Medical University Of South Carolina

NIH Research Projects · FY 2024 · 2023-08

PROJECT SUMMARY/ABSTRACT Compared to either disorder alone, co-occurring alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) has a more complex clinical and treatment course that imposes significant health burden on veterans. Identifying novel mechanisms to improve integrated AUD/PTSD treatment outcomes is a public health priority that aligns with NIAAA’s strategic goal to advance treatment of alcohol-related conditions through the refinement of behavioral and pharmacological treatments. Self-compassion is a cognitive skill that may facilitate more effective integrated AUD/PTSD treatment. Self-compassion is proposed to function by tapping into an innate care-giving system that could interact with oxytocin’s prosocial effects such as feelings of safety and trust. The current study will leverage an ongoing NIAAA-sponsored clinical trial that is examining the efficacy of oxytocin compared to placebo to improve outcomes in an integrated behavioral treatment among veterans with AUD/PTSD. The primary goal of the proposed study is to examine the bivariate longitudinal associations between self-compassion and treatment outcomes. The secondary goal is to examine whether veterans higher in self- compassion and administered oxytocin will outperform veterans in the placebo condition. Finally, we will utilize ecological momentary assessment (EMA) to capture the associations between self-compassion, alcohol consumption and problem severity, and PTSD symptoms in a real-world context. We hypothesize that self- compassion will enable more adaptive responding to AUD and PTSD symptoms (e.g., managing craving, lapses, maladaptive thinking patterns) thereby promoting a more efficient treatment course and reducing susceptibility to risky alcohol use or relapse. This is an important and feasible project that will provide novel insights into the role of self-compassion in AUD recovery among veterans with co-occurring PTSD. This project will also provide critical training experiences necessary to facilitate the candidate’s long-term goal to be an independent alcohol researcher. Under the proposed award, the candidate will have the opportunity to 1) master the extant literature on behavioral and pharmacological interventions for AUD/PTSD; 2) acquire new skills in the design and implementation of clinical trials; 3) hone skills in naturalistic assessment methods such as EMA; 4) advance longitudinal data analytic capabilities; and 5) increase scholarly productivity through grant and manuscript development. She will accomplish these deliberately selected training goals by leading the proposed research project, engaging in a comprehensive mentorship plan with highly skilled sponsors, and participating in a carefully selected program of didactic training opportunities. The training will be carried out at the Medical University of South Carolina (MUSC) in the Addiction Sciences Division. MUSC is a renowned academic medical center known for its innovative and excellence in alcohol research. Thus, the candidate will have access to an institution and sponsors with a strong history and commitment to clinical alcohol research.

NIH Research Projects · FY 2026 · 2023-08

Abstract Single stranded DNA (ssDNA) has been demonstrated to by extremely vulnerable to DNA damage. Cancers often carry long stretches of clustered mutations that likely arose due to damage of ssDNA. While, various studies have demonstrated that certain mutagens preferentially damage ssDNA, the mechanisms that alter mutation specificity due to damage in ssDNA and the pathways that prevent mutagenesis at ssDNA are unknown. The overarching goal of this proposal is to specifically identify the roles of DNA damage checkpoint proteins, translesion polymerases, ssDNA-specific glycosylases and ssDNA binding proteins in altering the mutation patterns obtained upon ssDNA-specific damage. My laboratory is in a unique position to advance this scientific front based on my strong track record in DNA damage and repair, assembled team of collaborators, and multidisciplinary approach. My expertise in using highly sensitive yeast reporter systems, human cell culture techniques and the use of bioinformatics tools to probe large data sets and to analyze next generation sequencing data allow us to develop our research program to understand the pathways modulating ssDNA mutagenesis in yeast and human cells. Previously, I have demonstrated that alkylating agents and acetaldehyde have an ssDNA-specific mutation signature in yeast and in cancers. These mutation signatures provide us with a highly sensitive tool to determine how changes in various DNA repair, damage bypass and damage sensing pathways alter mutagenesis by ssDNA-specific mutagens. Here, we propose to determine 1) How cell cycle dependent translesion polymerase expression alters mutation signatures in ssDNA; 2) The role of ssDNA binding Replication Protein A complex in protecting ssDNA from exogenous damage; 3) The role of DNA damage checkpoint activation in modulating the mutation signatures associated with ssDNA damage; 4) Which DNA glycosylases function on ssDNA and alter the mutation signatures due to ssDNA damage; and 5) What are the mutagenic outcomes when translesion polymerases are unable to bypass ssDNA damage. This set of research projects will address a key gap in knowledge in understanding the mechanisms that alter the hypermutability of ssDNA in cells. Our work will enable us to identify and develop better cancer preventative measures for individuals who are prone to increased genome instability and ssDNA formation in their cells.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the loss of nigral dopaminergic neurons and the presence of fibrillar cytoplasmic inclusions composed of alpha-synuclein (αS) known as Lewy bodies. Neurodegeneration in PD is not limited to only the nigral dopaminergic neurons but also involves cells located in other regions of the neural network. Besides motor symptoms, cognitive impairments are one of the essential non-motor manifestations of PD that severely affects the quality of life and has substantial economic consequences. The emerging view suggests that the abnormalities in αS are a strong pathological correlate for motor and neurocognitive dysfunction in PD and Dementia with Lewy Bodies (DLB), a disease clinically and pathologically related to PD. While the mechanism by which αS pathology leads to neuronal dysfunction is unknown, existing evidence suggests that compromised redox homeostasis, defects in protein quality control, mitochondrial dysfunction, and neuroinflammation cause αS aggregation and neurodegeneration in PD and DLB. Oxidation resistance 1 (Oxr1) has emerged as a vital protein that orchestrates a multifaceted response to modulate many of the etiological pathways involved in PD and α-synucleinopathies. The mechanism underlying this process, however, remains poorly understood. Our studies show that Oxr1 overexpression is neuroprotective in preclinical PD models due to its regulation of the lysosomal proton pump vacuolar-ATPase (V-ATPase) which is critical for lysosomal function. We show that Oxr1 interacts with V-ATPase and that neurons lacking Oxr1 exhibit an increase in lysosomal pH, reduce lysosomal proteolytic activity, and exacerbate neurodegeneration in PD preclinical models. We employed innovative systems biology approaches to compare similarities in affected pathways between single-nuclei transcriptomic data from human DLB patients and proteomic data from preclinical models of α-synucleinopathy overexpressing Oxr1. Our analysis revealed that besides lysosomal pathways, Oxr1 overexpression modulated novel non-canonical pathways involved in neuronal survival due to the overabundance of pathway drivers in preclinical PD and human DLB. We hypothesize that Oxr1 is a key mediator of intrinsic protective pathways in PD and DLB. Using rodent models of α-synucleinopathy, we propose to test the hypothesis that Oxr1 overexpression ameliorates αS-induced PD and DLB by modulating both lysosomal and non-canonical neuroprotective pathways. The proposed studies will provide novel insights into molecular mechanisms underlying Oxr1-mediated neuroprotection and identify new targets for therapeutic interventions in PD and DLB.

