to transform the emergency research enterprise, by exploring innovations in clinical trial designs, by better and earlier engagement of patient stakeholders in trial planning, and by creative improvements in implementing and performing trials.

NIH Research Projects · FY 2026 · 2022-12

Scientific abstract Epithelial ovarian cancer (EOC) and pancreatic ductal adenocarcinoma (PDAC) are two of the most devastating human malignancies in desperate need for improved treatment concepts. Treatment resistance in cancer therapy frequently includes, among others, reduced drug uptake, increased drug efflux, improved adaptation to chemotherapy-induced stress/DNA damage and inhibition of apoptosis. An example of such a resistance mechanism is the X-linked inhibitor of apoptosis proteins (XIAP), a potent negative regulator of caspases and promoter of cancer cell survival in both ovarian and pancreatic cancer. Inhibition of XIAP has been studied to increase apoptosis and to overcome drug resistance in vitro and in preclinical mouse models. Second mitochondria-derived activator of caspases (SMAC) is an endogenous inhibitor of both XIAP and cellular IAP (cIAP) by reactivating caspase activity (XIAP blockade) and cIAP degradation, leading to cancer cell death. These findings have initiated the development of synthetic small molecule mimics of endogenous SMAC, which have been studied in a wide variety of human malignancies either as single agents but also in combination with systemic chemotherapy as a means to further improve patient outcomes. The foundation of our work with respect to small molecule drug development is based on sigma-2 ligands (S2) that facilitate fast and selective uptake into the cancer cells due to ~10-fold higher abundancy of the corresponding sigma-2 receptor (S2R) compared to normal host cells. By generating chemical conjugates between S2 and a variety of small molecule drug cargos, we are now capable of delivering therapeutic payloads more efficiently and selectively than their non-targeted counterparts to the tumors (targeted therapy). LCL161 is a clinically explored IAP inhibitor (IAPinh) that induces target activation but failed to demonstrate objective responses in patients. In this grant, we propose to study an innovative experimental cancer therapeutic by chemically linking IAPinh (LCL161) to S2 ligand SW43, resulting in S2/IAPinh for tumor- selective drug delivery and therapy. We hypothesize that S2/IAPinh can be combined with systemic, low-dose chemotherapy to result in synergistic treatment regimens that lead to tumor eradication while systemic toxicities are reduced to a minimum. The overall goal of our current study is to find effective therapies for ovarian and pancreatic cancer. The proposed aims maximize the chance that a novel drug candidate, S2/IAPinh, will be effective clinically. This is envisioned either as single-agent, low-dose S2/IAPinh therapy in the context of a TNF-α gene signature in patient tumors or as combination regimens with clinically approved pathway enhancers, such as Nab-paclitaxel (Abraxane) (ovarian cancer) and Gemcitabine/Nab-paclitaxel (pancreatic cancer) but also statin-based inhibitors of cholesterol de novo synthesis. Our new findings represent an exciting innovative opportunity to enhance the activity profile of S2/IAPinh employing novel drug combinations for the benefit of cancer patients.

NIH Research Projects · FY 2026 · 2022-12

PROJECT SUMMARY/ABSTRACT This R01 proposal aims to test the efficacy of a tele-cognitive behavioral therapy (CBT) intervention as a novel treatment paradigm for body image-related distress (BID) among head and neck cancer (HNC) survivors, examine it’s underlying mechanism of change, and characterize factors affecting its future adoption into clinical practice. Treatment of HNC results in substantial life-altering morbidity related to disfigurement, challenges speaking, and difficulty swallowing. As a result, 75% of HNC survivors express body image concerns and 28% meet criteria for BID. BID is a source of devastating psychosocial morbidity, as HNC survivors with BID have a six-fold increase in depression, high rates of social isolation, decreased quality of life (QOL), and a 2-fold higher rate of suicide mortality relative to other cancer survivors. To date, evidence-based strategies to manage HNC- related BID are lacking. To address this gap, we developed BRIGHT (Building a Renewed ImaGe after Head & neck cancer Treatment), a 5-session manualized tele-CBT intervention based on a transactional coping model of HNC-related BID. Findings from our single-arm and pilot randomized controlled trial (RCT) showed that BRIGHT was feasible, acceptable, and resulted in a statistically and clinically significant reduction in BID relative to dose- and delivery-matched controls at 1- and 3-month follow-up. Our preliminary data suggest that BRIGHT reduces HNC-related BID by enhancing adaptive body image coping skills (reducing avoidance, increasing positive rational acceptance [i.e., rational appearance related self-talk]). Based on these promising preliminary efficacy and mechanistic data, we propose a multi-site RCT in which HNC survivors with clinically significant BID (N=180) will be randomized to BRIGHT or attention control (AC), a manualized tele-supportive care intervention that controls for time, professional attention, and common factors. HNC survivors will complete measures of HNC-related BID, psychological and social well-being, QOL, and measures of theory-derived mechanisms of change underlying CBT. We will conduct semi-structured interviews and in-depth site visits to develop an implementation toolkit to enhance the adoption of BRIGHT into clinical care. Specific Aim 1 will evaluate the efficacy of BRIGHT relative to AC on (a) HNC-related BID and (b) psychological and social well-being and QOL. Specific Aim 2 will examine the mechanism of change underlying BRIGHT for HNC-related BID. Specific Aim 3 will characterize key determinants that will affect the future adoption of BRIGHT into routine clinical practice. Findings from our study may support BRIGHT as the first evidence-based strategy to manage BID among HNC survivors, thereby developing new standards of care and improving psychosocial morbidity and QOL in this population. Theory-driven mechanism of change data may help identify specific therapeutic elements to optimize the effectiveness of CBT for BID as well as advance our understanding of the underlying theory of CBT. Finally, findings may enhance the implementation of psychosocial interventions for cancer survivors in diverse settings.

