Medical University Of South Carolina

NIH Research Projects · FY 2025 · 2021-08

Psychosocial traumatic events, and interpersonal violence experiences in particular, during childhood serve as strong and consistent predictors of substance use problems (SUP) during adolescence and adulthood. PTSD that extends from such IPV often co-occurs with SUP. Despite this well-established link, standard care for adolescents with co-occurring SUP and PTSD for the last several decades has been to treat these problems separately. This compartmentalized approach to treatment creates burden on teens and families, raises unique challenges to clinicians in both mental health and addiction domains, and may contribute to high rates of SUP relapse among adolescents with co-occurring PTSD. To address this problem, our team recently completed a rigorous NIDA-funded randomized controlled trial (RCT) supporting the efficacy of an integrative, exposure- based treatment we developed, Risk Reduction through Family Therapy (RRFT), in greater long term reductions in SUP, as well as PTSD avoidance and hyperarousal symptoms, in comparison to standard treatment in a large teen sample. The proposed RCT, with an effectiveness-implementation Hybrid Type I design, substantially builds on that prior research by proposing to: 1) evaluate whether RRFT's clinical effectiveness for reducing SUP and PTSD can be extended to youth in outpatient substance use treatment settings—where youth are presenting for SUP treatment and where clinicians often have less experience treating PTSD (Aim 1); 2) evaluate the cost- effectiveness of RRFT and to explore inner context variables (e.g., perceived treatment acceptability, attitudes, and satisfaction among the participating adolescents, caregivers, agency leaders, and therapists and barriers to and facilitators of implementation) that might affect RRFT implementation in diverse practice settings (Aim 2). The proposed effectiveness-implementation trial will recruit adolescents (13-18 years) with a history of IPV presenting with SUP and PTSD symptoms for outpatient substance use disorder treatment at sites in Denver, Colorado affiliated with NIDA's Clinical Trials Network. Participants will be urn randomized to RRFT or Treatment as Usual. A multi-method, multi-respondent approach will track clinical outcomes (SUP, PTSD, and putative targets of treatment, such as emotional suppression) at 3, 6, and 12 months post-baseline. To reduce the science-to-practice gap, as an Exploratory Aim, we will assemble and engage an Advisory Board of leaders from Colorado state departments (Offices of Behavioral Health and Criminal/Juvenile Justice for Colorado, which have committed to participate) and community mental health organizations that oversee policy and decision- making in selection and implementation of psychosocial treatments for high-risk adolescents, with the goal of building capacity for large scale (e.g., state-wide) uptake of evidence-interventions for teen SUP and PTSD, like RRFT, upon completion of the grant. This proposal is directly in line with NIDA's recent release of NOT-DA-20- 004, a Notice of Special Interest encouraging research on comorbid substance use, substance use disorders, and other psychiatric disorders.

NIH Research Projects · FY 2025 · 2021-08

One of the most common causes of treatment failure in T-cell leukemia is dissemination of malignant cells. The overarching goal of this proposal is to test whether inhibition of CDK6 kinase holds promise as an effective therapeutic strategy for treatment of T-cell leukemia dissemination. Cyclin D3/CDK6 is the major type of cyclin D/CDK in T-cell acute lymphoblastic leukemia (T-ALL), and kinase activity of CDK6 in T-ALL is dramatically enhanced as its inhibitor proteins are mutated in over 50% of T-ALL cases. Targeting CDK6 for T-ALL therapy is promising as it prevents leukemia cell proliferation and induces T- ALL apoptosis. It is not clear whether or how CDK6 regulates T-ALL dissemination. In this study, we will elucidate the novel regulatory mechanism of cyclin D3/CDK6 in T-cell leukemia dissemination. We obtained substantial preliminary evidence to show that CDK6 plays an important role in T-ALL dissemination by regulating nuclear translocation and phosphorylation of PFKP. We also found that CDK6-dependent nuclear enrichment of PFKP may have a prognostic impact in T-cell lymphoma/leukemia. In the proposed work, we will extend these findings. In Aim 1, we will examine how cyclin D3/CDK6 regulates PFKP nuclear translocation to promote leukemia invasion. In Aim 2, we will determine how CDK6 mediated PFKP phosphorylation increases CXCR4 and PD-L1 expression to enhance leukemia cell dissemination. In Aim 3, we will perform a translational study to test the prognostic value of nuclear PFKP in T-cell lymphoma/leukemia using an expanded clinically well-annotated cohort of T cell lymphoma/leukemia patients, and a pre-clinical study of the therapeutic effect of a CDK6 specific degrader on T-ALL mouse models. The expected overall impact of this proposal is that it may elucidate the molecular function of CDK6 in T-ALL dissemination, and it may lead to novel targeted therapeutic strategies based on CDK6 inhibition.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY/ABSTRACT: Olfactory dysfunction (OD) has been reported in more than 50% of older adults and is strongly associated with 5 year mortality. Unfortunately, a key weakness of prior research on OD in aging is that it comes primarily from broad population health surveys using limited screening tests for OD. The result is that currently there are no methods for organizing patients with OD in aging based on either disease site or mechanism. Various anatomic sites along the olfactory pathway may be involved in OD in aging, including the nasal cavity, olfactory neuroepithelium, olfactory nerves, cribriform plate, and central olfactory structures. At these anatomic sites, OD then likely occurs through distinct mechanisms that will be associated with unique olfactory-specific biomarkers. Although prior studies have been instrumental in demonstrating that OD is highly prevalent in older individuals, most were not designed to comprehensively evaluate the olfactory- specific measures that would allow classification into subtypes of OD. Our hypothesis is that patients with OD in aging can be grouped into clinically relevant phenotypes based on anatomic sites of dysfunction that will provide important mechanistic insights. Our long term objective is to develop better diagnostic protocols and personalized treatments for patients with OD in aging. However, in order to develop targeted treatments one must first be able to classify patients based on the underlying site of disease and likely mechanism. This hypothesis will be tested using the following Aims: 1) Establish reliable and clinically relevant phenotypes of OD in older adults, 2) Determine the impact of OD on health and quality of life (QOL) in older adults, and 3) Determine which baseline factors predict olfactory changes over time in older adults. The National Institute on Deafness and Other Communication Disorders has a stated its interest in this area, “as the population ages, (to) determine how many more people report…smell problems that affect quality of life.” This proposal will improve our understanding of clinical classifications, mechanisms, QOL impact and natural history of OD in older adults and lay the groundwork for future studies examining therapeutic options to prevent, delay the onset or treat OD in aging.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY Vulnerability to relapse remains a significant clinical hurdle in the treatment of addiction. Data from operant rodent models of addiction and relapse indicate that cocaine-conditioned cue exposure evokes a pronounced glutamate release in the nucleus accumbens core (NAcore). Cued glutamate release engages a cell type-specific transient synaptic potentiation in NAcore medium spiny neurons (MSNs), which does not occur during cued sucrose seeking. This transient synaptic potentiation consists of increased synaptic and structural plasticity in MSNs. Importantly, the magnitude of this plasticity positively correlates with relapse behavior. We posit that both the structural component (dendritic spine head expansion) and the synaptic component (increased insertion of glutamate receptors) of this plasticity are engaged by nitric oxide (NO); a gaseous transmitter produced by interneurons that express neuronal nitric oxide synthase (nNOS). Consistent with a role for these neurons in cued relapse, we have recently demonstrated that elevated NO release in the NAcore also occurs in parallel with glutamate release during cued cocaine seeking. The objectives of the proposed study are to reveal the inputs to the NAcore required for NO release during relapse, to determine which receptors on NAcore nNOS neurons regulate NO release and cued cocaine seeking, and to reveal how nNOS participates in the induction of the transient structural and synaptic plasticity in MSNs that drives cued cocaine seeking. In Aim 1, we will use chemogenetic inhibition of inputs to the NAcore while recording glutamate and NO release during cued cocaine seeking. We predict that inputs to the NAcore carrying discreet aspects of cue and contextual salience will differentially regulate NO release and cued relapse. In Aim 2, we will elucidate how glutamate and dopamine receptors, specifically expressed on NAcore nNOS interneurons, act in concert to regulate NO production and if they are required for cued cocaine seeking. To do this we will use transgenic mice that express Cre in nNOS neurons, Cre-dependent shRNA viral vectors, as well as cocaine self-administration and cued cocaine seeking trials. We predict that glutamate and dopamine receptor systems in nNOS neurons cooperatively regulate NO release and cued cocaine seeking. In Aim 3, we will determine if loss of nNOS in the NAcore will prevent cue- mediated synaptic and structural plasticity in MSNs. To do this we will use an shRNA vector to knockdown nNOS and concomitant viral labeling of D1 or D2 receptor expressing MSNs in the NAcore. This will be done using separate cohorts of D1-and D2-promoter driven Cre rats. In Aim 3, we will measure morphological and electrophysiological readouts synaptic plasticity induced by cues. We expect that loss of nNOS will prevent both forms of plasticity linked to relapse, predominantly in D1 MSNs. In conclusion, findings from these investigations will reveal the mechanistic aspects of how nNOS neurons translate cocaine cue exposure to relapse behavior. Accordingly, preventing this relapse signal transduction by preventing cued activation of nNOS neurons represents a potential therapeutic strategy to reduce drug craving and prevent relapse.