NIH Research Projects · FY 2025 · 2023-08

Dr. James J. Prisciandaro is a licensed Clinical Psychologist, Associate Professor in the Addiction Sciences Division of the Department of Psychiatry & Behavioral Sciences at the Medical University of South Carolina (MUSC), who is committed to making a measurable impact on our understanding and ability to treat individuals with bipolar (BD) and/or substance use disorders (SUD) through his program of patient-oriented research (POR). Dr. Prisciandaro has served as PI, Co-PI, or Co-I on 12 NIH-funded grant awards since joining MUSC in 2009, but his success in designing and executing NIH-funded research studies has come at a significant cost: his efforts to mentor new clinical investigators have been greatly limited by his employment within an academic medical center that is not able to provide faculty with protected time for mentoring or professional development. As a result of this lack of support, Dr. Prisciandaro has had to greatly limit the number of new clinical investigators that he has been able to mentor, and he has not been able to expand his methodological skillset since completing his K23 training 5-years ago. The proposed K24 award would allow Dr. Prisciandaro to fulfil his career goals by providing him with the protected time and supplementary funding needed to comprehensively train significantly more new clinical investigators and to develop and expand his methodological skills in MRI and statistics to include genomics. Towards this end, Dr. Prisciandaro has recruited several consultants and collaborators to help him create, execute, and monitor a comprehensive training plan, including longstanding collaborators within his fields of expertise (Drs. Richard Edden [MRI] and Michaela Hoffman [biostatistics]) along with three new consultants/collaborators, Drs. Ananda Amstadter (psychiatric genomics), Stefano Berto (genomics and bioinformatics), and Zhewu Wang (psychiatric genetics). With their guidance, Dr. Prisciandaro has proposed a research strategy to apply cutting-edge genomics methods to blood samples that he has collected from every participant enrolled in each of his NIH-funded studies to date, starting with those from his K23 study; a 2*2 factorial (BD*alcohol use disorder [AUD]), multimodal-MRI investigation of neurochemical (i.e., GABA and glutamate levels) and neurobehavioral overlap (i.e., activation to alcohol cues and response inhibition) between BD and AUD. Dr. Prisciandaro will devote the remainder of his effort to his current NIH-funded program of POR, focused on pharmacologically-manipulating intermediate MRI phenotypes of BD and/or SUD, which is tightly aligned with his career goals and a rich source for mentee training and productivity. As these pharmaco-imaging studies complete participant enrollment, Dr. Prisciandaro and his consultants/collaborators will apply to their data the proposed genomics methods, extended to include genetic variants underlying the mechanisms of action of the medications under investigation (e.g., gabapentin). He will involve mentees in all aspects of his POR, including all proposed genomics research. Together, these combined efforts will significantly advance both Dr. Prisciandaro's POR career as well as our understanding of and ability to treat individuals with BD+SUD.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY Cytochrome P450 2E1 (CYP2E1) is a unique, highly conserved, and highly regulated mammalian P450 monooxygenase. CYP2E1 undergoes extensive post-transcriptional and post-translational regulation, including bimodal targeting to endoplasmic reticulum and mitochondria. There are no known loss of function mutations in the human population, and no known polymorphic variants that change the coding region of the protein, indicating an important endogenous role for CYP2E1. However, knockout of CYP2E1 in rodent models has not yielded a dramatic phenotype, and has been reported to be protective against diet-induced obesity, nonalcoholic fatty liver disease, and ethanol-induced toxicity. Therapeutic targeting of CYP2E1 has been recommended for liver repair after alcoholic liver damage and to improve the efficacy of a ketogenic diet for the treatment of epilepsy. However, there remain major gaps in our understanding of the endogenous function of CYP2E1 that must be addressed before CYP2E1 can be safely inhibited in humans, particularly in the long- term. This proposal addresses these challenges using the expertise of the Hartman lab, resources and reagents we have generated to study CYP2E1, and the expertise of our collaborators. The overall goal of the research program is to discover the endogenous function and regulation of CYP2E1 and the consequences of CYP2E1 activity in mitochondria and endoplasmic reticulum. Overview of research and goals for the next five years: The Hartman Lab opened at MUSC during the beginning of the pandemic. It pursues key questions like: How does the cell decide how much CYP2E1 to send to mitochondria vs. the endoplasmic reticulum? Mechanisms of nascent polypeptide targeting will be determined through genetic and pharmacological approaches. What are the endogenous functions of CYP2E1 in multiple tissues? CYP2E1 is known to metabolize acetone to acetol and methylglyoxal, and to hydroxylate fatty acids at the omega and omega-1 position, but these activities have not been studied in the context of overall cellular metabolism and have generally only focused on liver. We are investigating the tissue-specific endogenous functions in multiple tissues. What are the consequences of CYP2E1 expression in mitochondria and endoplasmic reticulum? Emerging evidence in our lab suggests that for ethanol and acetaminophen, mitochondrial CYP2E1 is a liability for drug-induced cellular damage, but for fatty acids, endoplasmic reticular CYP2E1 drives lipid stress. Therefore, there are organelle-specific liabilities that must be further defined. Together this work will address arising and long-standing fundamental questions about CYP2E1.

NIH Research Projects · FY 2025 · 2023-08

This R01 proposal aims to test the effectiveness, mechanism, and implementation of a navigation-based multilevel intervention to improve the delivery of timely, guideline-adherent adjuvant therapy among patients with head and neck cancer (HNC). HNC is a disease with poor survival. For locally advanced HNC, guidelines recommend initiating postoperative radiation therapy (PORT) within 6-weeks of surgery to optimize survival. However, delays starting guideline-adherent PORT (i.e., > 6 weeks after surgery) affect ~50% of patients with HNC and are thus a key driver of poor survival. To date, interventions that improve the delivery of timely, guideline-adherent PORT among patients with HNC are lacking. To address this gap, we developed ENDURE as a navigation-based multilevel intervention that modifies the structure, care delivery pathways, and behaviors of the cancer care multiteam system to address patient-, team-, and organization-level barriers and thus improve the delivery of timely PORT following surgery for HNC. Data from our single-arm and pilot randomized trial provide evidence of NDURE’s feasibility, acceptability, and preliminary effectiveness at improving timely guideline-adherent PORT. To build on these promising data and characterize ENDURE’s implementation across different clinical settings, we propose a hybrid type 1 effectiveness-implementation study. We will conduct a stepped wedge cluster randomized trial with n = 4 cancer centers (N = 484 patients) randomized to sequentially deliver treatment as usual (TAU) then ENDURE to patients with HNC undergoing surgery and PORT. Concurrently, we will conduct a mixed-methods study with quantitative assessments supplemented by semi-structured interviews of patients, providers, and administrators to characterize the implementation of ENDURE. Specific Aim 1 will evaluate the effectiveness of ENDURE on starting timely, guideline-adherent PORT relative to TAU. Specific Aim 2 will identify the mechanisms through which ENDURE improves the delivery of timely PORT. Specific Aim 3 will characterize the implementation of ENDURE across different clinical settings. Findings from our proposal have potential to address three important gaps. First, effectiveness results may provide support for ENDURE as the first evidence-based strategy to improve the initiation of timely adjuvant therapy for patients with HNC. Such a result may help change the current standard of care and improve survival for these patients. Second, findings address an understudied but critical aspect of cancer care delivery and could be translated to other types of cancer (e.g., breast, colon, lung) for which delays initiating adjuvant therapy are common. Third, mechanism data may provide actionable knowledge to improve the delivery of effective interprofessional team-based cancer care.

