Wake Forest University Health Sciences

NIH Research Projects · FY 2026 · 2025-02

SUMMARY Tumor associated carbohydrate antigens (TACAs) are aberrant glycosylation products that are expressed on cancer cells but absent on most normal cells. Their expression is typically associated with metastasis, poor prognosis, and reduced overall survival. Our understanding of the mechanisms regulating antibody responses to TACAs is very limited. To overcome the limitations associated with studying the rare B cells that give rise to these responses, we generated a mouse in which the rearranged heavy chain variable region from a tumor glycan-reactive antibody was knocked into the endogenous heavy chain locus. We propose to characterize this mouse model by determining the potential for transgenic B cells to carry out antibody-dependent versus antibody-independent effector mechanisms in the productive anti-tumor response (Aim 1) and identify conditions which stimulate transgenic B cells to undergo isotype switching and differentiation to plasma cells (Aim 2). The findings emanating from these studies are expected to reveal novel strategies to harness the anti-tumor potential of B cells with specificities for cancer-expressed glycans.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY These is a growing population of lung cancer survivors (LCS) in the United States, estimated at nearly 655,000, many of whom experience disproportionate symptom burden compared to other cancer survivors. Among LCS, bothersome symptoms such as insomnia, fatigue, pain, anxiety, depression, and respiratory issues (e.g., dyspnea, cough) frequently co-occur. Insomnia is a top patient-rated concern and a leading risk factor for impaired quality of life endorsed by 50-80% of LCS. Cognitive Behavioral Therapy for Insomnia (CBT-I), the gold standard insomnia treatment, is safe and highly effective for cancer survivors in a variety of formats, and it has a high potential to improve insomnia and co-occurring symptoms among LCS. Despite the promise of CBT-I, it has not been adequately tested for LCS, a high need population that is often difficult to reach with supportive care interventions due to numerous barriers (e.g., diminished physical health, respiratory comorbidities, stigma). Attention to the unique needs of LCS through stakeholder engagement to refine CBT-I content and delivery will enhance its potential impact and facilitate implementation of CBT-I across care settings and clinically complex populations. Through multidisciplinary stakeholder engagement, the goal of this NCI Early K99/R00 is to refine (Aim 1) and test (Aims 2 & 3) CBT-I delivery and components for insomnia and related symptoms in LCS. The K99 phase of this project aims to: 1) conduct stakeholder interviews (N=20 LCS, N=10 clinicians) and convene an Intervention Development Advisory Board to refine CBT-I for the specific needs of LCS to enhance its feasibility and acceptability. The R00 phase aims to: 2) conduct a 2-arm pilot feasibility trial with N=30 LCS to determine the feasibility and acceptability of refined CBT-I for LCS with insomnia; and 3) measure key patient-reported outcomes (e.g., insomnia, fatigue, pain, anxiety, depression, dyspnea, cough) and objective measures (e.g., circadian and sleep health, pulmonary function) for a future randomized efficacy trial. To complete these research aims, the candidate (Dr. Sarah Price) requires mentored didactic and experiential training in 4 key areas: 1) psychosocial intervention development and optimization; 2) community and stakeholder engagement; 3) subjective and objective assessment of cancer-related symptoms; and 4) professional development. Dr. Price will receive training in these areas from her excellent mentoring team with the requisite expertise (Drs. Kathryn Weaver, W. Jeffrey Petty, Oxana Palesh, and Emily Dressler). This K99/R00 award will provide Dr. Price with essential training and pilot data to support a subsequent R01 grant proposal to conduct a large-scale multiphase optimization strategy (MOST) trial to identify an optimized treatment package to address insomnia and related symptoms. She will be well-equipped to reach her long- term goal to become an independent cancer control investigator with expertise in developing efficient symptom management interventions.

NIH Research Projects · FY 2026 · 2025-01

Football has a high risk of concussion and incidence of subconcussive head impacts which have long-lasting negative effects on brain health. With roughly 3.5 million athletes participating in youth football each year, there is a critical need to reduce head impact exposure and concussion risk. Over an entire season, most of an athlete’s head impact exposure is attributed to practice. Coach-directed activities (e.g., practice drills) influence the frequency and severity of head impact exposure. Practices are amenable to intervention; however, youth football leagues are often community-run organizations with limited resources, making implementation and enforcement of injury prevention strategies a challenge. Thus, engaging community members is essential for successful development, implementation, and sustenance of interventions. We partnered with a community stakeholder group to co-design and implement an evidence-based intervention program: COmmunities Aligned to reduce Concussion and Head impact exposure (COACH). COACH seeks to improve knowledge and skills of youth football coaches in effective practice planning that incorporates safe drills and to change attitudes and beliefs toward contact in practice. COACH has been pilot tested in two teams and shown to be acceptable and feasible. A critical next step of this research is the pragmatic evaluation of the effectiveness of COACH on a larger scale, while identifying factors that influence implementation. This proposal addresses this critical next step by determining the capacity of youth football organizations to adopt COACH and by testing COACH’s effectiveness while monitoring the implementation process. In Aim 1, we will engage youth football organizations in a mixed methods evaluation of capacity to adopt COACH. Semi-structured focus groups with coaches and parents, and interviews with organizational leaders from a diverse sample of youth football organizations will be conducted. We will measure organizational needs, capacity, culture, and readiness to adopt COACH. Data will be used to inform ways to strategically adapt COACH prior to implementation using a community-engaged approach. In Aim 2, we will use a stepped-wedge design to test the effectiveness of COACH at reducing head impact exposure in practices and adverse neurobehavioral health outcomes. Over four years, athletes enrolled across six organizations will be recruited to participate in parallel biomechanical data collection with an instrumented mouthguard to evaluate the effectiveness of COACH at reducing head impact exposure. A sub-sample of athletes will complete pre- and post-season neurobehavioral health and cognitive assessments. Head impact exposure and changes in neurobehavioral health outcomes will be compared across the control and intervention teams. In Aim 3, we will evaluate implementation outcomes via on-field video and field notes. We will also conduct a mixed methods assessment of contextual factors that influence adaptation. Successful completion of this project will help us achieve our goal of increasing access to a safe and effective practice environment and change the paradigm of safety for young athletes.