NIH Research Projects · FY 2025 · 2021-08

Overall – Abstract With Phase III COBRE support, the South Carolina Center in Oxidants, Redox Balance, and Stress Signaling (Redox COBRE) at the Medical University of South Carolina (MUSC) will complete its transition to long-term sustainability as a nationally competitive multidisciplinary research program in redox pathobiology. During Phases I and II, our Redox COBRE was successful in its efforts to (i) expand the critical mass of funded investigators at MUSC studying the causal role of redox pathways and metabolic dysfunction in a wide range of human pathologies (cancer, cardiovascular and neurodegenerative diseases, diabetes, gastrointestinal disorders and drug addiction) and (ii) develop advanced scientific core resources offering a broad range of capabilities for investigating the biologically significant effects of oxidative stress. Our current core membership comprises 44 senior and junior faculty members that have received more than $51 million in awards since the program’s inception. To date, the Redox COBRE has mentored a total of 20 target faculty (junior investigators + pilot project-supported PIs). Of these individuals, 10 have been promoted and 16 have been retained at our institution. As a group, these faculty members have published more than 250 peer-reviewed papers and secured 56 extramural grant awards (including 31 NIH grants (PI role) of which 16 are R01 awards and 8 are SBIR/STTR- supported start-ups). The major components of this Phase III proposal are: (1) an Administrative Core providing organizational, coordinating, fiscal and accountability functions; (2) an Analytical Redox Core delivering analytical biochemistry services for quantification of redox-sensitive molecule abundance and redox-based changes in cellular homeostasis; (3) a Proteomics Core that offers state-of-the-art mass spectrometry (MS) and MS-imaging capabilities; (4) a Cell & Molecular Redox Imaging Core that provides cell and tissue-based confocal, multiphoton and super-resolution microscopic imaging; and (5) a Pilot Projects Program (PPP) that fosters research endeavors utilizing Center resources and facilitates collaborations with Redox COBRE members. Towards our objective of becoming a stand-alone Center of Redox Biology and Signaling (abbreviated to “Redox Center”), we will build upon our substantial scientific and institutional achievements, to: (Aim 1) enhance the function and efficiencies of our scientific cores, achieving optimal positioning to serve Center thematic and translational goals and achieve/ maintain sustainability; (Aim 2) leverage the PPP to grow center membership and promote the importance of translational redox signaling research in the context of human disease; (Aim 3) develop the research portfolio and connections between the Redox COBRE and other IDeA programs to establish ourselves as a national presence coalescing various disciplines and areas of expertise. Thus, we are seeking to establish a strategic position for long-term success as an emergent, University- designated Redox Center that will be one of few national resources for investigators to utilize or develop new technologies, therapeutics and interventions targeting pathological redox pathways.

NIH Research Projects · FY 2025 · 2021-07

PROJECT SUMMARY: OVERALL The overall goal of this Program Project is to gain a better understanding of the underlying mechanisms that drive cachexia in cancer patients, especially patients with pancreatic ductal adenocarcinoma (PDAC) that exhibit one of the highest incidences of cachexia among all tumor types. Cancer patients who have lost > 5% of their pre-illness weight are considered cachectic. In comparison, 85% of PDAC patients lose an average of 14% body weight, and recent published data show that any loss of body weight > 10% in this population leads to poorer survival. Although some improvements have been made in PDAC to extend the 5-year survival rate, this is still among the lowest rate of all solid tumors. Thus, until therapeutics are found to effectively treat PDAC, understanding the causes of cachexia is vital to improving treatment responses, quality of life, and potentially overall survival. The main innovative concept in our Program Project is the belief that to effective treat PDAC-induced cachexia one must consider the macroenvironment of this syndrome, so as to treat the tumor and the wasting of peripheral tissues at the same time. The effectors we focus on in this Program Project are part of the NF-B/IL-6/STAT3 signaling axis. Our hypothesize is that the NF-B/IL-6/STAT3 signaling axis is a central regulator of the macroenvironment in PDAC-induced cachexia. This hypothesis will be tested in 3 Projects under the support of 4 Cores. Project 1 focuses on the IL-6/STAT3 portion of the NF- B/IL-6/STAT3 signaling axis. Specifically, studies will define the participation of IL-6 and the IL-6 receptor acting through STAT3 to mediate fat and muscle loss. Project 2 focuses on NF-B within the signaling axis, exploring two fresh concepts in how NF-B functions in muscle stem cells to promote local muscle inflammation and in PDAC progression by modulating the surveillance of innate and adaptive immune cells. Project 3 will explore the IL-6/STAT3 axis within stroma fibroblasts. Specifically, how STAT3 signaling in stromal mesenchymal cells in the tumor and peripheral tissues produces an immunosuppressive macroenvironment that favors PDAC progression and cancer cachexia. Core A (Administration) will provide administrative structure for the organization of the program. Core B (Human Biospecimens) will maintain a repository of tissues from PDAC patients with and without cachexia and support next generation sequencing analysis. Core C (Immunophenotyping) will provide expertise in scRNA-Seq and multispectral imaging of the tumor, skeletal muscle, and fat in PDAC-induced cachexia. Core D (Biostatistics) will provide biostatistical support. This Program contains multiple points of integration founded on collaborations between NCI designated Cancers Centers at the Medical University of South Carolina and Indiana University and their respective Cancer Cachexia Programs. The outcome obtained from these studies will advance our basic understanding of tumor-muscle/fat interactions within a PDAC macroenvironment that will likely apply to other cancer conditions where cachexia contributes to the morbidity and mortality of patients.