NIH Research Projects · FY 2025 · 2023-08

Project Summary/Abstract Pancreatic -cells are responsible for synthesis and secretion of insulin in response to a glucose challenge. They are essential for survival of the organism as the only cell type capable of expressing and secreting insulin. Since they are essential, yet they have a limited capacity to replicate, it would be evolutionarily advantageous for -cells to possess mechanisms to protect themselves from a variety of cellular stresses. The formation of reactive oxygen and nitrogen species (ROS and RNS), such as hydrogen peroxide and nitric oxide, have been implicated in the demise of -cells during diabetes development. Indeed, nitric oxide, produced in -cells in response to proinflammatory cytokines (IL-1β and IFN-γ), inhibits mitochondrial oxidative phosphorylation and insulin secretion, hydrogen peroxide causes oxidation of proteins, lipids, and DNA, and both cause DNA damage that can lead to cell death if the damage is not repaired. Furthermore, it has been suggested that -cells are vulnerable to damage due to reportedly low levels of antioxidants; however, this view is at odds with several fundamental characteristics of -cells. ROS are produced by the pathway responsible for glucose sensing and glucose-stimulated insulin secretion (mitochondrial oxidative metabolism), and their production is directly proportional to the blood glucose concentration. Additionally, this pathway is sensitive to inhibition by nitric oxide. Our central hypothesis is that, because they are essential for organism survival, β-cells are evolutionarily programmed to be protected from damage, and our long-term goal is to identify the mechanisms by which this protection occurs. There are two aims: (1) to test the hypothesis that the thioredoxin/peroxiredoxin antioxidant system promotes β-cell survival and function, and (2) to test the hypothesis that IL-1 signaling promotes protective responses in islet endocrine cells. Using biochemical, molecular, immunological, genetic, and omics approaches, these studies will initiate investigations into the mechanisms by which pancreatic β-cells protect themselves against oxidant, free radical, and environmental challenges. Proposed experiments will begin during the K99 phase, with expertise and technical assistance provided by the mentor and advisory team at MCW, and will be completed upon transition to the independent R00 phase. We believe that the pathways of protection that are identified in these studies will provide novel targets for therapeutic intervention designed to preserve functional β-cell mass and attenuate or prevent diabetes development.

NIH Research Projects · FY 2026 · 2023-08

Alzheimer’s disease (AD) is a heterogeneous and complex disorder and both genetic and environmental factors are likely to be involved in its etiology. Hundreds of putative susceptibility genes for late-onset AD have been reported, but the majority of these claims—with the exception of the e4 allele of the apolipoprotein E gene—have not been consistently replicated. Furthermore, the functional significance of the majority of the positional candidate genes in AD pathogenesis is not clear. One putative environmental (viral) factor that has been implicated in AD etiology is herpes simplex virus type 1 (HSV1). An infectious etiology for AD would suggest that the genes of the host immune system might also mediate the putative pathways towards the development of this disorder. Indeed, the genome-wide association studies (GWAS) and meta-analyses of AD have reported many risk-conferring genes that are enriched in the immune system pathways. The GWAS of AD, however, do not evaluate a major gene complex of the immune system—GM (g marker) allotypes encoded by immunoglobulin heavy chain G (IGHG) genes on chromosome 14. HSV1 is a ubiquitous herpesvirus. Not all HSV1-infected people are equally likely to develop AD-related complications, suggesting the involvement of host genetic factors in the HSV1-spurred dementia. Immunoglobulin GM allotypes are excellent candidate genes for modifying the HSV1-AD association, because they modulate the HSV1 immunoevasion strategies and, epistatically with Fcg receptor (FcgR) genes, contribute to the magnitude of antibody-dependent cellular cytotoxicity of HSV1-infected cells. In a recent study, we have shown that a GM genotype was associated with a 4-fold increased risk of AD. This association was independent of apolipoprotein e4 genotype and other AD risk genes. Based on these observations, we hypothesize that GM genes are risk factors for AD, and the underlying mechanisms include their influence on the magnitude of humoral immunity to HSV1 proteins and antibody-dependent cellular phagocytosis (ADCP) of neuronal cells. The following specific aims will test our hypothesis: 1) Determine if GM genotypes are risk factors for Alzheimer’s disease. DNA from a large study population of AD patients and controls will be characterized for several GM alleles to confirm our preliminary findings; 2) Determine if the magnitude of antibody responsiveness to particular HSV1 proteins is associated with GM alleles. We will quantitate antibody responses to HSV1-gD (a major glycoprotein and vaccine candidate) in the sera of AD patients and controls and determine if the magnitude of antibody responsiveness is associated with GM allotypes; 3) Determine if particular allelic combinations of Fc (GM) and cellular FcgR alleles influence the level of ADCP. Using HSV-gD as target, we will determine whether the level of anti-HSV1- gD-mediated ADCP is associated with particular combinations of Fcg (GM) and FcgRIIa alleles. Results of this investigation may begin to address the recurrent criticism of studies documenting the HSV1-AD association: Why the prevalence of HSV1 infection does not correlate with the prevalence of AD in the population?

NIH Research Projects · FY 2024 · 2023-08

Opioid use disorder (OUD) is a chronic disorder characterized by the ability of drug-associated cues (triggers) to persistently motivate drug-seeking behaviors, despite negative consequences. When drugs are associated with cues, a strong conditioned memory is formed between the drug and the cues. Normally, once these cues no longer predict a drug reward, this conditioned memory would be overpowered by an extinction memory. Extinction memory recall (EMR) describes the ability to behaviorally express this extinction memory. EMR deficits may underly the pathological drug seeking (relapse) seen in those with OUD. Importantly, a brain region involved in each step of this process (conditioning, extinction and EMR) is the basolateral amygdala (BLA). OUD is also characterized by distinct sex differences, with females being particularly susceptible to the rewarding effects of opioids and more reactive to opioid-associated cues. Unfortunately, the lack of females in many prior research studies on OUD has impaired our ability to describe the mechanisms behind, and thereby address, these disparities. To resolve this knowledge gap, we conducted preliminary studies to investigate the role of estradiol (E2) signaling in the BLA on heroin EMR in male and females rodents. In our first study, we found that blocking E2 synthesis in the BLA during cued extinction training impairs EMR in both sexes. On follow-up, we found that antagonizing estrogen receptor (ER) subtypes in the BLA led to sex-specific impacts on heroin EMR. Briefly, females who received an ERβ antagonist had a profound EMR deficit relative to all other groups tested. In agreement, ERβ agonism enhanced EMR in females only. The goal of this proposal is to evaluate the sex- specific impacts of ERβ signaling in the BLA on heroin EMR. We hypothesize that modulation of ERβ signaling in the BLA during extinction will alter EMR in females by changing neuronal function and plasticity-associated mRNA expression, an effect driven by sex-specific ERβ expression in the BLA. We will evaluate this hypothesis across 2 Aims. We propose to use pharmacologic and genetic approaches in males and females to identify alterations in BLA activity and signaling following negative (Aim 1) or positive (Aim 2) modulation of ERβ during cued extinction. Upon analysis, we expect that negative ERβ modulation by antagonist or shRNA (Aim 1) will impair heroin EMR, decrease ERβ+ neuronal activity, and decrease plasticity-associated mRNA expression in females. Contrastingly, positive modulation of ERβ by agonist or overexpression (Aim 2) will have opposite impacts on these measures in females. The proposed studies may better describe sex differences underlying heroin reward processing and OUD, allowing for more guided, sex- specific interventions to successfully prevent and treat this disorder. This fellowship will support my training under the mentorship of Drs. Carmela Reichel and Christopher Cowan. As outlined in this proposal, I will gain training in (i) numerous technical and non-technical scientific skills, (ii) investigation of sex as a primary biological variable, and (iii) consideration of biological and social determinants of mental health.