NIH Research Projects · FY 2025 · 2022-09

Improving alcohol use disorder (AUD) treatment access and outcomes among Veterans is an urgent public health priority. The lifetime prevalence of AUD among Veterans is twice that of civilians. Veterans also incur more severe and persistent AUD symptoms with more lengthy and complex treatment courses and negative outcomes compared to the general population. Despite the critical role that family members play in the etiology, course, and treatment of AUD, and the robust evidence base supporting the efficacy of several existing family AUD treatments, family treatment protocols are lengthy and burdensome for patients and clinicians. Thus, there is a critical need to develop efficacious family AUD treatments that are both brief and highly accessible to Veterans. Members of our team developed and refined the Brief Family Involved Treatment (B-FIT) protocol in an NIAAA-sponsored pilot trial among civilians. B-FIT is a 3-session cognitive behavioral therapy designed to be implemented in combination with any existing alcohol treatment program. The goals of B-FIT are to 1) increase reinforcement of treatmentfacilitating behaviors, 2) increase the perceived reinforcement value of abstinence by increasing anticipated positive rewards from abstinence, and 3) reduce drinking cues by decreasing negative communication and increasing positive communication with family members. This study resulted in findings that support feasibility, acceptability, and preliminary efficacy of B-FIT. In a separate study, our team has demonstrated excellent feasibility and acceptability of delivering dyadic AUD treatment via home-based telehealth. Thus, the primary objective of this Stage II trial is to examine the efficacy of B-FIT in combination with treatment as usual (TAU; CBT) versus TAU alone in 1) reducing alcohol consumption, 2) improving family functioning, and 3) improving treatment satisfaction, adherence, and retention among Veterans. To accomplish this, we will employ an open randomized controlled design and examine standardized, repeated, dependent measures of change at multiple time points. We will also leverage our team’s standard operating procedures for fully remote study implementation, close collaboration with regional VA clinics, and a robust national VA telehealth infrastructure which is prepared to efficiently translate positive findings into treatment. The proposed study is directly aligned with NIAAA’s mission and Strategic Plan in that it will 1) employ electronic health technology to improve the effectiveness and accessibility of AUD treatment for Veterans, 2) will advance AUD treatment access among Veterans with less access to treatment, 3) focuses on Veterans in a real-world treatment setting (i.e., VA clinics), 4) examines B-FIT for home-based telehealth delivery, and 4) will identify characteristics of Veterans and family members most likely to benefit from the addition of B-FIT to their recovery program. Our findings will directly inform clinical practice and accelerate treatment in this important but understudied area.