NIH Research Projects · FY 2024 · 2024-12

The eye is 10 times more susceptible to exposure to vesicants than other organs. The aftermath of these exposures and their impacts on human vision are easy to underestimate since many ocular symptoms may manifest long after exposure. Thus, it has been documented that the survivors of a vesicant attack during the Iraq–Iran War not only experienced corneal damage in the first 30 h after the attack but also manifested diminished scotopic and photopic electroretinogram responses 40 years later. In addition, delayed symptoms in these individuals also included central retinal vein occlusion and an increase of soluble VEGF-A in their tears. Currently, there is no effective antidote to combat vesicant-induced ocular damage and vision loss in humans. Therefore, our long-term goal is to generate effective medical countermeasures to mitigate the consequences of such exposures. This goal will not be achievable unless we increase our molecular understanding of the underlying mechanism responsible for the ocular damage and progressive ocular injuries caused by vesicant exposure. Therefore, in this proposal, we analyze direct ocular exposure (DOE) to vesicants to identify the molecular signaling driving the acute and chronic stages of corneal, vascular, and retinal pathobiology. Focusing on the unfolded protein response (UPR)-TRIB3 downstream signaling, we hypothesize that, upon DOE, not only the corneal tissue but also other ocular tissues, such as vascular and retinal tissues, are damaged, and depending on the severity, vesicant exposure activates UPR-TRIB3 signaling in the cornea, which further propagates the VEGF signal, causing blood vessel dysfunction and retinal injury. To dissect the mechanistic link between direct ocular exposure and pathophysiology, we propose a diverse spectrum of step-by-step strategies and a broad arsenal of tools. These tools include different animal models (mice and tree shrews), corneal and retinal ex vivo tissue, corneal and retinal cultured cells, two different toxicants (lewisite and nitrogen mustard), and genetic ablation of TRIB3 in the corneal, vascular, and retinal tissue to block the TRIB3-VEGF signal and delay the onset of ocular injuries. The latter will be confirmed in experiments with vesicant-exposed animals treated with a small-molecule inhibitor VEGF-Trap-Eye. Therefore, in Aim #1, we propose to investigate whether DOE to vesicants activates the UPR-TRIB3-VEGF axis, acting as a molecular driver of corneal tissue injury. We will demonstrate the molecular consequences of corneal-originated TRIB3-VEGF axis activation. In Aim #2, we intend to determine whether secreted corneal TRIB3-mediated VEGF signal drives vascular pathogenesis by assessing corneal neovascularization (NV) and retinal blood vessel disruption. In Aim #3, we plan to investigate whether secreted cornea- and vascular-mediated VEGF drives the pathophysiology of retinal injury through the activation of UPR-TRIB3. These studies will identify a novel and highly interesting molecular mechanism by which the activated UPR-TRIB3-VEGF axis acts as a molecular driver of ocular tissue pathobiology and will establish a groundwork for future mechanistic studies of ocular toxicity in exposed populations.