NIH Research Projects · FY 2024 · 2023-07

Abstract The incidence of human papillomavirus-positive (HPV+) head and neck squamous cell carcinoma (HNSCC) is rising and while treatment options are available, they remain limited primarily to surgical excision, radiation therapy, and chemotherapy which often result in long term morbidity. RNA interference (RNAi) appears to be a promising therapeutic tool for the treatment of many diseases, including HPV+ related cancers, through targeting viral oncogenes, E6 and E7, with small interfering RNAs (siRNA). The expression of E6 and E7 viral oncoproteins inhibits the p53 and pRb tumor suppressors, respectively, resulting in uncontrolled cellular proliferation. Knockdown of E6 and E7 in vitro has been shown to induce apoptosis in both HPV+ cervical cell carcinoma and HPV+ head and neck squamous cell carcinoma cell lines, indicating that E6 and E7 are viable therapeutic targets for RNAi therapy. However, the therapeutic application of RNAi requires a delivery platform that can overcome numerous challenges typically associated with this form of therapy. Peptide carriers show great promise as siRNA carriers based on the diversity of their physiochemical properties and functions. Recently, we demonstrated that a novel peptide carrier we designed, termed RD3AD, enhanced the intracellular delivery and availability of therapeutic, chemically synthesized siRNAs in oral cancer cells, in vitro, to levels that were ~4x that of Lipofectamine 3000, which some would consider to be the “gold standard” positive control for in vitro delivery of nucleic acids. It therefore stands to reason that RD3AD could be an effective delivery vehicle for siRNAs designed to target the E6 and E7 viral oncogenes (siE6 and siE7) in HNSCC cells. RD3AD-siRNA complexes were also observed to localize to cellular projections identified as filopodia. These observations were indicative of patterns previously reported for cellular uptake of viruses, bacteria, activated receptors, lipo/polyplexes, and exosomes, which utilized filopodia to undergo retrograde transport toward the cell, resulting in significant enhancements of uptake. It is therefore possible, given the observations with RD3AD, that this peptide is exploiting similar mechanisms. Thus, our overarching hypothesis is that RD3AD-siE6/7 (siE6 or siE7) complexes enter HPV+ oral cancer cells after binding to cellular filopodia and silence viral oncogenic E6 or E7 mRNA, in vitro. We will test our hypothesis through the following specific aims. Aim 1: Identify the RD3AD receptor on filopodia and exploit this receptor for cell specific targeting. Aim 2: Determine the mechanism(s) of RD3AD-siRNA complex uptake. In aggregate, this proposal will establish a molecular therapeutic option for HPV+ HNSCCs, while describing a novel mechanism of cell-specific delivery and uptake by a peptide nanocarrier. The results from this study will contribute significantly to a solution for a critical unmet clinical need and will be particularly impactful on the field of drug delivery while providing new insights into filopodia biology. This fellowship will also provide training in drug delivery and cancer biology and will foster the development of the trainee into a unique oral health academic clinician/scientist.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY/ABSTRACT Patient-reported outcome measures (PROMs) are crucial for understanding the impact of cochlear implants (CIs) on real-world functional abilities and for monitoring changes over time. However, CI clinical outcome measures traditionally focus solely on CI users’ speech recognition ability, which lacks ecological validity, relies on outcomes that are weakly associated with real-world functional communication ability, and disregards important CI benefits such as improved social engagement and listening effort. Therefore, our current clinical practice standards are not evidence based due to a critical knowledge gap that limits our understanding of the broad functional impact of CIs on patients’ everyday lives. Improvement in speech recognition represents a fundamental early step in the post-CI rehabilitation process. Further lasting real-world functional improvements may occur but depend on how well CI users deploy their enhanced speech recognition skills in their everyday lives. This two-phase process emphasizes the value of combining PROMs with measures of speech recognition to comprehensively assess the patient-centered benefits of cochlear implantation. The enhanced rigor of modern PROM development methodologies, as applied in the development and validation of the new Cochlear Implant Quality of Life-35 Profile (CIQOL-35 Profile), have the potential to improve the monitoring of CI user progress and inform clinical decision making. The proposed project includes a rigorous evaluation of the benefits of CIs on a broad range of functional abilities conducted using a multi-site, longitudinal study design, which will provide, for the first time, a comprehensive understanding of outcomes meaningful to patients and accomplish the following Aims. Aim 1 will apply a novel CIQOL functional staging system, which provides real-world context to CIQOL scores while maintaining the hierarchy of quantitative scores, in a group-based trajectory model to identify clusters of patients in the longitudinal study who follow similar progressions through the CIQOL functional staging system and identify patient factors associated with each trajectory cluster. Aim 2 will first determine the magnitude of change in CIQOL-35 Profile scores considered clinically meaningful to CI users, then apply these findings to better understand the association between early meaningful improvement after implantation and long- term functional outcomes. Specifically, we aim to promptly identify patients at risk of poorer long-term outcomes who may benefit from additional resources. Finally, Aim 3 will apply an implementation science approach to translate the findings from our longitudinal study into clinical practice and enhance the integration of CIQOL instruments into routine CI care. Together, the proposed research program will enhance the interpretation and application of real-world CI outcomes for individual patients, inform patient discussions regarding expected results and demonstrate the potential for PROMs to personalize and improve patient care.

NIH Research Projects · FY 2025 · 2023-07

Abstract Most smokers want to quit smoking, and most smokers try to quit smoking each year. Yet, most attempts to quit smoking fail. FDA-approved pharmacotherapies can help, but non-response, either through relapse or through inability to initiate cessation, is still the most common outcome. Despite the frequency of treatment non-response, few trials have investigated the best path forward for treatment in these instances—should smokers try to quit again with the same pharmacotherapy, consistent with package guidelines to continue with treatment for 12 weeks, or should early failure be preempted and met with a change in pharmacotherapy? Further, for smokers who have tried to quit with pharmacotherapy multiple times and are still smoking, is it better to switch to a less harmful tobacco product rather than trying to quit repeatedly with FDA-approved pharmacotherapy? The proposed adaptive treatment trial will test whether 1) switching between pharmacotherapies following an initial failure better promotes abstinence than a repeated attempt with the same pharmacotherapy, and 2) whether switching to e-cigarettes following successive failures with multiple pharmacotherapies better promotes abstinence from cigarettes than a third attempt to quit with the same course of pharmacotherapy. Daily smokers across South Carolina and Alabama who are willing to set a quit date (N=544) will be provided with a 4-week supply of FDA approved smoking-cessation medication and provided with instructions to set a date and to quit smoking completely. First-course medication will be either combination nicotine replacement therapy (transdermal nicotine patch and oral nicotine lozenge) or varenicline, counterbalanced. After four weeks of treatment, those who have not responded to initial treatment (i.e., non-responders) will be assigned in a 2:1 fashion to either Adaptive Treatment (medication switch) or Non-Adaptive Treatment (medication continuance; Aim 1). After a second four weeks of treatment, non-responders will be assigned in a 2:1 fashion to either a Harm Reduction Approach (to switch to a less harmful tobacco product; e-cigarettes) or Non-Adaptive Treatment (medication continuance; Aim 2), again with instructions to switch or quit completely. Outcomes include biochemically-confirmed 7-day abstinence from smoking, smoking reduction, measures of dependence, duration of abstinence, and dual use, each measured at key intervention timepoints: after each course of treatment, with follow-up through six months. This innovative R01 application is led by two seasoned investigators with expertise in smoking cessation, harm reduction, and remote clinical trials. The research question is highly significant and is positioned to provide strong, data-driven guidance on treatment decision making for the most common problem facing even the best treatments for smoking: failure. Trial results provide a significant opportunity to optimize cessation outcomes for smokers who continue to struggle in quitting.