NIH Research Projects · FY 2025 · 2022-09

Knowledge and confidence in entrepreneurship are increasingly important skills possessed by those pursuing careers in the biomedical research workforce. Entrepreneurship has emerged as “the most potent economic force” and can be an avenue to increase the number of research innovations that cross the bridge from bench to bedside. However, entrepreneurship training is not currently part of the standard curriculum of graduate or medical schools. Through ASCEnD - A national program of Academic Support and Coaching for Entrepreneurial Development - our goal is to increase innovation and entrepreneurial activities and the number of academic investigators who participate in entrepreneurial activities. One unique aspect of our approach is complementing mentoring with coaching, as coaching has been shown to be four times more effective than training/mentoring alone. Specifically, we will train coaches in behavioral coaching and establish teams of coaches as well as entrepreneurial experts who will serve as mentors. We will enhance entrepreneurial skills through one-on-one and group coaching for researchers. We will train nascent entrepreneurs in topics germane to innovation and entrepreneurship and establish an innovative environment. We will also facilitate institutional change by disseminating our findings via focused communications and interactions among all participants, ultimately establishing an entrepreneurial network. We will leverage the expertise of our Advisory Committee, as well as the commitment and support of our leadership and regional institutions. Our program evaluation will use the RE-AIM framework. We will assess how our program increases the number of investigators who participate in entrepreneurial activities through multi-method program evaluation including assessments of the program’s ability to reach applicants nationally, satisfaction with program offerings, and changes in entrepreneurship outcomes. Evaluations of program activities will be completed using REDCap questionnaires. Validated coaching, entrepreneurial, and satisfaction/experience measures will be utilized. Overall, our approach will increase the number of academic investigators who are entrepreneurs and increase the level of entrepreneurship in the nation, thus building an entrepreneurial workforce. Because the coaching component takes a comprehensive approach by encouraging participants to craft a vision for their work and life, it provides value that will last beyond their current projects and beyond entrepreneurship activities.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY Absent known deficits such as hearing loss or developmental disorder, approximately 15% of two-year-olds nevertheless have atypically small expressive vocabularies. These “late talkers” (LTs) are at increased risk for a later diagnosis of language disorder, and even those LTs who are not diagnosed still have poorer long-term language outcomes as compared to their typically developing peers (TDs). At present, we do not know why some children struggle to develop their vocabularies, and we are unable to predict which LTs are at greatest risk for language disorder. This project focuses on toddlers’ verb vocabularies because of the role that verbs play in developing grammar. Difficulty with verbs is considered a warning sign for later language disorder, and children with language disorder in turn struggle particularly with verbs. To learn new verbs, toddlers use information derived from the surrounding linguistic context, such as sentence structure. However, this ability is predicated on preexisting knowledge of verbs. Concerningly, our prior research indicates that LTs and TDs differ in early verb knowledge: LTs have more result verbs (i.e., verbs that denote the result of an event, such as “break”) than manner verbs (i.e., verbs that denote how an event unfolds, such as “run”) in their vocabularies. This pattern mimics biases for result over manner meanings observed in older children with language disorder. However, TDs have more manner than result verbs throughout development. In contexts where verb learning is dependent on knowledge of manner versus result meanings, LTs and TDs are likely to perform differently. In Aim 1/Study 1, we consider one such manipulation: Whether the sequencing of the linguistic information (i.e., the verb) and its referent action impacts verb learning. TDs appear to learn manner verbs best when the verb precedes the action, but they learn result verbs best when the verb follows the action. However, older children with language disorder better learn verbs when they follow the action, irrespective of verb meaning. We hypothesize that LTs will show the same pattern as older children with language disorder because they also have a bias for result over manner verbs. If true, this would be the first demonstrated verb learning difference between LTs and TDs. Learning a verb’s meaning from its linguistic context also requires that children be able to process the given linguistic information. Conversely, children who do not process the linguistic context fail to learn new verb meanings. It has been hypothesized that children who are faster linguistic processors are better verb learners, but this has not yet been demonstrated experimentally. In Aim 2/Study 2, we consider the relationship between concurrent processing of familiar words and performance on a verb-learning task (i.e., Study 1). We hypothesize that for both LTs and TDs, those who are faster to process familiar words will also be better at verb learning. The final sample will include 52 toddlers (26 LTs; 26 TDs, ages 24.0 – 30.9 months) who will complete both studies. Data will be collected using eye tracking, and regression analyses will be used to test our hypotheses. Results from Aim 1/Study 1 will support future research on verb-learning interventions for LTs. Results from Aim 2/Study 2 will provide the basis for future longitudinal studies aimed at predicting outcomes for LTs.

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT Rural residents are both more likely to smoke cigarettes and less likely to quit than their urban counterparts. Consequently, individuals in rural areas have a 7% higher incidence of tobacco-associated cancers. Comprehensive smoking cessation treatment dissemination strategies are needed to increase utilization of evidence-based treatment, improve cessation outcomes, and ultimately decrease cancer incidence among rural smokers. Primary care providers (PCPs) see 70% of smokers annually, and rural residents are more likely than urban residents to have a usual source of health care. As such, primary care offers a ripe opportunity to deliver cessation treatment to rural smokers. All primary care practices that qualify for Centers for Medicare and Medicaid Services reimbursement are required to maintain electronic health records (EHRs) with coded smoking status data for adult patients. These data can be utilized to proactively identify smokers and deliver remote treatment. Our team recently completed a pilot study to develop, refine, and preliminarily evaluate a proactive asynchronous smoking cessation electronic visit (e-visit) delivered via the EHR. The goal of the e-visit is to automate best practice guidelines for cessation treatment via primary care to ensure that all smokers receive an evidence-based intervention. An initial baseline e-visit gathers information about smoking history and motivation to quit, followed by an algorithm to determine the best FDA-approved cessation medication to prescribe. A one- month follow-up e-visit assesses progress toward cessation. Clinical outcomes of our pilot (N=51 followed for three months) were promising. Among rural participants who received the e-visit (n=6), 17% reported 7-day point prevalence abstinence (PPA), 67% reduced their cigarettes per day (CPD) by >50%, and 50% used a cessation medication. E-visit participants, relative to treatment as usual (TAU), were 4.2 times more likely to report 7-day PPA, 4.1 times more likely to have reduced their CPD by >50%, and 4.7 times more likely to have used a cessation medication. Acceptability outcomes were strong, with 100% of rural e-visit participants reporting that they would use an e-visit again in the future. These data suggest that the e-visit may be a feasible, efficacious approach to extend the reach of evidence-based cessation treatment via rural primary care. We now propose a Hybrid Type I effectiveness-implementation trial to comprehensively assess e-visit effectiveness relative to TAU while simultaneously evaluating implementation when delivered across rural primary care settings. Effectiveness outcomes will be assessed through 6-months of follow-up and include: 1) biochemically verified 7-day PPA, 2) reduction in CPD, and 3) evidence-based cessation treatment utilization. Implementation outcomes will be assessed at patient, provider, and organizational levels. This trial has the potential to expand cessation treatment access in a manner scalable across rural healthcare systems and ultimately reduce rural cancer disparities.