NIH Research Projects · FY 2026 · 2024-12

Project Summary While chemotherapy is the standard of care treatment for many cancer patients, a common side effect, chemotherapy-induced peripheral neuropathy (CIPN), is the leading cause of treatment discontinuation or dose reduction. This severe adverse event typically presents in the hands and feet as sensations of weakness, pain, burning, numbness, or tingling. Oxaliplatin is known to induce the highest incidence of neurotoxicity compared to other chemotherapies. Chronic oxaliplatin-induced peripheral neuropathy (OIPN) affects about 70% of oxaliplatin-treated patients, and its major symptoms last for months or years after treatment termination. Slow spontaneous recovery may occur in some patients, but lingering symptoms often result in permanent nerve damage. Little is known about mechanisms whereby oxaliplatin induces nerve damage, resulting in OIPN. The dorsal root ganglia (DRG) sensory nerve fibers extend to the periphery of the body and are known to interact with immune cells. Neuro-immune interactions are increasingly recognized in the pathobiology of CIPN, and several different types of immune cells have been implicated in the development of CIPN. However, CIPN studies have predominately investigated neuro-immune interactions at the DRG level; the peripheral neuro-immune interactions in the skin (specifically surrounding the hands and feet where CIPN most frequently presents) have been largely overlooked. To date, there is no comprehensive assessment of these skin neuro-immune interactions in the context of CIPN. Further, most current CIPN animal models test chemotherapeutic agents alone without cancer inoculation and effects of cancer on CIPN development are also overlooked. The objective of this proposed study is to bridge this research gap and characterize the neuro-immune interactions in the skin of tumor-bearing mice that have OIPN. Our specific aims are to (i) define how the cutaneous immune landscape is activated by tumor and repeated oxaliplatin and (ii) determine the mechanisms of cutaneous neuro-immune interactions mediated by tumor and repeated oxaliplatin. Using a tumor-bearing chronic OIPN mouse model, we will (i) define the cutaneous immune landscape using single cell RNA sequencing; (ii) determine how nerve and immune cells interact with one another in skin using immunohistochemistry; and (iii) explore the roles of cutaneous inflammation/immune cell component in OIPN development using proteomic analysis. Using an in vitro DRG culture system, we will address the effects of cancer-associated immune cells on the susceptibility of DRG neurons to oxaliplatin. This exploratory R21 proposal will (i) be the first to rigorously characterize cutaneous neuro-immune interactions in the tumor bearing and the chronic OIPN setting, (ii) provide robust data essential to establish a more specific hypothesis which lays the foundation for a future large-scale grant, and (iii) ultimately improve oxaliplatin-treated cancer patients’ quality of life.

NIH Research Projects · FY 2024 · 2024-12

PROJECT SUMMARY/ABSTRACT Motorsports drivers have an inherent risk of injury due to racing at high speeds and risk of collisions. Pilot studies have shown stock car drivers and grassroots dirt racing drivers are exposed to low magnitude head acceleration events during green flag racing. At the grassroots level of dirt racing, another pilot study showed that drivers can experience medium to high magnitude head accelerations during crashes within a short time period, unlike stock car crashes. Recent studies have shown exposure to subconcussive head impacts, or head impacts that do not result in clinically diagnosed concussion, can result in microstructural and functional changes to the brain in contact and collision sports. However, there is a paucity of research examining brain injury biomechanics and neurological effects of crashes in motorsport. Additionally, there are numerous disparities in the implementation of safety interventions between the grassroots level and professional levels of motorsport, such as the requirement of head and neck restraints. As a result, there are significantly more injuries and deaths reported for drivers participating in grassroots dirt racing than there are at the highest professional levels of motorsport. By identifying factors influencing kinematic loads and tissue-level brain response of a crash and evaluating acute clinical outcomes of drivers post-crash, future safety interventions could be made to target the disparities seen at the grassroots level. The objective of this study is to use an instrumented mouthpiece sensor to measure head impact exposure in drivers participating in a grassroots dirt racing crashes to identify potential factors that influence kinematic loads and tissue-level brain response and evaluate the neurological effects of crashes. The study team identified in this proposal has extensive history in quantifying head impact exposure, finite element modeling for evaluation of tissue response, and assessing clinical outcomes. A well-developed research and mentoring plan has been prepared fro the successful completion of the following aims. In Aim 1, factors that influence kinematic loads will be identified by outfitting drivers with custom mouthpiece sensors. We will quantify peak head kinematic metrics and compute kinematic-based head injury risk. Relationships between metrics and potential factors will be evaluated. In Aim 2, we will use the mouthpiece sensor data as inputs to an anatomically accurate finite element brain model to assess the tissue-level biomechanical response of the brain to head impact events during crashes. We will quantify various strain and stress-based injury metrics and examine their relationship with the potential factors that were evaluated in Aim 1. Finally, in Aim 3, we will evaluate the effect of crashes on changes in acute clinical outcomes. This study will provide accurate characterization of head motion experienced by drivers during crashes while dirt racing at the grassroots level, identify factors influencing kinematic loads and injury risk, and evaluate neurocognitive and neuromotor changes after a crash. The results from this research can inform sanctioning body safety standards and track safety regulations and injury diagnoses.