NIH Research Projects · FY 2025 · 2023-07

The primary aim of this K23 Mentored Patient-Oriented Research Career Development Award is to provide the candidate (Dr. Delisa Brown) with the opportunity to acquire the knowledge and skills necessary to become an independent investigator focused on alcohol use disorder (AUD) and health disparities. Social stress (SS) is common and is associated with increased risk of developing AUD. However, little research has focused on SS and AUD, especially in underresourced individuals. Given the dearth of scientific information available on the effects of SS among individuals with AUD, the proposed study will employ a well-controlled human laboratory paradigm to identify the subjective (craving, stress), physiological (heart rate, galvanic skin conductance), and neuroendocrine (cortisol) reactivity to personalized imagery cues (i.e., SS, alcohol, and neutral) among underresourced individuals (N = 60) with AUD. The relationship between individual-level factors and reactivity to SS cues will be examined to further inform the science in this highly understudied area and support the future development of targeted interventions. Ecological momentary assessment (EMA) will be used to obtain real-time information on alcohol craving, affect, and drinking patterns following exposure to SS. The data obtained from this project will provide new knowledge and insights to inform our understanding of the link between SS and AUD in ways not previously possible. The candidate has assembled a mentorship team of experienced and nationally renowned investigators with a history of collaboration who bring expertise in AUD, health disparities, human laboratory paradigms, EMA, clinical trials, and treatment development. On-site mentors and consultants include Drs. Sudie Back, Colleen Halliday, and Erin McClure at MUSC. Off-site mentors and consultants include Dr. Kathleen Burlew at the University of Cincinnati and Dr. Rajita Sinha at Yale University. The K23 project will provide the mentorship, formal coursework, hands-on data collection, and career development opportunities needed to ensure the candidate achieves the following career goals: 1) enhance knowledge of the underlying pathophysiology of AUD among individuals experiencing social stress, 2) develop competence in best practices for conducting alcohol research across a broad range of AUD conditions, 3) obtain new training in EMA methods and advanced statistical analysis, 4) enhance understanding of research ethics, and 5) increase scholarly productivity through manuscript writing, conference presentations, and grant writing.

NIH Research Projects · FY 2024 · 2023-07

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the top five deadliest cancers due to a lack of effective treatment options. One hallmark of PDAC is the expansion of cancer associated fibroblasts (CAFs). CAFs play critical and complex roles in PDAC microenvironment to modulate tumor progression and therapeutic response. The long-term objective of my research program is to determine the cellular origin, heterogeneity and function of CAFs in pancreatic cancer. To identify the tissue origin of CAFs in PDAC, I performed lineage tracing experiments using genetically engineered mouse models. The splanchnic mesenchyme is a particular type of mesenchyme adjacent to the pancreatic epithelium during fetal development. My studies demonstrated that the splanchnic mesenchyme is the fetal origin of CAFs in PDAC (Han et al, Nat Commun, in press). In this current proposal, I aim to further investigate whether splanchnic-derived CAFs maintain certain molecular signatures of their fetal progenitors. The Hedgehog pathway is a critical paracrine signal between the epithelium and mesenchyme during fetal development and is reactivated during tumorigenesis of the pancreas. The Hedgehog signal modulates PDAC progression, but its downstream targets in CAFs have not been identified. My graduate study showed that transcription factors FOXF1 and GATA6 are downstream targets of the Hedgehog pathway in the fetal splanchnic mesenchyme. My preliminary studies suggested that these factors are also expressed in PDAC CAFs in a regionally distinct pattern within the tumor microenvironment. In Aim 1, I will determine whether FOXF1/GATA6 patterning in CAFs is regulated by the Hedgehog pathway activity. Hedgehog agonist or antagonist will be utilized in in vitro cell or organoid culture and in vivo mouse models. In Aim 2, I will determine the function of FOXF1+ CAFs and GATA6+ CAFs in PDAC by deleting these genes specifically in CAFs both in vitro and in vivo as well as in patient correlation studies. The completion of this study will provide critical insights in PDAC CAF biology, including novel cellular heterogeneity defined by selective persistence of fetal signatures in coordination with the epithelium, and certain fetal signatures playing tumor-suppressing roles in a non-cell autonomous manner. Ultimately, such knowledge in tumor microenvironment may reveal critical targets and therapeutic avenues to inhibit tumor progression and prolong PDAC patient survival. I received rigorous training in developmental biology during my graduate study. Four years ago, I started my training in cancer biology as a postdoctoral fellow in the Hollings Cancer Center. During the K99 phase, I aim to further enhance my expertise in pancreatic cancer research and to acquire several additional skills, which are essential to launch my independent research program during the R00 phase. I aspire to draw from paradigms in both embryology and oncology to develop novel perspectives and to tackle fundamental biological questions.

NIH Research Projects · FY 2025 · 2023-07

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the top five deadliest cancers due to a lack of effective treatment options. One hallmark of PDAC is the expansion of cancer associated fibroblasts (CAFs). CAFs play critical and complex roles in PDAC microenvironment to modulate tumor progression and therapeutic response. The long-term objective of my research program is to determine the cellular origin, heterogeneity and function of CAFs in pancreatic cancer. To identify the tissue origin of CAFs in PDAC, I performed lineage tracing experiments using genetically engineered mouse models. The splanchnic mesenchyme is a particular type of mesenchyme adjacent to the pancreatic epithelium during fetal development. My studies demonstrated that the splanchnic mesenchyme is the fetal origin of CAFs in PDAC (Han et al, Nat Commun, in press). In this current proposal, I aim to further investigate whether splanchnic-derived CAFs maintain certain molecular signatures of their fetal progenitors. The Hedgehog pathway is a critical paracrine signal between the epithelium and mesenchyme during fetal development and is reactivated during tumorigenesis of the pancreas. The Hedgehog signal modulates PDAC progression, but its downstream targets in CAFs have not been identified. My graduate study showed that transcription factors FOXF1 and GATA6 are downstream targets of the Hedgehog pathway in the fetal splanchnic mesenchyme. My preliminary studies suggested that these factors are also expressed in PDAC CAFs in a regionally distinct pattern within the tumor microenvironment. In Aim 1, I will determine whether FOXF1/GATA6 patterning in CAFs is regulated by the Hedgehog pathway activity. Hedgehog agonist or antagonist will be utilized in in vitro cell or organoid culture and in vivo mouse models. In Aim 2, I will determine the function of FOXF1+ CAFs and GATA6+ CAFs in PDAC by deleting these genes specifically in CAFs both in vitro and in vivo as well as in patient correlation studies. The completion of this study will provide critical insights in PDAC CAF biology, including novel cellular heterogeneity defined by selective persistence of fetal signatures in coordination with the epithelium, and certain fetal signatures playing tumor-suppressing roles in a non-cell autonomous manner. Ultimately, such knowledge in tumor microenvironment may reveal critical targets and therapeutic avenues to inhibit tumor progression and prolong PDAC patient survival. I received rigorous training in developmental biology during my graduate study. Four years ago, I started my training in cancer biology as a postdoctoral fellow in the Hollings Cancer Center. During the K99 phase, I aim to further enhance my expertise in pancreatic cancer research and to acquire several additional skills, which are essential to launch my independent research program during the R00 phase. I aspire to draw from paradigms in both embryology and oncology to develop novel perspectives and to tackle fundamental biological questions.