NIH Research Projects · FY 2025 · 2022-09

PROJECT DESCRIPTION/ABSTRACT Epidermal growth factor receptor (EGFR) is overexpressed in majority of tumors including oral squamous cell carcinoma (OSCC). The over-expressed/-activated EGFR contributes to epithelial-mesenchymal transition (EMT) and tumor progression by contributing to tumor metastasis and chemo-resistance. Hence, EGFR has become one of the major therapeutic targets for OSCC. Endocytosis is a key biological pathway for internalization of ligand activated EGFR, following which it gets routed for lysosomal degradation by the endosomal sorting complex for recruitment and transport (ESCRT) machinery. ESCRT is a key mediator of endocytic vesicle trafficking (EVT). While vesicle trafficking defects result in the poor downregulation of activated EGFR, persistent surface and cellular EGFR expression and signaling is subsequently linked to the development of cancer. Surprisingly, the molecular events/mechanisms that regulate ESCRT pathway which is critical for maintaining EGFR homeostasis and preventing EMT and tumorigenesis are largely unknown. Here, based on solid preliminary data, we propose to investigate a previously unknown mechanism that regulates ESCRT dependent EVT, EGFR levels and signaling, EMT, and OSCC growth. We found that 1) depletion of CPAP caused the prolonged expression of EGFR and an EMT-like phenotype in oral cancer cells; 2) while depletion of CPAP enhanced the tumorigenicity of an OSCC cell line, overexpression of CPAP in this cell line suppressed its tumor inducing potential; 3) overexpression of CPAP caused the de novo generation of EGFR- positive multivesicular bodies, whose biogenesis requires ESCRT and are essential intermediates that route EGFR to lysosomes for degradation and termination of its signaling; and 4) the absence of CPAP resulted in diminished cellular levels of VPS4 protein, an essential ESCRT associated ATPase that facilitates pinching off of endocytic vesicles. These collective observations suggest that CPAP induced positive regulation of ESCRT pathway and EVT maintains EGFR homeostasis, resulting in prevention of EMT and tumorigenesis in OSCC. This novel hypothesis will be tested systematically under two specific aims. The primary goals of aim 1 will be to define the molecular mechanisms by which CPAP positively regulates EVT and EGFR homeostasis in OSCC. This will be done by using OSCC and normal oral cells with gain-and-loss-of-function of CPAP as well as by studying CPAP-ESCRT interaction in the context of EGFR homeostasis. We will then, under aim 2, determine the role of CPAP in preventing EMT and oral tumorigenesis. This will be achieved by characterizing CPAP gain- and-loss-of-function in OSCC cell lines for EMT features, and growth and tumorigenic properties, and by studying the oral cancer susceptibility using a conditional CPAP-knockout mice. Overall, this study will delineate a novel ESCRT dependent mechanism that prevents OSCC.