NIH Research Projects · FY 2026 · 2024-12

The US is facing a maternal and infant health crisis. Food insecurity (FI) affects 30% of pregnancies and is a significant contributor to the health crisis. FI leads to worse health in pregnant women and their children, including an increased risk of gestational diabetes, pre-term birth, and future cardiometabolic chronic conditions. Interventions used to address FI in clinical care settings include 1) referring patients to the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) or providing food via 2) produce vouchers and 3) medically tailored meals. Although there is evidence for each, patients differ in the support they need to reduce FI. Rather than using a single FI intervention, adaptively allocating interventions could be a more effective and efficient approach to improve food security for the large, vulnerable population of pregnant patients with FI. Our long-term goal is to develop an effective adaptive intervention that health systems can use to address FI and improve metabolic health in pregnant patients and their children. The objectives of this pilot study are to determine 1) the feasibility of recruitment and retention and 2) the potential effectiveness of the interventions in anticipation of a large, definitive Sequential Multiple Assignment Randomized Trial (SMART). SMART uses experimental design principles to build optimal adaptive interventions. In this pilot study, pregnant patients with FI will be randomized to 1 of 2 first-stage FI interventions: 1) an electronic health record (EHR)-based WIC referral or 2) EHR WIC referral + care navigation. Participants who do not have an improvement in FI will be re-randomized to 1 of 2 second-stage interventions: 1) produce vouchers or 2) medically-tailored meals. In Aim 1, we will determine the feasibility of recruitment and which first-stage intervention is potentially more effective in reducing FI. In Aim 2, we will evaluate the feasibility of re-randomization, data collection, and retention and assess which FI intervention may be the best next step for those who do not respond to the initial intervention. In Aim 3, we will explore heterogeneity in response to the first and second stage interventions by conducting semi-structured interviews with participants. The proposal complements NIDDK’s priority to “understand the impact of metabolic dysfunction on the intrauterine environment and subsequent metabolic health of mothers and offspring.” This study is the first to evaluate an adaptive FI intervention in pregnant patients. Given health systems’ focus of integrating FI interventions in clinical practice, an efficacious adaptive intervention could be broadly disseminated. Adaptive interventions can reduce the burden and costs for patients and providers by providing no more treatment than is needed for patients who respond to a less intensive approach and redirecting the saved resources to those who need a more intensive approach. Our team of established investigators has successfully used the methods proposed and has the full support of the health system where the study will occur.

NIH Research Projects · FY 2026 · 2024-11

My goal is to establish myself as an independent biomedical researcher in brain aging and Alzheimer’s disease (AD) and AD related dementias (ADRD). My passion to build a career in aging stems from my profound desire to help older people to maintain their functionality and quality of life. AD/ADRD are particularly interesting to me due their complex heterogeneous nature and my enthusiasm to work on complex health problems. The Wake Forest School of Medicine provides an exceptional environment to build a career in this field as it’s a nationally recognized leader in geriatric research with multiple NIH-funded P30 centers (P30AG072947 ADRC and P30 Pepper OAIC) focused on aging process and age-related disorders. The K25 Mentored Career Development Award will provide a unique opportunity for me to build a rigorous foundation in this new direction by leveraging the didactic research and training opportunities offered by this environment. I have briefly described my research and training objectives for this award. Research. The most common form of neuropathology in older adults is mixed cerebral small vessel disease and AD pathologies. Despite this, we have major gaps in our practical understanding of small vessel disease contribution to cognitive dysfunction and decline. Specifically, the impacts of small vessel disease on brain networks are largely unknown. In my K25 application, by focusing on cerebral microbleeds (CMB), as common manifestations of small vessel disease, I seek to address this critical gap. My specific aims are to: 1) utilize advanced brain network modeling to uncover and quantify network resilience/disruption from CMB, 2) use an integrative machine learning model with novel brain network biomarkers of CMB to improve predicting cognitive impairment, and 3) develop and deploy software packages to disseminate the developed methods that enable researchers to ask similar questions with other biomarkers of neuropathology and verify findings of this study. My proposed research can provide novel tools and insights to enable a translational shift in our practical understanding of mechanistic impacts of CMB on the brain to allow incorporating them into current diagnostic and treatment frameworks. Training. My specific training objectives for the protected time provided by this award are to: 1) establish knowledge of healthy and abnormal aging within the context of AD/ADRD, 2) gain expertise in the vascular contributions to AD/ADRD, 3) acquire in-depth knowledge about imaging biomarkers of small vessel disease, and 4) improve collaborative research, networking, and grant writing skills. I will be guided by an outstanding team of multidisciplinary clinicians and scholars in aging and AD/ADRD, neuroscience, and statistics to accomplish these objectives through attending courses, conferences, seminars, workshops, and shadowing geriatric clinicians and neuroradiologists. The preliminary work from this study will open opportunities to study the effect of small vessel disease and other age-related pathology on brain health and risk for AD/ADRD and preclinical results for future R01 submissions.