NIH Research Projects · FY 2024 · 2023-07

PROJECT SUMMARY/ABSTRACT There has been a significant rise in opioid use disorder (OUD) in the United States over the past decade, making it imperative to gain a better understanding of the behavioral characteristics underlying OUD vulnerability. Current rodent models focus on how one or few traits interact in a linear manner to predict substance use disorder (SUD), however, OUD consists of several symptoms that interact with one another across the addiction process and can vary between individuals to affect OUD vulnerability or resiliency. I contributed toward a rat model that captures this behavioral complexity using male and female heterogeneous stock rats in an effort to better model human OUD. Bayesian stochastic block model (SBM) network-based clustering analysis is used to separate rats into resilient and vulnerable subpopulations. Using this model, we are able to assess the neurobiological mechanisms contributing toward OUD vulnerability and resiliency, the latter of which is not well understood. These opposing phenotypes are likely mediated by different cellular and circuitry adaptations, and will be the focus of this proposal. The K99 aims assess how functional and morphological neuroplasticity differences in nucleus accumbens core (NAcc) D1/D2 medium-spiny neuron (MSN) contribute to OUD resiliency and vulnerability. I will first use whole-cell patch-clamp electrophysiology to characterize changes in AMPA/NMDA ratios in vulnerable and resilient subpopulations following cued reinstatement (Aim 1). I will then inject an intracellular label into the recorded cell and examine differences in D1/D2-MSN dendritic spine morphology (Aim 2). This approach will allow for the tracking of NAcc neuroplastic adaptations within the same cell across the two phenotypes. The R00 portion of the proposal will assess how pathway specific regulation of dorsolateral ventral pallidum (dlVP) projections contribute to OUD resiliency and vulnerability. Comparable to the NAcc, the dlVP, the main functional output of the NAcc, shows cell-specific functional regulation of drug seeking and refraining behavior, making it an ideal structure to evaluate circuit heterogeneity in individual variation in OUD propensity. Using confocal microscopy and viral tracers, I will assess functional connectivity from the dlVP to the subthalamic nucleus (STN), a region known to enhance seeking and likely vulnerability, and to the lateral habenula (LHb), known to mediate aversion and hypothesized to promote resiliency (Aim 3a). I will then employ chemogenetic technology to selectively isolate and manipulate these pathways in OUD resilient and vulnerable rats. (Aim 3b). Lastly, using whole-cell patch-clamp electrophysiology, I will evaluate input adaptations in the STN and LHb following dlVP stimulation within the two phenotypes following cued reinstatement (Aim 4). Experiments in this proposal employ a novel rat model capturing individual variation in OUD propensity similar to what is observed in humans. Work from this proposal will greatly contribute to our knowledge of the cellular and circuitry mechanisms contributing to OUD resiliency versus vulnerability.

NIH Research Projects · FY 2024 · 2023-07

The Role of BHLHB2 in Scleroderma-Associated Lung Fibrosis Scleroderma/Systemic Sclerosis (SSc) is a fibrosing multi-system rheumatic disease associated with excessive deposition of extracellular matrix (ECM) components such as collagen and fibronectin. The predominant and fatal complication of SSc is Pulmonary Fibrosis (PF), for which current treatments are marginally effective. IL-6 is a pro-inflammatory and pro-fibrotic cytokine produced in excess in SSc fibroblasts. Likewise, insulin-like growth factor (IGF)-II, a member of the IGF family, is produced in excess in SSc fibroblasts and is implicated in the development of pulmonary fibrosis. Our lab has shown that IGF-II levels are increased in both SSc lung tissues and the primary fibroblasts derived from them, and that IGF-II induces a fibrotic response in normal lung (NL) fibroblasts. IGF-II increases levels of collagen, fibronectin, and the pro-fibrotic transforming growth factor beta-2 (TGF2). In this application, we demonstrate that IL-6 increases IGF-II mRNA levels. Microarray analysis of IGF-II-treated NL fibroblasts revealed increased expression of the Basic Helix-Loop-Helix transcription factor family member, BHLHB2, a known regulator of the circadian rhythm, adipogenesis, and fibroblast autophagy. Our preliminary data further show that both IL-6 and IGF-II increase nuclear BHLHB2 levels in NL fibroblasts. We show that BHLHB2 activation is a common link between, and downstream mediator for several profibrotic agents: TGF, IL-6 and IGF-II. Silencing BHLHB2 downregulated IGF-II. IGF-II induced BHLHB2 via signaling through the Insulin Receptor. Thus, our central hypothesis is that BHLHB2 contributes to the progression of Scleroderma-associated Lung Fibrosis by increasing levels of ECM genes. Our goal is to delineate the role of BHLHB2 in the development of lung fibrosis in Systemic Sclerosis by (1) identifying the mechanism by which IL- 6 and IGF-II regulate BHLHB2, comparing differentially-expressed genes in single cell RNASeq of IGF-II-and IL- 6 stimulated normal lung and (2) elucidating the role of BHLHB2 in lung fibrosis. These aims are consistent with the National Heart Lung and Blood Institute’s mission since they will provide important fundamental basis for addressing translational aspects of the interaction between genetic dysregulation due to IGF-II and development of SSc-associated PF. We envision that our work will provide a rationale for a therapy to block IL-6 and IGF-II function concomitantly to halt the progression of lung fibrosis in SSc. Since SSc-PF is characterized by activation of common fibrotic pathways and increases in ECM components (collagen, fibronectin), which are also increased in different diseases characterized by lung fibrosis, our findings may have wider implications for lung fibrosis associated with other diseases. In addition to facilitating a deeper understanding of mechanisms of SSc-PF, this proposal provides Adegboyega Timothy Adewale with a rigorous training under the mentorship of Dr. Carol Feghali-Bostwick and equips him with cutting-edge techniques to develop as an astute and skillful physician- scientist.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY Compared to Caucasians, African American (AA) kidney transplant recipients have twice the risk of graft loss. Despite recent studies demonstrating marginal improvements in access to transplant, a kidney transplanted today functions about half as long in AA recipients as compared to Caucasians. Our formative research demonstrates that in contemporary kidney recipients, several late (≥2 years) post-transplant clinical markers, including acute rejection, high tacrolimus trough variability and sub-optimal control of hypertension and diabetes can explain disparities in AAs. We completed a 60 patient prospective interventional pilot study demonstrating significant improvements in the control of hypertension and diabetes through a technology-enabled intervention. This study demonstrated that clinical improvements in hypertension control were more substantial in AAs. We also completed two randomized controlled trials demonstrating that real-time medication adherence monitoring is feasible and highly accepted within kidney recipients. This demonstrates a technology-based automated medication monitoring system is a promising intervention to identify and prevent late medication non-adherence, thus reducing high tacrolimus variability and the risk of late rejection. Based on this formative research, we propose to conduct the Multifaceted Intervention to Improve Graft outcome disparities in African American Kidney Transplants (MITIGAAT) study. The overarching hypothesis for MITIGAAT is that the increased burden of late clinical events and comorbidity burden within AA kidney transplant recipients are the primary contributor to disparities in graft survival and a multimodal intervention that achieves improved identification and management of these issues will address this disparity. We will test this hypothesis through a rigorously conducted large-scale, long-term, prospective, randomized, controlled clinical trial in kidney transplant recipients aiming to demonstrate improved tacrolimus trough variability and control of hypertension and diabetes in those randomized to the intervention arm, as compared to the control arm while reducing disparities in AAs. Our secondary aim is to conduct a cost benefit analysis to demonstrate that the intervention reduces healthcare utilization and associated costs; our exploratory aim is to measure the incidence of acute rejection and graft loss in AA kidney recipients, comparing this between the intervention and a control cohort. The enduring goal of this proposal is to demonstrate an effective, efficient, and feasibly deployable method to improve long-term outcomes in AA kidney recipients while reducing health disparities.