NIH Research Projects · FY 2026 · 2021-05

The Medical University of South Carolina (MUSC) Libraries will support the mission of the Network of the National Library of Medicine (NNLM) to advance the progress of medicine and improve the public’s health by ensuring broad access to biomedical and health information resources and data for U.S. researchers, health professionals, public health practitioners, educators, and the public. Located in Charleston, South Carolina, the MUSC Libraries serve as the Regional Medical Library (RML) for NNLM Region 2, encompassing Florida, Georgia, Mississippi, Alabama, South Carolina, Tennessee, the Commonwealth of Puerto Rico, and the U.S. Virgin Islands. Communities across Region 2 face persistent challenges related to health outcomes, poverty, natural disasters, and limited access to broadband internet, all of which affect individuals' and organizations' ability to access and use reliable health information. To address these challenges, the RML employs a multi-pronged approach to build and sustain strong, collaborative relationships with Network members using a variety of communication, training, engagement, funding, and service strategies. These efforts create multiple, flexible pathways for members to engage with Region 2, the NNLM Offices and Centers, and the broader mission of the National Library of Medicine (NLM). The RML leverages data and tools from a broad range of national organizations, including the National Area Health Education Center, BroadbandNow, the Centers for Disease Control and Prevention, the Health Resources and Services Administration, and the National Rural Health Association to support regional partners in addressing information access, workforce development, and regional health needs. Through these coordinated efforts, the RML seeks to strengthen the capacity of organizations across Region 2 to support informed decision-making, improve health outcomes, and improve access to trusted health information. The MUSC Libraries request $607,452, including indirect costs, for the period May 1, 2026, through April 30, 2027, to support the completion, evaluation, documentation, and transition of NNLM Region 2 activities.

NIH Research Projects · FY 2025 · 2021-05

Abstract: The alarming rates of obesity among children and adults, particularly among ethnic minorities, has been identified by the National Institutes of Health as one of the most serious public health challenges facing our nation in the 21st century. South Carolina (SC), part of the “Stroke Belt,” has the 3rd highest obesity rate among US children at 39.2% and the 12th highest obesity rate among US adults at 32.3%. Unfortunately, African Americans in SC are disproportionately more likely to be overweight or obese (75.7% of adults, 40% of children), which places them at considerable high-risk for obesity-related diseases such as asthma, Type 2 diabetes, cardiovascular disease, hypertension, stroke, and some forms of cancer. This public health challenge is compounded by the lack of available intervention strategies specially tailored to meet the unique needs of ethnic minorities. This R01 randomized clinical trial, informed by the results from a recently completed NHLBI/NICHD center grant (“FIT Families Project,” U01HL097889; PI-Naar) that followed the National Heart, Lung, and Blood Institute, Obesity Related Behavioral Intervention Trials (ORBIT) model for developing behavioral interventions, will examine the efficacy of FIT Families compared to a credible attention control condition. Each of four evidence-based behavioral components of FIT Families (home-based services, contingency management, motivational interviewing, cognitive behavioral skills training) were culturally tailored and optimized through a proof of concept sequential multiple randomized trial that produced weight loss among African American adolescents, a large and understudied population. One hundred and eighty obese African American adolescents aged 12-17 and their primary caregiver will be randomly assigned to one of two treatment conditions: 1) FIT Families or 2) Home-Based Family Support (HBFS) attention control condition. It is predicted that FIT Families will lead to greater reductions in adolescent and caregiver percent overweight, and increases in physical activity and the use of evidence-based weight management behaviors (self- monitoring of diet and exercise). If effective, FIT Families, which was carefully developed and adapted through successive Phases of ORBIT, has the potential to reduce disparities in obesity-related diseases (cardiovascular and metabolic) by addressing multiple risk factors among African American families and their adolescent children. Thus, this project has high significance in terms of potential public health impact and reduction in obesity related healthcare costs.

NIH Research Projects · FY 2025 · 2021-05

Varying perspectives that include those of psychologists are essential to maximize scientific rigor, innovation, and generalizability in alcohol research. Investigators from the field of psychology are vital in the conduct of interdisciplinary alcohol research and evidence-supported treatment provision, and integral to the dissemination and implementation of novel behavioral, pharmacological, and combined treatment approaches for alcohol use disorders. Thus, the primary objective of the proposed alcohol research training program is to increase engagement and retention of psychology trainees in alcohol research careers. The EDAR program is aligned with NIAAA’s longstanding mission to support research education and the NIAAA Strategic Plan for 2017-2021. The specific aims of the EDAR program are to: 1) attract psychology trainees into internship programs with robust alcohol research training opportunities by providing individualized mentoring from near-peers and senior experts in the alcohol field, structured didactics focused on professional development, and financial support, 2) retain psychology trainees in alcohol research careers by engaging them in NIAAA-supported T32 programs and providing them the skills to become near-peer mentors, 3) examine the effects of the program on research engagement and career trajectories following program completion, and 4) identify barriers and facilitators to engaging and retaining trainees in alcohol research. Each year, we will recruit and retain cohorts of six outstanding psychology graduate students during the summer before internship application. The proposed EDAR program will provide two years of formalized didactic training and individual mentorship including: personalized feedback on internship and postdoctoral fellowship application materials, interview skill development, and financial support to offset trainee application and interview expenses. Thorough program evaluation will occur with direction from an expert panel of federally-funded alcohol researchers and educators in our Advisory Council to refine and improve the program and provide innovative data on potential barriers and facilitators to alcohol research involvement for trainees. The highly qualified leadership team, strong partnerships with senior alcohol investigators leading NIAAA-supported T32/T35 training programs, and a team of exceptionally qualified and dedicated faculty mentors will ensure that the proposed alcohol research education program is implemented with a focus on rigor and sustainability within a vibrant educational setting.

NIH Research Projects · FY 2025 · 2021-04

PROJECT SUMMARY / ABSTRACT Abstract: Despite the vast and ever-growing scientific literature on the efficacy of behavior, social, and structural interventions, interpreting the scientific literature is challenging. Identifying relevant studies is time intensive. The quality of research from published reports requires careful analysis. There are conflicting findings across studies. Metrics and study designs used across studies are typically inconsistent. Pooling results across studies also requires advanced statistical techniques. The state-of-the-art strategy to address these challenges is to use systematic reviews and meta-analyses to analyze and interpret the effects of interventions evidenced with research across multiple studies. In the prposed study we will conduct systematic reviews and meta- analyses on studies from LMIC that focus on behavioral, social, or structural interventions. There are three key areas we will analyze: (1) interventions designed to support linkage, retention, and adherence to ART and PrEP with a focus on modes of service delivery; (2) interventions that integrate non-HIV health issues with HIV- specific health issues; and (3) assessing the impact of the COVID-19 epidemic on HIV-related care and prevention in LMIC. In addition, we will add to our rigorous data extraction information on both the theoretical basis of the interventions under consideration, as well as data on the implementation characteristics of each intervention. Data extraction on implementation characteristics and theory will also be done retrospectively for all 435 studies we have previously reviewed and added to our data repository.