NIH Research Projects · FY 2025 · 2024-09

Well-Child visits (WCV) are an opportunity to maximize the health, development, and future well-being of children. Scheduled but not attended (“no-showed”) visits can lead to negative health and economic consequences for patients and families (delayed preventive care including screening and immunizations, and avoidable ED visits and hospitalizations) and for the healthcare system (decreased efficiency and productivity, lower quality measures, productivity, and revenue loss). Though adherence to the recommended WCV schedule has improved for the U.S. population over time, disparities persist. Children who are less adherent to the WCV schedule are more often identified to be Black or African American, as Hispanic or Latino, or whose families are lower-income and may be uninsured or publicly-insured. There is a need to identify high impact, cost-effective approaches to engage families who have missed WCV, especially among these populations. Health systems increasingly utilize text messaging technology or personnel such as community health workers (CHWs) to interact with patients or caregivers, and both approaches indicate positive effects. Indeed, pilot work from this research team comparing text message follow-up only to usual care suggested that sending text messages contributed to greater completion of a WCV within six weeks of no-show for some families, but that there is a need to look at patterns over a full year to eliminate seasonal variation. CHWs are most typically engaged following provider referral, hospitalization, or recurring ED utilization, and so there is a need to explore deploying CHW resources more proactively through outreach following a missed visit. No-shows may reflect barriers to care such as lack of transportation or competing priorities like food insecurity, which CHWs are well-positioned to address, thus through a relational approach CHWs may help promote improved engagement in preventive care for families. In turn, economic evaluation of technological and relational follow-up combined with trial data about which strategy(ies) works for whom can help inform resource allocation. The aims of this exploratory study are to: (1) demonstrate feasibility of merging a new referral protocol into existing resources for CHW outreach following WCV no-show; (2) compare WCV attendance following no-show between families who receive care-as-usual, text message (low-touch), and CHW outreach (high-touch) interventions, using a year-long randomized controlled trial; and (3) define costs and cost-effectiveness of using a low-touch or high-touch intervention to improve WCV attendance compared to care-as-usual. The study will reach a demographically varied, urban population, in English and Spanish. Findings from the proposed study will help inform a future, larger scale trial that expands into rural areas and other health system markets, tests tailored strategies for no-show follow-up, and incorporates advanced economic simulation methods to consider implications of applying such strategies to even larger populations, all with the long-term goal of reducing disparities in pediatric preventive care.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Low-dose computed tomography (LDCT) screening reduces lung cancer mortality. However, screening rates remain low in the United States. Existing lung cancer screening guidelines—such as those issued by the U.S. Preventive Services Task Force (USPSTF) and the American Cancer Society (ACS)—base eligibility primarily on age and smoking history. Alternative strategies, such as risk prediction models (e.g., PLCOm2012), incorporate additional clinical risk factors and may improve the identification of individuals at elevated risk for lung cancer. This project will evaluate the cost-effectiveness and population health outcomes of three real-world screening strategies: USPSTF guidelines, ACS guidelines, and the PLCOm2012 model-based approach. The study will use an enhanced cost-effectiveness framework to assess how each strategy performs across clinically relevant subgroups, including variations in age, smoking history, and other health indicators. Aim 1 will compare the relative cost-effectiveness of each strategy under real-world implementation conditions. Aim 2 will examine trade-offs between maximizing population-level benefits and optimizing resource allocation. Aim 3 will develop a decision-support tool to aid policymakers and healthcare administrators in selecting effective screening approaches across different population segments. This project will inform the development of practical, evidence-based screening policies to improve lung cancer detection and outcomes in the U.S. adult population.

NIH Research Projects · FY 2025 · 2024-09

The IMPACT PAD Trial DCC Project Summary This U24 application from the Wake Forest University School of Medicine (WFUSM) describes plans by expe- rienced investigators and staff to serve as the data coordinating center (DCC) for the IMProving mobility After revasCularizaTion in Peripheral Artery Disease: the IMPACT PAD Trial (IMPACT PAD), a 2 × 2 factorial N=386 trial. We will build on our successes in dozens of large, long-term trials and epidemiologic studies. Our DCC experience will help ensure success in the implementation of this trial by overseeing all data related aspects of the trial. We have a single specific aim: to provide project coordination, administration, data management, and biostatistical support for the IMPACT PAD Trial. We will accomplish this by facilitating and guiding the protocol development process, providing scientifically sound study design, excellent operational and analytical methodology, a dedicated focus on recruitment, high quality follow-up and fidelity to the interventions, moni- toring safety and working with the DSMB to ensure participant safety and careful study management, working with the CCC to monitor the seven field centers, and by leading development and maintenance of the protocols, manual of procedures (MOP), forms and other study documents. We believe that this trial will have nearly all the complexities of large multi-center studies, particularly for the DCC in standardization across sites. We have several strengths: (1) a team whose members are experts in the coordination of multi-center trials, including several that are ongoing, (2) experience with peripheral artery disease (PAD) trials including the on- going PROVE trial, (3) experience with exercise trials working with the intervention proposed in this trial and nutraceuticals, (4) specific project management expertise, (5) a history of efficient and effective communication with field centers, the executive committee, and the project office, and (6) success working with Dr. McDermott (of the CCC) on three prior studies (LIFE, ENRGISE, and PROVE). WFUSM views clinical trial conduct and coordination as a scientific undertaking, which advances through continuous evaluation and innovation. While web-based randomized controlled trials (RCTs) have been con- ducted for over two decades, we continue to develop new and innovative strategies for integrating web-based technology into daily trial activities and incorporating other methods of electronic data capture into trial man- agement. We coordinated ACCORD, which was the first large-scale RCT coordinated primarily over the web. The ACCORD system has evolved into the Database for Efficient Administration of Clinical trial OperatioNs (DEACON) system for web-based trial management which we use for all of our studies. We are constantly in- venting and evaluating new features to add to the DEACON framework. The highly experienced and talented team at WFUSM will create a state-of-the-art DCC for the IMPACT PAD trial using proven coordinating center models. Personnel will be available from day 1 and have long-standing working relationships across multiple NIH-funded studies.