NIH Research Projects · FY 2026 · 2023-06

PROJECT DESCRIPTION / ABSTRACT Unhealthy changes in the gut microbiota might trigger the pathogenesis of many diseases. We have reported that priming the gut by -glucan-shaped microbiota, prior to clinical disease onset, can profoundly suppress autoimmune and colitis severity. Accumulating evidence suggests that microbes and their metabolites critically modulate the pathophysiology of various diseases. However, vast majority of microbial metabolites including those resulting from microbiota-diet interaction remain unknown and/or uncharacterized. Non-digestible, microbiota-accessible carbohydrates (MACs) including -glucans are thought to have major impact on microbiota composition and function. Our findings show that high-pure -glucans (BGs) from yeast (yeast -1,3/1,6-glucan; YBG) and microalgae (algal -1,3-glucan; paramylon, PM): a) have prebiotic properties, b) can increase the intestinal production of SCFA, c) can enhance gut integrity, and d) can suppress autoimmune progression and gut inflammation. However, to fully explain the mechanisms associated with the host-benefits of BG-shaped microbiota and to develop nutraceutical approaches, it is important to identify metabolites generated from BG- like CDP degradation and characterize their functional impacts. In this regard, our observations from in vitro and in vivo studies suggest that “BG-degradation” by gut microbes produces a distinct metabolite profile that includes the higher abundance of immune regulatory SCFAs. Therefore, we hypothesize that “identification and functional characterization of unique microbial metabolites of BG-degradation could lead to the development of precision- nutrition and -medicine approaches to enhance gut and systemic immune regulation”. Here, in response to PAR-21-253, we have proposed to, first identify BG degradation- and autoimmunity- associated novel microbial metabolites. Our studies will focus on i) determining if BG degradation, by human fecal microbiota, produces a distinct metabolite profile and ii) identifying the novel microbial metabolites of this process. We will also examine if fecal microbes from autoimmune type 1 diabetes and systemic lupus erythematosus patients produce pro-inflammatory metabolites and determine if BG-degradation process skews this pro-inflammatory metabolite profile to immune regulatory type. The pro- and anti- inflammatory properties of BG degradation- and autoimmunity-associated microbial metabolites will be studied in a series of in vitro and in vivo studies. The functional impacts of candidate metabolites on T-, B- and dendritic- cell responses will also be studied. We will then examine if in vivo immune function and autoimmune disease outcomes can be modulated by select microbial metabolites. Overall, these studies will demonstrate if fermentation of BG-like MACs generates microbial metabolites with therapeutic value, in terms of preventing and/or treating immune mediated disorders. We will work closely with the Knowledgebase Management Center (KMC) for different aspects of the project and share data and experimental details freely with KMC and other grantees.

NIH Research Projects · FY 2026 · 2023-06

Alcohol misuse has a salient precipitous effect on intimate partner violence (IPV), which is a persistent public health crisis affecting approximately one-third of the U.S. population. Posttraumatic stress disorder (PTSD) is highly prevalent, has a clear causal effect on alcohol misuse, and it is a robust independent predictor of IPV. However, few studies have examined the combined effects of PTSD and alcohol misuse on IPV. This question is critical to address because effective prevention and treatment approaches for alcohol-related IPV are scant. Integrating these two siloed areas of the literature can help inform the development of novel, trauma-informed modalities for couples to produce stronger and more sustainable outcomes. Dr. Flanagan is the ideal candidate to advance the clinical science in this area. Under the proposed mid-career development award, she will accelerate her thriving patient-oriented alcohol research program by enhancing her skills with 1) oral alcohol administration, 2) intensive ambulatory assessment, and 3) psychophysiology. She will achieve these goals through expert consultation, didactic training, and implementation of the proposed research project. Her team will examine the combined effects of alcohol misuse and PTSD on alcohol-related IPV among couples (N=70) in both a controlled laboratory setting and in naturalistic settings. The study, which was designed to complement mentees’ independent research interests, will also compare outcomes across settings and explore heart rate variability as a physiological mechanism underlying the hypothesized relations. The invaluable protected time and resources provided by this K24 will enable Dr. Flanagan to achieve her primary goal of expanding her mentoring availability and skillset at this pivotal mid-career stage. She will engage a program of didactics and expert coaching to amplify her investment in mentoring, leadership, and science. Achieving these synergistic objectives will accelerate the science of couple and family alcohol research and set the stage for innovative new dyadic treatments. This award will also ensure that Dr. Flanagan is equipped to support the next generation of enthusiastic new investigators and to ensure the longevity of this vital yet underrepresented area of the alcohol field.

NIH Research Projects · FY 2026 · 2023-06

ABSTRACT COVID exposed the critical need for new and improved treatment interventions for chemosensory (i.e. smell and taste) dysfunction. Evidence indicates that COVID-related smell loss (SL) often endures well past recovery of the initial infection and is highly associated with other long COVID neuropsychiatric symptoms including impairments in mood, sleep, and cognition. To date, there are few interventions available to treat COVID-related persistent SL and its related impairments. While smell/olfactory training (ST) has emerged as a widely prescribed, front-line treatment for COVID-related persistent SL, rigorous study is required to determine its efficacy in long COVID. Moreover, given that ST is a lengthy treatment, requiring 12 weeks or longer of training, and is associated with slow improvement, non-compliance, drop-out, and modest effect size, additional study of adjunctive methods to improve its efficacy and speed of recovery are warranted. Here we propose the first study to investigate combinatorial trigeminal nerve stimulation (TNS) and ST in the treatment of post-COVID persistent SL and associated deficits in mood, sleep and cognitive impairment. Our previous work suggests that TNS, an easy-to-use and very safe form of non-invasive brain stimulation, increases olfactory sensitivity and has the potential to improve other symptoms of long COVID including mood, daytime sleepiness, and attention. Therefore, we will conduct a larger at-home, randomized, controlled trial of ST and determine whether TNS enhances the effects of ST in adults with COVID-related persistent SL. Our primary objectives are 1) to determine the efficacy of ST, compared to any natural gain in function, on olfactory-specific deficits (active ST versus sham ST), 2) to determine the TNS-enhanced effects of ST on olfactory-specific deficits (active TNS+ST versus active ST), and 3) to determine if TNS+ST, compared to ST, is also more efficacious in the treatment of other impairments (i.e. mood, sleep, and cognitive) associated with both SL and long COVID. While this research is focused on COVID-related persistent SL, the results will provide the necessary information to extend the study and use of ST and TNS to address wider chemosensory dysfunction. This line of investigation has the potential to make a substantial impact on how chemosensory dysfunction is treated and in turn significantly improve the current standard of care.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Mild Cognitive Impairment (MCI) is a heterogenous syndrome of cognitive and neuropsychiatric symptoms. As many as 40% of MCI patients have comorbid depression, and even past depression doubles their risk of incident dementia. We propose that repetitive transcranial magnetic stimulation (rTMS), an FDA-approved treatment for depression, may be a promising treatment to prevent dementia in MCI. By stimulating shared neurocircuitry implicated in both affective and cognitive control, prior work has shown that conventional rTMS to left dorsolateral prefrontal cortex (l-dlPFC) improves both affective and cognitive symptoms in various neuropsychiatric syndromes. Thus, our main hypothesis is that excitatory rTMS to the l-dlPFC, which is hypoactive in MCI, may simultaneously ameliorate depression and bolster cognitive abilities, potentially preventing dementia incidence. To test this hypothesis, we first need to address a critical gap which is to resolve the functional form of the doseresponse curve to identify the optimal dose for symptom remediation. This has yet to be established for accelerated, high-dose intermittent theta burst (iTBS)-rTMS, which reduces the conventional rTMS treatment course by >50%. Our Preliminary Data from two open-label phase I trials support the safety, feasibility, and acceptability of iTBS-rTMS to l-dlPFC in patients with amnestic MCI due to AD or Vascular Cognitive Impairment due to stroke. While these trials were not explicitly dosed for efficacy, we found large effect size improvements in fluid cognition in both groups. We therefore propose to conduct a double-blind, randomized sham-controlled, parallel group, dose-ranging phase II trial, where all participants will be recruited to undergo 6 treatment days within a span of 2 weeks. Participants will be randomized to 1 of 6 dose-step combinations of active/sham iTBSrTMS, ranging from 0 active pulses (all sham; dose step 1) to 36,000 total active pulses (all active; dose step 6). Scalp-based Beam F3 targeting will be used for generalizability, while neuronavigation will ensure precise coil placement. Participants with MCI due to AD and/or cerebral small vessel disease with any lifetime history of depression will be recruited, with a target sample of N=48 (i.e., 8 participants in each of the 6 dose bins). All will undergo clinical assessments and brain MRI at pre-treatment and at 1-week post-treatment, and clinical assessments at 8-weeks and 6-months post-treatment. We will use established primary outcomes and supplement these with psychometrically robust secondary outcomes. As a team with collective expertise in rTMS, MCI, neuropsychology, affective neuroscience, and clinical trials biostatistics, we seek to establish the dose-response curves for reduced depression (Aim 1) and improved cognition (Aim 2) following iTBS-rTMS. We also seek to examine alterations in functional connectivity following treatment as an Exploratory Aim. This trial will pave the way for subsequent randomized controlled trials to optimize therapeutic delivery, including variations in sites beyond dlPFC, indications such as other prodromal states or symptom presentations, and combinatorial designs where behavioral interventions provide potent adjuncts to rTMS-induced neuroplasticity.