NIH Research Projects · FY 2025 · 2021-04

PROJECT SUMMARY / ABSTRACT Following a stroke, deficits in independent mobility are a primary contributor to decreased quality of life, as many people with chronic stroke (PwCS) are prevented from returning to their prior levels of activity participation or involvement in the community. A major cause of mobility deficits is gait instability, which can increase the risk of falls and limit independent function. While several common rehabilitation methods (e.g. locomotor training, traditional balance training, strengthening) can improve some aspects of function, they have failed to address fall incidence among PwCS. In part, this lack of success is likely due to current interventions not being targeted toward the specific mechanisms causing post-stroke gait instability. A long-term goal of this research is to develop a toolbox of mechanism-based interventions to improve various aspects of post-stroke function. As a step toward this goal, the objective of the present proposal is to determine whether targeted perturbation training can reduce falls in PwCS by improving gait stability. While perturbation training has previously been used to reduce fall risk in other clinical populations, it has thus far been unsuccessful at doing so among PwCS. This lack of success may be due to the nature of the applied perturbations, which are traditionally designed to elicit discrete Reactive responses to avoid a loss of balance. In contrast, the present proposal will apply mechanical perturbations designed to elicit Proactive adjustments in the neuromechanical strategies used to ensure walking stability with every step. Such Proactive perturbations may be better suited to prevent the intrinsic movement errors that are a primary contributor to losses of balance and falls among PwCS. The central hypothesis of this work is that that unlike Reactive methods, Proactive perturbation training will retrain generalized gait stabilization strategies, reducing the risk of falls. This hypothesis will be addressed through three Specific Aims. The first Specific Aim is to determine whether fall rate in PwCS is reduced by Proactive or Reactive training, with immediate clinical implications for the development of interventions that can be applied in the real world. The second Specific Aim is to characterize the neuromechanical mechanisms that underlie gait changes with perturbation training, revealing whether the stabilization strategies normally used to ensure walking balance can be strengthened with appropriately targeted perturbations. Finally, the third Specific Aim is to determine whether Proactive or Reactive training produces generalized gait stabilization, as an ideal intervention would improve resilience even to untrained perturbations that may be experienced in real world walking. The proposed project is based on a neuromechanical framework of bipedal walking control, and thus allows investigation of both clinically relevant outcomes (fall rate) and mechanistic measures of the strategies used to ensure stability. The knowledge resulting from this project has the potential to contribute to the development of a larger-scale rehabilitation paradigm addressing the important problem of post-stroke falls.

NIH Research Projects · FY 2025 · 2021-04

PROJECT SUMMARY/ABSTRACT Alcohol and cannabis are the first and second most commonly used substances among adolescents. Adolescence is a period of considerable development, making the adolescent brain particularly vulnerable to negative effects of alcohol and cannabis use. Developing and testing interventions that target both alcohol and cannabis use during adolescence are vital to decreasing costly consequences. Biases in cognitive processing of drug-related stimuli play an important role in the development and maintenance of problematic substance use. The Approach-Avoidance Task (AAT) is a computerized program, effective in assessing implicit approach biases for both alcohol and cannabis, in which participants push or pull a joystick in response to an irrelevant feature of an image presented on a computer screen (e.g., push when in portrait, pull when in landscape). A modified version of the AAT (mAAT) is also used as a Cognitive Bias Modification (CBM) intervention, to retrain participants’ implicit biases toward or away from stimuli by presenting the target stimuli predominantly in one format (e.g., push or pull). Despite research demonstrating the effectiveness of mAAT interventions to reduce problematic alcohol and cannabis use, there is a dearth of research examining this intervention among adolescents. The proposed research will test a pilot randomized controlled trial of an integrated mAAT intervention to target co-occurring alcohol and cannabis use among treatment-seeking adolescents (N=52). Specific aims include to test the effect of the intervention on approach biases for cannabis/alcohol stimuli (Aim 1) and cannabis/alcohol use at 1- and 3-months post-intervention (Aim 2), and to examine the role of intentions and cravings as mediators in the relationship between treatment condition and use. The research environment, facilities, and resources at MUSC are ideally suited for mentored career development in addiction research. K23 training objectives are to: 1) increase knowledge of etiological and treatment mechanisms for cannabis use; 2) acquire essential knowledge and experience across the stages of clinical trial research among treatment-seeking adolescents with substance use problems, including incorporating EMA methods; 3) develop expertise in CBM; 4) gain experience incorporating EEG to identify change mechanisms in substance use interventions; and 5) enhance scientific communication and overall academic productivity. Structured mentorship from Drs. Carla Kmett Danielson, Lindsay Squeglia, Lisa McTeague, and Robert Miranda Jr. will ensure training goals are met. The candidate’s long-term career goal Is to direct a research portfolio that: 1) develops and tests innovative intervention approaches for substance use problems among adolescents and emerging adults; 2) delivers these innovative interventions in existing real-world settings; and 3) identifies change mechanisms within interventions using multiple units of analysis. The training proposed herein is designed to develop expertise across these areas, represents a clear progression from prior training and would not be possible without this K23.

NIH Research Projects · FY 2026 · 2021-03

With advances in antiretroviral therapy (ART), people living with HIV (PLWH) are living longer, are more likely to die from non-AIDS-related causes, and are less likely to die from AIDS-related complications. In fact, lung cancer is now the leading cause of cancer death among PLWH. Tobacco use is a major contributing factor to lung cancer incidence and mortality among PLWH since smoking rates among PLWH are approximately 40-50%. Indeed, this is more than double or triple the 15.5% rate of smoking in the general United States population. With several evidence-based tobacco treatment approaches at the patients' disposal, including pharmacotherapy and behavioral counseling, optimizing how those treatments are delivered to patients requires an empirical approach. Routine clinical care through the healthcare system may not be optimized to reach this patient population. Prior research has shown that proactive tobacco treatment increases the likelihood of treatment engagement and downstream cessation. Beyond the method for engaging in the initial contact session, prior studies have demonstrated that there are optimal ways for framing how the tobacco treatment is being provided. That is, presenting smoking cessation in an opt-out fashion results in increased patient reach and likelihood of abstinence. Despite the evidence in support of a proactive, opt-out method for smoking cessation intervention delivery, this strategy has not been evaluated in the context of tobacco treatment for PLWH. Further, because this approach can connect patients with available, evidence-based interventions that can be delivered remotely, it holds promise for implementation in the context of healthcare settings across the country. In the proposed study, we will conduct a type 1 hybrid effectiveness-implementation trial to evaluate the impact of a proactive, opt-out smoking cessation intervention on smoking cessation outcomes and advance understanding of key barriers and facilitators of implementation processes. We propose a comparison of Treatment As Usual [TAU; reactive, opt-in smoking cessation treatment delivered through Infectious Diseases clinical pathways] to Proactive Outreach with Medication Opt-out for Tobacco Treatment Engagement (PrOMOTE) and characterization of key determinants of PrOMOTE implementation outcomes. The intervention will consist of a tobacco treatment specialist proactively and remotely contacting a patient to assess smoking status, provide a brief motivational interview and counseling, and provide a mail-order prescription for varenicline (or dual NRT if indicated) in an opt-out fashion. This proposed study will examine this novel approach to optimizing delivery of smoking cessation care for PLWH. Integrating effectiveness and implementation results will help define best practices for engaging PLWH with existing evidence-based smoking cessation interventions. This hybrid effectiveness-implementation trial presents on opportunity to optimize tobacco treatment delivery, and identify barriers and facilitators towards future implementation and dissemination to ambulatory HIV clinics across the country.