NIH Research Projects · FY 2024 · 2022-09

ABSTRACT Liver failure is a major cause of death worldwide. Hepatic mitochondrial depolarization (mtDepo) is one of the earliest responses to ethanol and likely is the first in a chain of events leading to subsequent liver disease. Initially, mtDepo in response to ethanol facilitates more rapid two-step oxidation of ethanol and its toxic metabolite acetaldehyde (AcAld) to acetate. I hypothesize that mtDepo underlies a swift increase in alcohol metabolism (SIAM) after acute ethanol administration that is an adaptive response to eliminate ethanol more rapidly. Chronically, the response becomes maladaptive leading to disordered mitophagy and hepatic inflammation and fibrosis. Furthermore, I hypothesize that mtDepo after EtOH is brought about via mitochondrial uncoupling due to proton leaks through either the adenosine nucleotide translocator (ANT1/2), the mitochondrial F1FO-ATP synthase, uncoupling proteins (UCPs) or mitochondrial permeability transition (PT) pores. Since mtDepo leads to elimination of mitochondria by mitophagy, I also hypothesize that recovery from mtDepo after ethanol involves mitochondrial biogenesis. In two Specific Aims, I will: 1) Characterize hepatocyte mitochondrial oxygen consumption rate (OCR) in relation to mitochondrial depolarization and repolarization after acute ethanol. I will assess time-dependent changes in OCR and mitochondrial membrane potential (ΔΨ) of hepatocytes freshly isolated from ethanol-treated and untreated mice using Seahorse extracellular flux analysis, Hansatech oximetry, and confocal microscopy of fluorescent ΔΨ indicators. By injecting in vivo prior to hepatocyte isolation MitoTracker dyes, fluorophores that label only polarized mitochondria, I will identify hepatocytes having undergone mtDepo in vivo in relation to mtDepo and repolarization in vitro. To address my mechanistic hypotheses, I will assess how specific inhibitors of ANT, ATP synthase, UCPs, and PT pores reverse/prevent ethanol-induced mtDepo and increased OCR. 2) Assess the role of mitochondrial biogenesis and mitophagy in recovery from mtDepo after acute ethanol. As mice metabolically eliminate ethanol, hepatocytes recover from mtDepo. In Mitotimer mice, newly synthesized DsRed- E5 fluoresces green but over time (12-24 h) shifts irreversibly to red fluorescence. If repolarization of preexisting mitochondria occurs after ethanol, then Mitotimer fluorescence should be predominantly red in mitochondria recovering from mtDepo. If repolarization results from mitochondrial biogenesis, then recovering mitochondria will fluoresce green. I expect that repolarization of preexisting mitochondria and biogenesis of new mitochondria will both contribute to recovery from mtDepo after acute ethanol. Together, Aims 1 and 2 will characterize key mechanisms in the hepatic mitochondrial response to ethanol, as well as identify the basis for recovery. This fundamental knowledge could lead to development of new therapeutics to treat and prevent alcoholic liver disease.

NIH Research Projects · FY 2025 · 2022-09

Severe insomnia occurs during the withdrawal from chronic use of alcohol. To gain relief from insomnia, alcoholics begin drinking again. Although the cause of the insomnia is unknown, indirect measurements of neuronal activity (c-FOS, fMRI) suggest that during insomnia, more of the arousal- promoting neurons are hyperactive. The status of the sleep-promoting neurons is unknown but are likely to be less active. Our overall hypothesis is that it is the imbalance in activity between wake versus sleep-promoting neurons that is the basis of insomnia during the withdrawal from alcohol. We will directly test this hypothesis in a proven mouse model of chronic ethanol intoxication using newly developed neuroscience tools. Aim 1 will use a miniscope to image Ca2+ influx (as a readout of cell activity) in specific hypothalamic wake-promoting (orexin) or hypothalamic sleep-promoting (GABA) neurons before, during and after chronic intermittent exposure to alcohol (CIE). We will image the neurons during waking, NREM, and REM sleep. We hypothesize that during the CIE-period of insomnia, the orexin neurons are more active while the sleep-promoting GABA neurons are less active. We have robust preliminary data indicating that the GABA neurons have become less active after chronic alcohol exposure. Similarly, our preliminary data reveals that orexin neurons have become more active. The deep-brain Ca2+ imaging method provides descriptive data. Thus Aims 2 and 3 will use pharmacogenetics to mechanistically test the hypothesis that CIE has shifted the excitability thresholds of the GABA and orexin neurons. In-vitro slice electrophysiology studies will confirm the hypothesis. To induce sleep to correct the insomnia, Aim 2 will activate the GABA neurons, while Aim 3 will inhibit the orexin neurons. Aim 4 will test the hypothesis that after CIE, because sleep has improved with our pharmacogenetic manipulations, then the mice will show less preference for drinking alcohol. This aim goes to the core of our hypothesis that improving sleep prevents alcohol relapse. The overall impact of our studies is that, for the first time, hard evidence will mechanistically link insomnia during the withdrawal from chronic ethanol intoxication to changes of activity in specific phenotypes of hypothalamic sleep or wake-promoting neurons. Furthermore, our aims are translational and will aid in the development of appropriate treatments for insomnia. Our aims are integrated and employ cutting-edge tools to understand how chronic ethanol exposure disrupts sleep homeostasis. This project will be conducted jointly by experts in the areas of sleep neurobiology and alcohol addiction.