NIH Research Projects · FY 2025 · 2023-05

PROJECT SUMMARY/ABSTRACT The goal of the proposed Behavioral and Integrative Treatment Development Program (R34) is to develop and test a mobile health (mHealth) application of evidence-based behavioral treatment for sleep problems in persons beginning treatment for opioid use disorder (OUD) with medications for OUD (MOUD). OUD is a highly prevalent problem with major public health implications. MOUD is the first-line treatment for OUD, though sleep complaints in persons receiving MOUD are highly prevalent, persistent, and connected to negative treatment outcomes. Interventions for insomnia and other sleep problems in those receiving MOUD are lacking, as pharmacological options are limited and there are multiple barriers to receiving evidence-based non-pharmacological/cognitive behavioral treatment, including competing treatment demands, lack of trained providers, and time and effort involved in in-person sessions. Modifying evidence-based behavioral sleep interventions for delivery via a patient-focused mobile application with special consideration to factors specific to persons receiving MOUD would fill this treatment gap by circumventing many of these obstacles related to accessing in-person treatment. The proposed research will develop and test a behavioral sleep medicine- based mobile application that includes components of interventions for sleep problems that are highly prevalent in MOUD treatment, including insomnia, circadian rhythm disorders, nightmares, and pain-related sleep difficulty. The ultimate goal of this project is to prepare for a large scale randomized clinical trial. Specific aims include: 1) Develop a mHealth application, NightRighter, based on cognitive behavioral therapy for insomnia and augmented with other evidence-based sleep interventions that address common sleep-related problems in OUD/MOUD utilizing input from persons beginning MOUD (n=5), stabilized on MOUD (n=5) or providing treatment for those receiving MOUD (n=5); 2) Run usability tests of NightRighter through alpha and beta testing (n=15-20); 3) Conduct a pilot randomized clinical trial (RCT) of NightRighter compared to a sleep hygiene control group (n=40) in preparation for a larger RCT. This proposal leverages the skills and expertise of all team members, including measurement of sleep problems in OUD of Dr. Wilkerson, OUD clinical care and clinical research experience of Drs. Book and McCrae, implementation of digital health tools of Dr. Ruggiero, and qualitative data collection and analyses in substance use disorders of Dr. Moreland.

NIH Research Projects · FY 2026 · 2023-05

Abstract The Food and Drug Administration (FDA) is working to finalize a ban on menthol cigarettes. Finalizing a ban, navigating litigation from the tobacco industry, and implementing the ban will be a lengthy process. Some organizations have advocated that non-tobacco flavorings, including menthol, should also be banned from other tobacco products like e-cigarettes. Despite the wealth of cross-sectional and uncontrolled studies of menthol, we have very little prospective, experimental data investigating the impact of a menthol ban on tobacco use for menthol smokers in the United States, and even less evidence on how a menthol ban for e-liquids might interact with a cigarette menthol ban. If menthol is banned from both cigarettes and e-cigarettes, menthol smokers who otherwise would have tried to switch to e-cigarettes may continue to smoke cigarettes or quit using tobacco altogether. Thus, the impact of a cigarette menthol ban on changes in tobacco use may depend on whether menthol is banned in e-cigarettes. The proposed trial is a 2x2 between-subjects randomized controlled trial investigating the impact of a menthol bans for cigarettes and e-cigarettes on tobacco use patterns including cigarette smoking, e-cigarette use, use of medicinal nicotine, and cessation-related behaviors. Current menthol smokers (N=240) will complete a 1-week baseline period before being assigned to either menthol or non-menthol cigarettes and either menthol or tobacco-flavored e-liquid for 7 weeks. To model a ban, smokers will be instructed to only use their assigned products, and adherence will be assessed using self-report and a urinary biomarker for menthol. Changes in tobacco use patterns (cigarettes smoked per day, e-cigarette use, ability to abstain from smoking) will be assessed through electronic daily diaries (Aim 1). Secondary outcomes include cigarette and e-cigarette subjective effects, and cigarette and e-cigarette dependence (Aim 2). To assess the ability to abstain from smoking, participants will complete a 1-week practice quit attempt in Week 7, and we will assess the time to first smoking lapse. Self-reported tobacco use is corroborated by biomarkers for smoke and nicotine exposure (expired carbon monoxide, urinary cotinine). Finally, it is critical to understand how menthol regulation will impact the entire population of US menthol smokers, as well as the effect on vulnerable groups where menthol smoking is concentrated. Thus, we will use advanced statistical techniques to assess whether any baseline demographic or smoking variables moderate the treatment effect. Then, we will calibrate the treatment effects to the US population of menthol smokers, and model the impact on smoking and vaping attributable deaths and life years lost (Aim 3). The strong investigative team, coupled with our success using the proposed methodology, enhances the probability of success in achieving our aims. This project will be the largest, most rigorous clinical trial to directly test the impact of menthol regulation for cigarettes and e-cigarettes on current menthol smokers.

NIH Research Projects · FY 2026 · 2023-05

Project Summary Stroke is one of the leading causes of long-term disability in the United States. Recovery from stroke-induced disability affects patients’ long-term quality of life. The goal of the proposed project is to unravel the circuit mechanisms underlying functional recovery after stroke. We will employ innovative approaches using state-of-the-art two-photon imaging techniques combined with optogenetic stimulation in mice. These approaches will allow us to monitor and manipulate the same neural circuits longitudinally. Through these novel approaches, we will test the hypothesis that different classes of neurons have different roles in stroke recovery. Our approach will provide the basis for identifying more effective interventions that promote stroke recovery through cell-type-specific manipulation.