NIH Research Projects · FY 2025 · 2024-09

Home-based medical care (HBMC) is essential for the growing population of community-living persons with Alzheimer's Disease and Related Dementias (ADRD). People living with ADRD (PLWD) often also have multiple chronic conditions that necessitate complex care regimens, but as functional impairment worsens, PLWD may struggle to leave home to access medical care. HBMC then becomes instrumental in enabling continuity of patient care, tailoring medical management to evolving patient needs and risks and mitigating the caregiving burden. HBMC is provided by physicians and advanced practice providers and has long been covered by public (Fee for Service) Medicare. Due to its limited availability, there are likely many more people who may benefit from HBMC than there are persons who receive HBMC. Two changes in the Medicare landscape over the last decade may significantly alter access to and outcomes from HBMC for PLWD: rapid enrollment and switch to private (Medicare Advantage) plans and the swift expansion of telemedicine use since early 2020. Our study aims to examine HBMC use among PLWD with private and public Medicare, its change following the expansion of telemedicine, and its overall impact on patient outcomes and disparities. While the rationale for HBMC is compelling, evidence of its impact on PLWD is scant. Evidence of differences in healthcare utilization patterns between private and public Medicare enrollees is recent and evolving, particularly for PLWD, with virtually no prior work on patterns of HBMC use. HBMC providers can combine home visits with telemedicine services and expand the scale and range of services. The extent to which these have occurred in public and private Medicare is unclear. Using national Medicare administrative data (2017-2023) covering public and private Medicare enrollees with PLWD, we propose to fill the significant evidence gaps by identifying the national trends in HBMC and telemedicine use and rigorously evaluating their potential impact on the management and outcomes for community living PLWD. Our main outcomes will be indicators of treatment for ADRD, deprescribing long-term medications, acute care complications, proportion of days at home, transition to long-term care and hospice, death, and healthcare spending. Using quasi-experimental models of causal inference, we will estimate the potential impact of HBMC (before and after the expansion of telemedicine) and telemedicine, separately in public and private Medicare. We will estimate the impact across subgroups by sex, race, ethnicity, dual Medicaid eligibility, multiple chronic conditions and, provider quality performance. PLWD have complex medical needs with high mobility and transportation barriers, and HBMC and telemedicine may be vital avenues to facilitate better care continuity, alleviate patient and caregiver burden, and improve patient outcomes. Our findings aim to develop rigorous, generalizable, and policy-oriented evidence on the potential impact of HBMC and telemedicine for PLWD.

NIH Research Projects · FY 2025 · 2024-09

As we work to build addiction data science literacy, the field of addiction research could benefit from an increased workforce with clinical and data fluency. The complexities of addiction as a clinical domain present challenges, including the intersection of mental health and chronic pain. Understanding how these factors influence data collection, oftentimes due to subjective reporting, differential health outcomes, and longstanding challenges to care, can impact data analytics and interpretation. Moreover, the separation between clinical experts and data expertise can create additional barriers to advancing addiction research. Aligning addiction knowledge with data science expertise could enhance the potential of emerging addiction researchers. Another impediment to progress is limited representation of addiction researchers with dual data and clinical proficiency in the workforce, which could be attributed in part to a lack of awareness of the field during training (undergraduate to postgraduate). As we look to analyze larger and more heterogeneous addiction datasets, a global concern is the risk of algorithmic bias. Developing training for a broad workforce that understands challenges at the intersection of addiction medicine and data science will accelerate our understanding of addiction's complexity. The long-term goal of this Workforce Innovation in Data Science, Education, and Addiction Research (WISER) R25 application is to support the training of a broader workforce by building an addiction data science short course and scalable educational content with a focus on addiction data analytics through a comprehensive lens. The overall objective of this proposal is to provide a curated research framework and resources to support emerging investigators with varied data science addiction approaches. Our central hypothesis involves developing an addiction data science training program that will expand the research capacity of trainees and emerging investigators. We will achieve the goals of this proposal through the following aims: Aim 1: Develop and refine immersive, tailored addiction data science skills course that provides hands-on demonstrations, tutorials, and presentations on FAIR (Findable, Accessible, Interoperable, Reusable) data principles, computational analytical methods (AI and ML), systems modeling, natural language processing, and analysis and linking of addiction big data. Aim 2: Incorporate novel methods of program evaluation and dissemination using natural language processing to track participant outcomes and career pathways. At the successful completion of the proposed research, the expected outcome is a scalable and widely disseminated education intervention for addiction data science with enduring content to support emerging researchers removing many of the barriers to traditional pathways (e.g., asynchronous conceptual and project-based content that will be evergreen). This innovative research will make curated and refined addiction data science content freely available to educators from undergraduate to postgraduate training levels. This will provide a strong basis for the conceptual foundation needed to begin addiction data science research, without sustained effort from a limited pool of addiction data science expertise. This research aligns with the mission of NIH NIDA to train a broad workforce to perform addiction data science research at the highest quality levels.