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT There is a tremendous unmet need for effective synthesis methodologies and strategies for the construction of aleutianamine and other members of the discorhabdin class of natural products. This has significantly hindered the mechanistic, basic and applied science studies for this unique class of alkaloids which offers significant value in the control of a variety of diseases and clearly warrants additional basic research into the synthesis, mechanism of action and basic pharmacology. Natural Products (NPs) have played a key role as therapeutics for a variety of diseases and the data presented in this application reveals the tremendous potential for these molecules. After 25 years of studying marine organisms for new and innovative chemistry we have identified a single truly remarkable molecule called aleutianamine. Aleutianamine has been recovered from a Latrunculia sponge collected from the deep ocean off the coast of the Aleutian Islands by NOAA Alaska. We have exhaustively interrogated extracts for any detectable quantities of this molecule and the only remaining option to generate mechanistic and in vivo data is to first generate the drug through a reliable synthesis. This molecule is extremely unique chemically and is a member of two very rare groups of bioactive natural products including the iminoquinones and the thioalkaloids and is certain to be a product of the extreme conditions of these deep ocean environments where cold temperatures, high pressure, and anoxic conditions deplete of UV irradiation provides a unique environment for biosynthesis and rearrangement to form highly unusual molecules. Aleutianamine and other members of this class as well as their synthetic intermediates offer unique controls for a diversity of diseases including malaria, inflammation, viral diseases and cancer strongly supporting the development of strategies to provide consistent supply of the drug and approaches to the generation and diversification of the class. Due to the rare and limited supply of this molecule the specific aims of this program involve the development of synthesis methodologies using two different routes in addition to the isolation and characterization of starting materials and related molecules for SAR and investigations into alternative approaches involving biosynthetic starting materials for the construction and optimization of the molecule.

NIH Research Projects · FY 2025 · 2022-08

Although patients with systemic sclerosis (SSc) have increased disability, morbidity, and mortality, no current FDA-approved medications for SSc prevent or reverse fibrosis. Our long-term goal is to understand how E2 influences fibrosis in SSc, which provides the rationale for using medications that inhibit E2 production and signaling (aromatase inhibitors and fulvestrant, respectively) for SSc treatment. The overall objectives of this proposal are to identify the estrogen receptors (ERs) needed for E2-induced fibrosis, the transcriptomic alterations caused by E2 and ER signaling in human skin, and any associations between systemic E2 levels and disease outcomes. The central hypothesis is that hormonal dysregulation promotes dermal fibrosis through time- dependent signal propagation via ER(s), leading to increased pro-fibrotic gene transcription and worse SSc clinical outcomes. The rationale for this project is to understand how E2 leads to fibrosis by incorporating the cellular, transcriptomic and systemic effects of estradiol. We will test our hypothesis with the following specific aims: (1) Identify the contribution of ERs in E2-induced dermal fibrosis; (2) Determine the novel transcriptomic profile of E2-induced dermal fibrosis ex vivo; and (3) Determine associations between hormonal dysregulation and clinical outcomes in SSc. In the first aim, we will use 3 models to examine how ERs affect fibrosis: human and mouse primary dermal fibroblasts in vitro, ERα-null and GPER1 KO mice in vivo, and human skin tissue ex vivo. In the second aim, we will stimulate human skin with E2 at various time points to assess differential gene expression using mRNA seq and determine which ERs are responsible for these specific transcriptomic alterations. In the third aim, we will compare levels of the sex hormones E2, dehydroepiandrosterone sulfate and testosterone in African American and Caucasian patients with limited SSc and diffuse SSc as well as in healthy controls and estimate associations among hormonal level, autoantibody status, and clinical measures of disease severity. The project is innovative because understanding the role of ERs (ERα isoforms and GPER1) in fibrosis and discovering clinical associations between sex hormones and SSc raise the prospect of using systemic hormonal levels as a biomarker for SSc disease characteristics, severity and prognosis. The proposed research is significant because it provides the basis for using estrogen modulators to treat SSc. My long-term career goal is to understand the relationship between SSc-related fibrosis and estrogen using basic science and clinical research, with the hope of developing personalized medicine targets. To accomplish this goal, I will obtain training in receptor signaling biology, bioinformatic data interpretation and clinical research. MUSC contains resources such as the Core Center for Clinical Research and the CTSA-sponsored South Carolina Clinical & Translational Research Institute which provide necessary research support and career development. My mentor and co-mentor, advisory committee and the Division of Rheumatology all foster a supportive environment, allowing for successful completion of this proposal and continued progression toward independence.