NIH Research Projects · FY 2025 · 2021-03

PROJECT ABSTRACT The proposed K23 Mentored Patient-Oriented Research Career Development Award launches a line of work aiming to comprehensively target mechanisms of avoidance in anxiety and other disorders; and, it provides Dr. Christopher Sege with skills necessary to becoming a leading clinical researcher. Dr. Sege’s primary clinical research career goal is to use cutting-edge translational science to improve mental health care by targeting precise disorder mechanisms. Need for this research is significant and consistent with NIMH priorities and the RDoC framework. Avoidance is a core target of anxiety and related disorder treatment, but avoidant behaviors often persist after symptom reduction and keep many from engaging in treatment at all. Novel methods to target multiple motive drivers of avoidance early in treatment are needed to improve retention and outcome especially for the 20% of individuals who do not benefit from and 40% who do not complete treatment. Basic science provides critical clues as to the multiple mechanisms of real-world avoidance that may be indirectly or inadequately addressed by current treatment techniques. Crucial goals of work proposed here is to determine how these mechanisms drive clinical behavior and support subsequent work that develops direct intervention tools. The proposed project uses direct neurostimulation (repetitive transcranial magnetic stimulation; rTMS) in concert with precise experimental methods to test how specific reactive (escape) and proactive (avoidance) coping neurocircuits can be modulated to alter downstream fear and approach-avoid decision-making. Subsequent R-level applications build on this work to determine coping profiles of treatment completers versus non-completers, and to test how profiles can be more precisely targeted to improve outcomes. A team of expert mentors (George, Liu, McTeague, Mobbs, Uhde) will use their extensive knowledge in research-based and clinical neurostimulation, advanced fMRI analysis and research methods, and creation of translational science-informed treatment adjuvants to support Dr. Sege in his development. Mentorship, hands-on research tutorials, coursework, seminars/ workshops, and international conference attendance afforded by the K23 will ensure that Dr. Sege achieves his career goals to: 1) develop expertise in cutting-edge neurostimulation for research and clinical use, 2) develop expertise in fMRI analysis and research tools for use in concert with rTMS to more precisely target ecologically-relevant avoidance behavior, and; 3) develop expertise in creating adjuvants that improve cognitive behavior therapy outcomes through application of translational science. The proposed K23 will also foster development in areas of publication, grant writing, and inter-departmental collaboration, all at an institution – the Medical University of South Carolina – which has a strong track record and commitment to early stage investigators. Proposed K23 activities will prepare Dr. Sege to become a cutting-edge clinical researcher and a leader in the development of a precision medicine of psychiatry.

NIH Research Projects · FY 2025 · 2021-03

SUMMARY/ABSTRACT Substance use disorder (SUD) is associated with abnormalities in the dorsomedial prefrontal cortex (dmPFC), a brain region that is activated by drug-predictive cues and contributes to drug seeking. Recent studies show that non-overlapping cell populations within dmPFC, defined by gene expression or projection target, display unique activity profiles during reward seeking. Interestingly, even within these defined cell populations considerable cell- to-cell variability is found suggesting that greater resolution is needed to understand the influence of unique dmPFC neuronal ensembles on behavior. Overall, the influence of unique dmPFC neuronal ensemble activity patterns on drug seeking is unclear. Activity in the dmPFC is highly suppressed following persistent drug use in rodents and humans, in part due to the reduced function of channels that control the intrinsic excitability of dmPFC output neurons. Considering this suppressed excitability, it is surprising that the presentation of drug-associated cues can evoke robust activity in dmPFC of patients with SUD, with that activity being a reliable predictor of future relapse. Thus, a rapid shift in the excitability of dmPFC neurons likely occurs during drug-associated cue exposure, a change that may be controlled by the neuromodulator noradrenaline. In support of this idea, here I show that chemogenetic inhibition of locus coeruleus noradrenergic axons in dmPFC (LC dmPFC) abolishes cue-induced reinstatement of heroin seeking. Furthermore, I confirm that downstream dmPFC excitatory output neurons display bidirectional plasticity following heroin use, becoming hypoactive following heroin self-administration but recovering normal activity during cue-induced relapse. Considering these findings, here I investigate the hypotheses that noradrenergic LC dmPFC neurons become active during the presentation of drug-predictive cues (Aim 1), that noradrenergic activity in dmPFC is critical for cue-induced drug seeking and for amplifying activity in downstream dmPFC neuronal ensembles (Aim 2), and that activity in select dmPFC neuronal ensembles modulates cue-induced drug seeking behavior (Aim 3). Overall, these experiments will characterize the activity dynamics and function of precisely defined dmPFC circuit elements during cue-induced heroin seeking. Findings from these studies are critical for the development of strategies that could normalize dmPFC activity and reduce relapse vulnerability in patients suffering from SUD.

NIH Research Projects · FY 2025 · 2021-01

ABSTRACT Among pediatric brain tumors, medulloblastoma is the most common form. While most children with medulloblastoma can be cured, ~25% of these kids will die, and those that survive will live with severe long-term side effects as a result of the devastating effects of current therapies on the developing brain. In patients with medulloblastoma, prognosis depends heavily on the molecular makeup of the tumor. New genomic approaches have enabled to classify medulloblastoma into molecular subgroups, allowing physicians to better predict patient outcome and design treatment adequately. Among these subgroups, patients having alterations in the developmental pathway SONIC HEDGEHOG (SHH), along with mutations in the tumor suppressor gene P53 have a poor outcome. These tumors are resistant to therapy what results in rapid tumor relapse, which almost uniformly leads to patient death. Loss of P53 activity results in significant genomic instability and, consequently, large scale alterations in the signaling networks that drive cellular proliferation, survival, differentiation and/or stemness are created. Subsequently, a smaller number of these networks are selected for during the tumorigenic process and behave as tumor drivers. Here, I hypothesize that the growth of TRP53 mutant medulloblastoma will be abrogated by targeting this P53-specific set of signaling pathways. My previous work allowed me to identify two distinct drivers of these tumors, controlling independently tumor growth and propagation. The goal of this proposal is to understand how these identified tumor drivers control overall medulloblastoma viability, and to further validate them in murine and human derived TRP53 mutant SHH medulloblastoma models.