NIH Research Projects · FY 2025 · 2024-09

Population-wide genomic screening (PGS) for Hereditary Breast and Ovarian Cancer Syndrome, Lynch Syndrome, and Familial Hypercholesterolemia offers great promise in identifying the 1-2% of the population that unknowingly carries a pathogenic variant that puts them at elevated risk for serious, yet preventable disease. Rapidly decreasing sequencing costs, endorsement of PGS by national bodies, and attention to precision medicine applications have rapidly accelerated the spread of PGS programs. To date, no clear guidelines or implementation strategies exist to support the rapid growth of PGS. Contextual factors, including program-level procedures, organizational structure, and characteristics of the patient population, influence implementation of these large-scale PGS initiatives. To help facilitate growth of PGS programs and enhance recruitment and retention of representative populations into genomic initiatives, we propose to identify best practices for PGS implementation and develop and test a freely available, online multicomponent implementation guide (FOCUS toolkit). This project will establish a gold standard approach for integrating PGS and offer the field generalizable methods and knowledge about PGS implementation. Specifically, using a stakeholder-engaged Implementation Mapping approach we will: 1) conduct a qualitative needs assessment among ten PGS programs (FOCUS design sites) at various implementation stages (emerging, implementing, sustaining) guided by the Consolidated Framework for Implementation Research, 2) develop and produce the FOCUS toolkit consisting of implementation strategies, materials, and protocols, and 3) evaluate the impact of the FOCUS toolkit on Reach, Effectiveness, Implementation, Adoption, Maintenance outcomes for PGS in 12 PGS sites (FOCUS test sites) using a stepped wedge cluster randomized trial design. All aspects of this project will be conducted by an exceptional investigative team and supported by a ten-person Implementation Mapping Advisory Panel consisting of representatives from public health and regulatory agencies, communities and patient groups, and clinical stakeholders. These findings will: 1) provide a standardized approach and evaluation framework for programs seeking to strategically implement and expand population-based approaches for identifying individuals and families at high risk of serious, yet preventable disease, 2) provide generalizable methods and knowledge about PGS, and 3) support efforts to bring the promise of precision health to all.

NIH Research Projects · FY 2025 · 2024-09

. Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Kidney-risk variants (KRVs) in the apolipoprotein L1 gene (APOL1) are present only in African-derived populations, including African Americans. More than 30% of cases of end-stage kidney disease (ESKD) in African Americans are attributable to these variants. APOL1 KRVs also contribute to the more rapid failure of transplanted kidneys from African American deceased donors. However, only ~20% of those with APOL1 high-risk genotypes develop ESKD, and only a similar portion of transplanted kidneys from deceased donors with APOL1 high-risk genotypes fail rapidly. Hence, modifiers (inherited or environmental second hits) likely impact development of kidney disease in individuals and donors with APOL1 high-risk genotypes. The APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is an NIH-funded national prospective study of donor and recipient APOL1 genotype effects on transplantation outcomes. To optimize allocation of kidneys from deceased African American donors with APOL1 high-risk genotypes, we propose an ancillary study focused on critical questions not addressed in APOLLO. These include identification of APOL1 gene expression profiles in donor kidneys and factors modifying effects of APOL1 high-risk genotypes. The primary goal of this application is to reveal a clinically actionable approach to identify which kidneys are truly “high risk” among deceased donors with APOL1 high-risk genotypes. We, and others, reported that overexpression of APOL1 KRV proteins induces cellular toxicity. Moreover, APOL1 KRVs cause cytotoxicity in a dose-dependent fashion. We propose to prospectively assess correlations between APOL1 protein abundance in kidney tissue and the main APOLLO study primary and secondary outcomes (i.e., time to allograft failure, long-term kidney function and proteinuria) – using kidney tissue from African American deceased donors studied at the time of transplantation. In addition, we will perform APOL1 mRNA (transcript) and global RNA sequencing analyses in kidneys to link transcripts in pathways that act in concert with APOL1 for associations with transplant outcomes. We will also perform single cell RNA sequencing to verify cell-specific genetic components that regulate APOL1 expression. Our state-of-the-art trans-omics approach integrates kidney-specific genetic and transcriptomic data and will infer component contributions to kidney transplant outcomes from African American deceased donors while accounting for recipient APOL1 genotype. Among donors with APOL1 high-risk genotypes, we hypothesize that kidneys with higher levels of APOL1 KRV proteins at implantation will fail more rapidly, whereas those with lower levels will function longer, similar to donor kidneys with APOL1 low-risk genotypes. These results could lead to a rapid testing panel to optimize and transform kidney allocation of deceased donors with APOL1 high-risk genotypes. This work has the potential to shift current paradigms to optimize renal allograft survival, reduce the discard of good-quality kidneys, and increase numbers of kidney transplants, a critical need for patients with ESKD.