NIH Research Projects · FY 2025 · 2022-08

Project Summary Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disorder that slowly destroys memory with no known cure. While the cause of AD is unknown, a large body of evidence suggests that oxidative stress, mitochondrial dysfunction, neuroinflammation, and proteinopathy are all implicated in AD pathogenesis. Nuclear-factor-erythroid 2-related factor 2 (Nrf2) is a key transcription factor that orchestrates a multifaceted response to modulate multiple etiological pathways involved in AD. A decline in the expression of Nrf2 and alteration of the Nrf2-related pathways are observed in humans and animal models of AD. Consequently, activation of the Nrf2 pathway represents a promising therapeutic approach in AD. Unfortunately, canonical Nrf2 activators are electrophiles as they not only react with cysteines on Kelch-like- ECH-associated protein 1 (Keap1) to activate Nrf2 but non-specifically react with thiol groups on a variety of cellular proteins resulting in side effects. A critical barrier to developing effective Nrf2-based therapeutics for AD is the current lack of understanding of mechanisms that can safely activate this pathway. BTB (broad- complex, tramtrack and bric-a-brac) and CNC (cap’n’collar protein) homology 1 (Bach1) is a transcription factor that represses Nrf2 gene expression. We propose to conduct a rigorous evaluation to validate Bach1 inhibition as a novel therapeutic strategy for AD pathogenesis and to identify new target(s) for intervention. Our central hypothesis is that Bach1 inhibition protects against behavioral and neuropathological outcomes in AD due to Nrf2-dependent and Nrf2-independent mechanisms. Using state of the art mouse models and novel non- electrophilic Bach1 inhibitors, we propose to a) delineate the role of Bach1 inhibition in the onset and progression of AD pathology in vivo, b) establish to what extent loss of Bach1 in neurons, astrocytes, and microglia modulate AD development, c) differentiate between Bach1- and Nrf2-dependent pathways in neuroprotection and d) identity novel targets for therapeutic interventions. The proposed studies are based on a strong premise and will provide a rigorous test of the hypothesis using innovative pharmacologic and genetic interventions. The outcomes will provide the critical evidence to justify Bach1 inhibition as a novel therapeutic target and validate novel non-electrophilic Bach1 inhibitors as potential therapeutic agents for AD.

NIH Research Projects · FY 2025 · 2022-08

While it was initially believed that only a minority of CRC are driven by inflammation, studies showing that treatment with anti-inflammatory medications may prevent or delay the development of CRC in hereditary and sporadic cases, clearly identify inflammation as a key driver in the development and progression of all types of CRC. Yet, it is still unclear what are the mechanisms that in the complex intestinal environment contribute to the activation of the inflammatory pathways that initiate CRC. The intestine holds a delicate balance between host protection and control of excessive inflammation, and we posit that a dysregulated communication between the epithelial and the immune component of the intestinal barrier may link a sub-acute state of inflammation and CRC initiation. The complement system is emerging as an important player in the gastrointestinal tract. Specifically, the complement anaphylatoxin C3a and its receptor, C3aR, regulate the immune and epithelial compartments in the intestine and exert antibacterial properties. By mining publicly available datasets, we found that C3aR is down-regulated in patients with CRC and the fact that this down-regulation occurs already in stage 1 tumors, suggests that it may be an early event during CRC development. By crossing C3aR-/- mice with the APCMin/+ mice, that carry a mutation in the apc gene, similarly to the majority of human CRC, we showed that C3aR is protective in CRC. Indeed, while in APCMin/+ mice tumors mostly developed in the small intestine, in APCMin/+/C3aR-/- mice tumorigenesis dramatically shifted almost exclusively to the colon. We also found intestinal barrier dysfunction and microbial dysbiosis in mice lacking C3aR, suggesting that C3aR may be a novel gatekeeper in intestinal homeostasis. However, it is currently unknown how C3aR contributes to CRC development. We hypothesize that loss of C3aR causes intestinal barrier dysfunction by affecting the communication between epithelial and immune cells. This then leads to development of microbiota-driven inflammatory immune responses that promote the development of CRC. To test this hypothesis we propose: 1) to investigate how loss of C3aR affects the epithelial component of the intestinal barrier and the communication with the immune cells; 2) To investigate the contribution of C3aR on immune, non immune cell types, and microbiota to CRC development; 3) To investigate the C3aR status in human pre-invasive lesions and CRC. Bone marrow chimera in combination with single cell high dimensional analysis of immune infiltrates using mass cytometry and REAPseq will determine the contribution of C3aR on immune and non immune cells to colon inflammation and CRC development and progression. We will assess how C3aR down-regulation affects human CRC and survival by using human specimens from our well characterized patient cohorts. As loss of C3aR represents an early event during CRC, identifying the mechanisms linking loss of C3aR to the development of CRC will not only further our understanding of CRC but is highly significant for the prevention of CRC.