NIH Research Projects · FY 2024 · 2020-09

Specific Aims A major challenge for individuals suffering from substance use disorders (SUDs) is the lack of effective treatments that reduce relapse vulnerability. Drug predictive cues in the environment are powerful triggers for relapse and understanding how these persistent associations are formed and maintained is a critical focus of preclinical SUD research. In this proposal, we have built on our discovery that immediately after the end of cocaine self administration (SA), an infusion of brain-derived neurotrophic factor (BDNF) into the prelimbic (PL) prefrontal cortex prevents the cocaine SA-induced dephosphorylation of key glutamatergic-related plasticity- related proteins (PRPs), including GluN2A, GluN2B, ERK MAP kinase, and CREB32,96. This early intervention with BDNF also prevents prolonged cocaine-induced deficits in PL-NA core glutamatergic transmission that promote subsequent cocaine seeking9. In contrast, by the end of the first week of abstinence, protein kinase A (PKA)-dependent augmentation of GluA1 and CREB phosphorylation emerges. At that time, intra-PL BDNF has no effect on relapse8 but intra-PL infusion of a PKA inhibitor, Rp-cAMPs, reverses the hyperphosphorylation and decreases relapse70,92. More recently, we have shown that the biphasic changes in GluA1 and pCREB within the first week of abstinence are associated with similar biphasic changes in the head diameters (dH) of dendritic spines of PL–NA core neurons89. These data have spurred the overall hypothesis that interventions to decrease drug seeking must be tailored to the dynamic changes in neuroadaptations that emerge during different phases of the addiction cycle. In chemogenetic studies to investigate the contribution of specific pathways originating in PL cortex to drug seeking, we discovered that PL-NA core and PL-posterior paraventricular thalamic nucleus (pPVT) pathways oppose each others’ effects during early withdrawal. Selective cre-dependent DREADD inhibition of PL-NA core neurons infected with a retrogradely transported cre-AAV immediately after cocaine SA has no effect by itself, but reverses the suppressive effect of intra-PL BDNF on subsequent drug seeking31. In contrast, selective inhibition of the PL-pPVT pathway immediately after cocaine SA decreases subsequent cocaine- seeking, an effect that is prevented by intra-PL BDNF31. Interestingly, we also found that selective inhibition of the PL-pPVT pathway reduces anxiety-related behavior in rats withdrawing from cocaine and inactivation of pPVT decreases conditioned aversion to cocaine, suggesting that cocaine’s engagement of anxiety- and aversion-related circuitry that contributes to drug seeking includes pPVT. Taken together, our new findings suggest the novel hypothesis that cocaine SA produces differential regulation of PL-NA core and PL-pPVT pathways and that these two distinct circuits conspire to support future drug seeking. In this proposal, we will use pathway-specific, combinatorial chemogenetic approaches, slice electrophysiology, and state-of-the-art dendritic spine and PRP imaging in PL-NA core and PL-pPVT circuitry to explore the time-dependent plasticity occurring in this network that influences cocaine seeking and aversion. We will use these approaches in the following aims that will be performed in male and female rats. Aim 1. BDNF regulation of PRPs and structural and synaptic plasticity in PL-NA core vs. PL-pPVT neurons during early withdrawal. Using viral vector approaches, we will investigate the effects of intra-PL BDNF infusion on (A) dendritic spine plasticity and PRP changes and (B) synaptic plasticity in PL-NA core vs. PL-PVT neurons during early withdrawal. Aim 2. PKA regulation of PRPs and structural and synaptic plasticity in PL-NA core vs. PL-pPVT neurons after 7 and 30 days of abstinence. (A) We will investigate the effects of inhibiting cAMP/PKA signaling on (A) dendritic spine plasticity and PRP changes and (B) synaptic plasticity in PL-NA core vs. PL- PVT neurons after 7 or 30 days of abstinence with or without relapse testing. Aim 3. The role of PL-NA core and PL-pPVT neurons in cocaine-induced anxiety and aversion in relationship to cocaine seeking after abstinence. We will use a retro-Gi DREADD approach to test the effects of inhibiting PL-NA core or PL-pPVT neurons (A) on withdrawal-induced anxiety immediately after the end of cocaine SA and (B) on conditioned avoidance of cocaine in an operant runway task before or after cocaine SA followed by cue-induced relapse testing. Scientific Impact: These studies will expand our understanding of how to reverse critical neuroadaptations underlying prefrontal dysfunctions during different phases of the addiction cycle that trigger relapse to drug- seeking. By understanding temporally dynamic, differential neuroadaptations in the PL networks regulating reward and aversion, we may be able to discover novel therapeutic targets to decrease drug-seeking.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) frequently co-occur and are associated with significant morbidity, mortality, and health care expenditures. Military Veterans are at increased risk for co- occurring AUD and PTSD, with prevalence rates 2-4 times higher than the general population. Our group developed an integrated intervention entitled Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure (COPE). COPE incorporates empirically validated cognitive-behavioral techniques for AUD with Prolonged Exposure (PE) therapy for PTSD. Several randomized controlled trials among Veterans and civilians demonstrate efficacy of COPE in significantly reducing AUD and PTSD symptoms. Despite the positive findings, there remains substantial room for improving treatment outcomes and enhancing retention. Accumulating data suggest that the neuropeptide oxytocin (OT) is a promising candidate to enhance psychosocial interventions for co-occurring AUD and PTSD, as OT targets neurobiological and behavioral dysregulation common to both disorders. Preclinical and clinical studies demonstrate the ability of OT to ameliorate a variety of alcohol-related behaviors (e.g., craving, withdrawal symptoms, tolerance, ethanol self- administration), enhance fear extinction, and promote prosocial behaviors associated with successful psychosocial treatment outcomes (e.g., trust, social cognition). In a randomized controlled pilot study, our group found that OT administration prior to weekly PE therapy sessions was safe, well-tolerated, and resulted in accelerated reduction in PTSD symptoms as compared to placebo. Although the empirical and theoretical support for augmenting psychosocial interventions such as COPE with OT is robust, no studies to date have examined this combined approach. The primary objective of the proposed Stage II study is to examine the efficacy of OT as compared to placebo in reducing (1) alcohol use, and (2) PTSD symptoms among Veterans receiving COPE therapy. To accomplish this, we will employ a manualized, evidence-based, cognitive-behavioral intervention (COPE); a randomized, double-blind, placebo-controlled study design; standardized, repeated dependent measures of clinical outcomes at multiple time points; and we will leverage close collaboration with well-established VA clinics prepared to efficiently translate positive findings into practice. In addition, to evaluate purported neurobiological mechanisms of change, we will employ functional magnetic resonance imaging (fMRI) at pre- and post-treatment and examine AUD biomarkers. The proposed study directly addresses the mission of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) in that it aims to identify pharmacologic treatments to address co-occurring AUD and PTSD simultaneously. The findings from this study will provide new information and mechanistic insights to directly inform clinical practice and accelerate the research in this highly understudied area.

NIH Research Projects · FY 2024 · 2020-09

A growing multidisciplinary evidence critically underpins that Porphyromonas gingivalis, a leading pathobiont of the oral cavity that successfully remodels oral microbial communities to a pathophysiological state, can live in concert with human gingival epithelial cells (GECs). Epithelial cells are emerged as an integrally important arm of innate defenses in the oral mucosa, while recent observations suggest that these cells can be exploited as privileged growth niches and a reservoir by P. gingivalis, which can intracellularly multiply and remain largely unharmed in GECs. Despite, extensive systems level molecular knowledge exists on the P. gingivalis and GEC interaction, there is considerably little known on the intracellular life of the organism in this central cell type. We recently revealed that formation of autophagosomes is critical for the P. gingivalis' intracellular replication and evasion of the anti-microbial degradation pathways in the GECs. Our novel preliminary findings also support that lipidation of LC3-C, a key molecule in the `selective autophagy' pathway, which targets intracellular pathogens is significantly modulated by P. gingivalis under the control of an anti-stress molecule, HSP27. Further, glutathione peroxidase (GpX1), a major host redox balance enzyme and a regulator of autophagic flux largely impacted on the global LC3 lipidation state of GECs upon infection. The inhibition of either HSP27 or GpX1 appears to severely affect the intracellular trafficking and viability of the microorganism. The central hypothesis is that P. gingivalis induces a distinct form of selective autophagy, which results in protection of bacterial life and ultimately securing of P. gingivalis' persistence in the oral mucosa. To test this novel hypothesis, we will pursue two-pronged approach, where we propose the selective autophagy requires tightly coordinated actions of HSP27 and GpX1 to form autophagosomes that fully function as protected replicative niches for P. gingivalis. Aim 1 will define the selective molecular machinery that drives P. gingivalis-containing autophagosome assembly under the control of HSP27 and the mechanisms that disrupt autophagic flux for the evasion of cellular degradation pathways. Aim 2 will establish the role of GpX1 in regulating the selective autophagy in infection via redox homeostasis and suppressing autophagolysosomal machinery. Both aims will employ reductionist primary GECs culture systems to functionally dissect out the mechanisms and phenotypically characterize the molecular events and sub-cellular components. Aim 3 will establish the dual significance of these two components using oral epithelial-tissue-specific knockout mice models. Thus, this proposal aims to fill a significant gap in our fundamental knowledge that is how P. gingivalis, a facultatively intracellular pathogen, establishes a privileged cellular environment and converts nutritionally rich epithelial cells into potentially a central reservoir for bacterial growth and persistence in the oral mucosa. Ultimately, the knowledge gained may translate into molecular strategies that can control or reduce the intracellular colonization and survival methods employed by this important opportunistic pathogen.

NIH Research Projects · FY 2024 · 2020-09

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive neoplasms derived from the Schwann cell lineage that occur commonly in patients with neurofibromatosis type 1 (NF1) as well as sporadically in the general population. The prognosis for patients with an MPNST is grim, as current radio- and chemo- therapeutic regimens are ineffective. Ras hyperactivation, which results from loss of functional NF1, typically in combination with other tumor suppressor mutations (CDKN2A, TP53, or SUZ12), is characteristic of MPNSTs. This suggests that inhibiting Ras signaling would be an effective means of treating MPNSTs. However, Ras has proven to be difficult to directly target therapeutically and drugs targeting Ras effector pathways have not been effective in patients with MPNSTs. This led us to investigate the effectiveness of therapeutically targeting key upstream activators of Ras, such as receptor tyrosine kinases (RTKs) in MPNSTs. We examined the role of all 58 RTKs in sporadic and NF1-associated MPNST cell lines using both pharmacologic and genome-scale shRNA screens coupled with comprehensive genomic analyses. Our RTK-based pharmacologic screens established that the broad-spectrum ERBB inhibitor canertinib and the IGF1 receptor (IGF1R) inhibitor picropodophyllin effectively inhibited MPNST growth and Ras activation. In keeping with these results, our genome-scale shRNA screens established ERBB3 and IGF1R as essential for the growth of MPNST cells. Based on these findings, we hypothesize that MPNST growth in vivo is dependent on the action of ERBB3 and IGF1R and that therapeutic regimens simultaneously targeting these key RTKs will effectively treat MPNSTs. We will rigorously test this hypothesis in three Specific Aims. In Specific Aim 1, we will test the hypothesis that combinatorial therapies targeting ERBB receptors and IGF1R will effectively inhibit MPNST xenograft growth in vivo. We will also determine if other RTKs are reproducibly activated to promote resistance to ERBB and IGF1R inhibitors and tumor recurrence. In Specific Aim 2, we will test the in vivo role of ERBB3 in tumor initiation and drug sensitivity using xenografts and a genetically engineered mouse model (GEMM). In Specific Aim 3, we will test the hypothesis that drug relapse is mediated by “secondary” RTKs that compensate for ERBB and IGF1R inhibition to drive key cytoplasmic signaling pathways. This experimental plan will thus allow us to logically develop effective therapies for a currently untreatable type of sarcoma. As NF1 mutations and Ras hyperactivation are increasingly recognized in other sporadic tumor types, our approach has broader application to many other types of human cancers.!

NIH Research Projects · FY 2024 · 2020-09

ABSTRACT The overall objective of the proposed Mentored Patient-Oriented Research Career Development Award (K23) is to support Dr. Christine Hahn in acquiring the skills necessary to become an independent investigator with a program of research focused on the development of interventions for alcohol use disorder (AUD) and comorbid mental health conditions, in particular posttraumatic stress disorder (PTSD). AUD and PTSD frequently co-occur among people who experience traumatic life events, such as sexual assault. There is a lack of established evidence-based interventions, however, to reduce AUD and PTSD among recent victims. The proposed study directly addresses this clinical gap by testing the novel integration of two, evidence-based, cognitive-behavioral interventions for AUD and PTSD to be delivered in five sessions beginning in the six weeks following sexual assault. In Phase 1, we will adapt the intervention using an iterative process informed by expert feedback. In Phase 2, we will conduct an open label trial (n = 10) to finalize the treatment protocol. In Phase 3, we will use the treatment protocol in a pilot randomized controlled trial among 54 recent sexual assault victims to evaluate feasibility and preliminary efficacy in reducing AUD severity and PTSD symptoms. Ecological momentary assessments (EMA) will be used to assess alcohol use, craving, and affect during the five-week treatment phase. The candidate has assembled a team of experienced mentors with expertise in AUD, PTSD, sexual assault, psychotherapy development, clinical trials, and ecological momentary assessment. On-site mentors (Drs. Sudie Back, Kathleen Brady, Michael Saladin) have extensive knowledge in developing and conducting clinical trials of behavioral and pharmacological interventions for co-occurring AUD and PTSD. Dr. Saladin has expertise in real-time data collection methods in addiction research. Off-site mentors (Dr. Barbara Rothbaum at Emory University and Dr. Brian Marx at Boston University) will provide additional guidance on early, brief interventions to reduce AUD and PTSD symptoms following sexual assault. The mentorship, formal coursework, seminars, and national conference attendance afforded by the K23 award will ensure that the candidate achieves the following career goals: (1) Gain new knowledge in AUD mechanisms and interventions; (2) Develop skills in designing and implementing clinical trials for AUD and co-occurring PTSD; (3) Increase statistical skills with multilevel and longitudinal data analyses; (4) Enhance understanding of research ethics; and (5) Continue professional development through manuscript writing, professional presentations, and grant writing. The candidate will complete the proposed K23 activities at the Medical University of South Carolina, which has a strong track record of commitment to the advancement of early stage AUD investigators. The proposed K23 activities will ultimately prepare Dr. Hahn to lead a program of rigorously-designed AUD treatment outcome research.

NIH Research Projects · FY 2024 · 2020-08

This Mentored Research Scientist Development Award (K01) application supports the career development and additional advanced technical training of Dr. Paula Zamudio-Bulcock to facilitate her transition to an independent academic investigator in the alcohol research field. She has extensive experience in ex-vivo slice electrophysiology, and during the mentoring period will gain experience with animal models of alcohol consumption and dependence. In addition, during the course of the proposed studies she will learn highly relevant techniques in the addiction research field including super-resolution confocal microscopy and epigenetic research methods. Importantly, Dr. Zamudio-Bulcock will also use the K01 protected training time to sharpen her career skills with a strong focus on manuscript preparation and submission, grantsmanship training and development of mentoring skills. Dr. Zamudio-Bulcock’s training will be supported by a strong institutional commitment to her career development and an outstanding and multifaceted mentoring team of leaders in the alcohol research field, each providing expert guidance throughout the progress of the proposed studies. The research plan evolved from Dr. Zamudio-Bulcock’s long standing interest in alcohol effects on the cerebellum and her experience studying the effects of acute and developmental alcohol exposures on cerebellar physiology. Thus, it is clearly distinguishable from the research focus of her mentor’s laboratory. Studies from the mentor and co-mentors have characterized functional, structural and epigenetic alterations after chronic alcohol exposure in brain regions implicated in alcohol consumption and dependence. Dr. Zamudio-Bulcock’s proposal will apply the methodologies used by her mentors to evaluate chronic alcohol–induced alterations in the cerebellum which, despite being highly sensitive to alcohol, has been understudied in the context of chronic alcohol use and dependence. The aims in this proposal have been tailored to test the hypothesis that chronic alcohol exposure leads to functional, structural and epigenetic alterations in the sole output of the cerebellar cortex, the GABAergic Purkinje cell. Importantly, the cerebellar cortex has been recently found to be a heterogeneous brain region with marked molecular, functional and structural differences among cerebellar lobules. Such differences are postulated to support the ample diversity of behavioral functions the cerebellum provides neuronal computation for. Given the functional connectivity of the posterior cerebellum with higher- order brain regions known to be affected in alcohol-dependent mice, the effects of chronic alcohol exposure will be studied in a sub-lobular specific manner with a focus on posterior lobules that are inter-connected with midbrain and cortical areas involved in reward and decision making. The opportunity to carry out these studies and engage in comprehensive career development training activities will provide a solid foundation for the candidate’s path to independence in the alcohol research field.