NIH Research Projects · FY 2025 · 2022-07

The South Carolina Biomedical Informatics & Data Science for Health Impact (SC BIDS4Health) training program seeks to train informaticists and data scientists to address population-level variations in health outcomes, observed in SC as a model geographic region. Through engagement with local communities, this impact is achieved by mobilizing telehealth services and informatics to improve access, interoperability and enhanced health information exchange, resulting in improved healthcare quality and e-health innovations that benefit all SC communities. Given that chronic illnesses underlie variability in SC patient health outcomes, our curriculum is based on the application of the Wagner model of chronic illness care to address these outcomes through informatics to make chronic care more available and effective across the state. This model provides a framework to enhance health systems for those at risk of adverse health outcomes with informatics and data science driven approaches to enhance the health of those at risk through more effective, patient-centric healthcare. SC BIDS4Health builds on the existing joint Clemson University – Medical University of South Carolina (MUSC) PhD program in Biomedical Data Science and Informatics, and includes faculty who are nationally and internationally recognized leaders in biomedical informatics, public health, computer science and engineering and multiple biomedical and health domains. We leverage many existing resources and partnerships to enable a curriculum that provides state-of-the-art training and makes a notable impact on SC communities including those that demonstrate a higher disease burden. Through these same partnerships we create pathways into our program from local institutions of higher education. We hypothesize that systematic training in SC BIDS4Health is achieved by (Aim 1) synthesizing new didactic curricula building on the foundations of Biomedical Informatics, Data Science, and Population Health to achieve understanding of how these concepts can be applied in a variety of local contexts to advance health and improve health outcomes for all population groups; (Aim 2) developing new immersive practical and research experiences in communities to allow for direct trainee interactions and measurable impactful research outcomes; (Aim 3) providing teaching experiences to pre-doctoral trainees and promoting students’ exposure to biomedical data science and informatics research and careers; and (Aim 4) developing a new postdoctoral training program in SC BIDS4Health. We further propose to (Aim 5) evaluate the careers and community impact of the SC BIDS4Health training program. The predoctoral program is 2 to 3 years, while the postdoctoral program is 1 year with possibility of renewal for another year. At full capacity the program will concurrently support 3 predoctoral and 2 postdoctoral trainees across Clemson and MUSC.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY Centrosome amplification (CA) is highly prevalent in cancer and strongly associated with tumor progression and worse prognosis in several different cancers, including breast, prostate, ovarian and lung. Centrosome amplified cells also demonstrate increased motility and invasiveness leading to metastasis. Moreover, CA is associated with genetic aberrations, such as p53 mutation that are commonly observed in aggressive forms of cancers, such as the triple negative breast cancer (TNBC). Our long-term goal is to target the growth and metastatic dissemination of aggressive breast tumors with CA that will ultimately lead to improved patient outcome. The overall objectives of this project are to (i) inhibit tumor growth in breast cancer models with CA via inducing centrosome de-clustering and formation of multipolar spindles upon targeting transforming acidic coiled-coil 3 (TACC3), and to (ii) block local invasion and metastatic dissemination in CA models by preventing cell polarization, migration and invasion upon inhibition of TACC3. The central hypothesis is that TACC3 inhibition will, on one hand, prevent active clustering of amplified centrosomes into two spindle poles during mitotic cell division leading to multipolar mitosis and apoptotic cell death in p53 altered cells, and on the other hand disrupts centrosome and Golgi re-orientation, microtubule nucleation and cell polarization in interphase cells leading to decreased migration. The rationale for this project is that TACC3 inhibition represents a unique opportunity to eliminate the most aggressive tumors that have supernumerary centrosomes, while sparing the normal cells. The central hypothesis will be tested by pursing two specific aims: 1.) To inhibit tumor growth in aggressive breast cancer models with CA by targeting TACC3, and 2.) To prevent metastasis in aggressive breast cancer models with CA by targeting TACC3. State-of-the-art experimental settings with translatable approaches will be employed, including tumor organoids, patient- derived xenografts and immunocompetent transgenic mouse model of advanced breast cancer that we characterized in terms of CA. The research proposed in this project is innovative as it aims to study mitosis/interphase-specific interactomes of TACC3 that are essential for TACC3-mediated cell division in mitotic cells and cell polarity in interphase cells that we propose to block using our novel and highly potent TACC3 inhibitor as well as using CRISPR-mediated knock-out. The proposed project is significant because it is expected to provide key mechanistic and phenotypic pre-clinical data to support the notion that targeting TACC3 concomitantly inhibits tumor growth and metastasis in breast cancer models with CA, which will then dramatically reduce mortality rates among patient subpopulation with highly aggressive cancers.

NIH Research Projects · FY 2026 · 2022-05

Abstract This proposal responds to the NIH High-Priority Research Topics announcements for PAR-19-070: mechanism underlying the vascular risk, sleep efficiency, and chronic circadian disruption in the etiology of Alzheimer's disease (AD). We are a research group focusing on the brain circuitry of sleep disorder narcolepsy (caused by loss of the hypothalamic wake-promoting orexin neurons). By following the emerging scientific evidence on the protective effects of sleep for AD, we propose investigating the intrinsic mechanism involved. Pericytes, a type of mural cells of the capillary and a key component of the neurovascular unit (NVU), become our focus because of their unique function in regulating cerebral blood flow (CBF) and the blood-brain barrier (BBB) permeability. Strong evidence suggests that pericytes malfunction or degeneration contributes to AD pathology by affecting CBF and breaking down BBB. Intriguingly, similar mechanisms also underlie the contribution of sleep loss to AD pathology. Thus, we ask whether pericytes are the mediator between sleep and AD pathology. Improving sleep might delay AD pathogenesis by protecting pericytes and maintaining BBB integrity. It is the first time that brain pericytes are studied in the framework of sleep and AD. Recent advances in pericyte research and our latest preliminary data show the feasibility of the approach. This project will have confirmed the functional correlations among pericytes, sleep, and AD pathogenesis at the end of the funding period and provided valuable evidence for future pericytes-based therapies for AD and sleep disorders.