NIH Research Projects · FY 2024 · 2020-08

Project Summary: Post-stroke hand impairment is prevalent, persistent, and difficult to treat, with negative impact on functional ability and independence. One way to improve treatment efficacy is to augment therapy with peripheral sensory stimulation. While promising, most modalities of sensory stimulation interfere with natural hand tasks. Thus they are administered prior to therapy, requiring additional time commitment and hindering patient adherence and implementation. Further, effects diminish after stimulation, weakening its potency during therapy. To address limitations of existing sensory stimulation and fully leverage the therapeutic benefits of sensory stimulation, a novel sensory stimulation `TheraBracelet' has been developed: A wristwatch applies imperceptible vibration during task practice to stimulate the sensorimotor cortex neurons for coherent firing during hand tasks, leading to enhanced neural communication and hand function recovery. The objective of this project is to determine if combining TheraBracelet with hand task practice is superior to hand task practice alone in an adequately powered study. The study design is a double-blinded randomized controlled trial. Chronic stroke survivors will undergo a standardized hand task-practice therapy program (3 days/week for 6 weeks) with the TheraBracelet device worn on the paretic wrist. The device will deliver vibration for the treatment group and no vibration for the control group. Double blinding is possible because the treatment vibration is imperceptible. Evaluation will be performed at baseline, 2, 4, and 6 weeks of therapy, and 1 month after. Aim 1: To determine clinical potential of TheraBracelet in improving hand functional recovery. Hypothesis: Improvement of hand motor function will be greater for the treatment than control. Hand function will be assessed using the Wolf Motor Function, Box and Block, and Action Research Arm Tests, along with the quantity/quality of the upper limb use in daily living, abilities for daily activities, and participant feedback. Aim 2: To determine the effects of TheraBracelet on sensorimotor grip control and neural communication. Hypothesis: The treatment will enhance sensorimotor grip control and neural communication for hand grip compared with control. Sensorimotor grip control will be assessed using the well-established biomechanical measure of digit force directional control and efficient scaling of grip force during grip-and-lift. Neural communication for hand grip will be quantified as increase in EEG coherence in the cortical sensorimotor network for grip compared to rest. Secondary analyses will include characterizing the time course of effects and responder analysis. Impact: This research will determine clinical utility and biomarkers of this novel stimulation to guide potential translation. This research is translational as this stimulation is implemented in an aesthetically appealing smartwatch, does not interfere with hand motion, and can be easily integrated in clinical practice. Enhancing hand function should substantially increase stroke survivors' independence and quality of life, and reduce caregiver burden.

NIH Research Projects · FY 2024 · 2020-07

Abstract: Smoking is the leading risk factor for preventable morbidity and mortality, and smoking cessation remains the primary goal for population-based tobacco and cancer control. Many smokers lack resources to initiate and sustain a successful quit attempt. For the last decade we have been testing innovative approaches for delivery of pharmacotherapies that allow smokers to try evidence-based cessation medications and self- determine their goals and pace for cessation. Medication sampling is a brief, concrete, and easily understood exercise that often induces attitudinal shifts in favor of quitting smoking, and more importantly promotes quit attempts and actual cessation. Medication sampling is also favored by healthcare providers, augmenting their brief advice as per clinical guidelines. We have conducted three trials of nicotine replacement therapy (NRT) sampling (N=157, 849, 1245), all of which were remote, and some of which have been applied within medical settings. Each trial demonstrated increases in cessation behavior. Our prior work on NRT sampling creates a compelling question as to whether varenicline sampling would have similar, or potentially better, effects. Varenicline is inarguably the most effective single cessation medication available, superior to other monotherapy options. As a prescription medication, whether varenicline is suitable for sampling is unclear but worth testing empirically. On one hand, unstructured use, over a brief time, may not deliver sufficient pharmacologic benefit. Prescription delivery incurs its own barriers to widespread dissemination (which can be overcome). On the other hand, much like NRT sampling, it could provide a tangible cue to action that provides psychological engagement (motivation, confidence, autonomy) to sustain subsequent use and ultimately enhance cessation. A trial of varenicline sampling is not merely a routine extension of NRT trials, yet the significance is even more compelling given evidence of its unique benefits. We therefore propose a randomized clinical trial with primary aims to determine the 1) use, 2) consequences (on cessation), and 3) mechanisms of varenicline sampling. A demographically diverse sample of 648 smokers will be recruited across South Carolina and randomized (2:1:1) to receive I) a 4-week sample of varenicline, II) a 4-week supply of NRT, or III) nothing. Thus, our design is strengthened by both active and inactive comparison groups. Outcomes will be assessed through 6 months of follow-up. We employ innovations in mobile health technologies throughout to enhance methodological rigor, including remote biological verification of smoking behavior. If varenicline sampling were to show promise through this and future trials, this would offer great dissemination appeal to physicians, quitlines, etc in that, much like our NRT work, varenicline sampling could be a pragmatic strategy to engage more smokers in better treatments, sooner. Ultimately, the population impact of medication/varenicline sampling could be profound, offering a significant and measurable opportunity to lessen the impact of tobacco on public health and to reduce the risk, incidence and mortality of cancer.

NIH Research Projects · FY 2024 · 2020-07

PROJECT SUMMARY There is a high incidence of tobacco use among patients with cancer. Many are unable to quit smoking before surgery, and relapse rates are high among those who are able to abstain after the initial cancer diagnosis. Tobacco use is linked to serious complications with treatment, including increased problems with wound healing after surgery. Contingency management, a behavioral intervention in which abstinence is reinforced (typically with monetary incentives), has shown promise as an intervention for smoking. In our preliminary work, we designed a contingency management protocol for pre-surgical cancer patients. A pilot study was conducted to generate an effect size for smoking cessation at the time of surgery (7-day point prevalence abstinence), and a secondary aim of creating an effect size for long-term abstinence at 3 months post-surgery. Patients (N=40) were randomized to receive either: Standard Care + Monitoring (SC; i.e., 3-6 counseling sessions + nicotine replacement therapy [NRT] + monitoring breath CO 3 times per week with no contingencies; N=19) or CM (i.e., 3-6 counseling sessions + NRT + monetary payment delivered contingent on a negative breath CO; N=21). In the CM group 52% (11/21) of the patients were abstinent for 7 days prior to surgery compared to 16% (3/19) of the patients in SC (adjusted RR=3.3, CI: 1.1-9.7, p=0.03). At the 3-month follow-up, 43% (9/21) of CM patients remained abstinent compared to 5% (1/19) in the SC group (adjusted RR=8.6, CI: 1.5-49.4, p=0.02). For the present study, we propose a powered, large scale (N=282) smoking cessation clinical trial to test a CM intervention for cancer patients. The intervention will mirror our prior work, focusing on patients who are undergoing surgery for their cancer. No studies have evaluated a CM intervention with smokers who have a life-threatening illness. However, our pilot data with pre-surgical cancer patients who smoke has shown that this may be a promising intervention with cancer patients. We hypothesize that this highly effective treatment, by promoting high rates of smoking cessation, will also be associated with better surgical outcomes. Interventions for smoking cessation prior to cancer surgery are understudied and a valuable tool in promoting improved surgical outcomes.