NIH Research Projects · FY 2025 · 2024-09

Project Summary This proposal is prepared in response to PAR-23-041, which supports projects that functionally validate and/or characterize genes or variants implicated in substance use disorder (SUD). We propose to illuminate the roles of several transcript variants of rat Drd3 gene, encoding dopamine D3 receptor (D3R), in the regulation of cocaine-seeking and taking behavior. The D3R has long been implicated in SUD and has recently become an attractive target of pharmacotherapy of SUD. Although a few reported splice variants of Drd3 gene appear to be conserved across species between human and rodents, their functions, especially in the context of SUD, have not been explored previously. We have confirmed the expression of a few Drd3 transcript variants and identified a new variant in rat ventral tegmental area (VTA) and nucleus accumbens (NAc), two brain regions critically involved in drug reward. Some variants are expressed in a striking sex- and region-specific manner and importantly, some are sensitive to cocaine self-administration (SA). Built on these novel observations, we will in the R21 phase: a) characterize the function of each Drd3 variant using the heterologous expression system; and b) develop and validate neuron type-specific AAV tools to express Drd3 variants that are sex- specific and cocaine-sensitive. In the R33 phase, we will use the developed AAV tools to determine a) if sex- specific Drd3 variants contribute to sex-dependent cocaine-seeking and taking behavior; b) if cocaine-sensitive Drd3 variants regulate cocaine-seeking and taking behavior; and c) if overexpression of Drd3 variants influences D3R function and dopamine (DA) transmission.

NIH Research Projects · FY 2025 · 2024-09

Clinic-based hypertension care falls short in achieving blood pressure control, particularly for patients with hypertension and high social needs or social risk factors. Sporadic clinic visits do not support adequate time to improve patients’ skills in hypertension self-care or provide reliable and adequate blood pressure values to clinicians to support therapeutic decisions. Telemedicine management of hypertension (TM-HTN) is a team-based approach that overcomes many of the challenges of clinic-based care by offering more time for self-management support and better diagnostic accuracy by leveraging multiple home blood pressure values to support clinicians’ confidence in titrating medications. In a meta-analysis of US-based clinical trials, we found that TM-HTN improved blood pressure by 7.3/2.7 mmHg, compared with usual clinic-based care. However, the effect was significantly diminished in trials that enrolled patients with high social needs or social risk factors (4.4/1.1 mmHg), likely because TM-HTN is not tailored for these patients. Creating a contextually responsive TM-HTN intervention for patients with high social needs or social risk factors and the clinics they attend has the potential to control hypertension in this population who suffer the highest burden and disparity in hypertension control. Our Specific Aims are to: 1) Evaluate barriers and facilitators to TM-HTN use among patients with high social needs or social risk factors, healthcare providers, and health system leaders; 2) Refine TM-HTN intervention for these patients using a Human-Centered Design approach and identify suitable implementation strategies; and 3) Assess feasibility of TM-HTN intervention in a pilot randomized controlled trial. Evaluating the feasibility of the intervention that is responsive to the patient, provider, and system-level contextual factors has the promise to improve blood pressure in patients with high social needs or social risk factors and will help to launch the candidate’s independent patient-oriented research career in cardiovascular disease prevention among vulnerable populations. The candidate has dedicated his professional life to becoming a physician-scientist, studying cardiovascular prevention, epidemiology, and outcomes research. He has accepted a faculty position at the Wake Forest University School of Medicine, where a supportive research environment in the Department of Internal Medicine has made his career advancement and approach to independence possible. To accomplish the goals of the proposed research, he has assembled an experienced mentoring team with unique yet complementary expertise in qualitative and mixed methods, implementation science and clinical trials to guide his career development. The candidate will undertake formal training in these areas to complement his prior medical, graduate, and postgraduate training to transition to independence.

NIH Research Projects · FY 2025 · 2024-09

People with HIV (PWH) who use stimulants experience profound intersectional stigma and discrimination that can cause considerable psychosocial stress. An overactive, unresolved stress response fuels systemic inflammation, which may be a common pathway linking psychosocial stressors to complex neuropathology in HIV. Chronic stress can disrupt central nervous system functions that regulate reward processing. Our team and others have shown that these pathophysiologic alterations are amplified by stimulant use and potentiate neuropsychiatric symptoms. However, the inflammatory mechanisms through which stress affects brain networks that subserve substance use and psychiatric multi-morbidity in HIV remain unknown. The overarching goal of this proposal is to identify neuroimmune mechanisms that underlie the intersection of social stigma, anhedonia, and altered reward processing in PWH who use stimulants (e.g., cocaine, methamphetamine). Embracing the experimental rigor of a randomized controlled trial (RCT) design, we will leverage an evidence-based positive affect intervention (ARTEMIS) as a mechanistic probe to elucidate the neural and immunologic substrates linking psychosocial stress to substance use and depression in PWH. With this translational approach, we aim to: (1) Investigate the causal link between ARTEMIS-induced improvements in anhedonia and neural functioning in reward circuitry using resting-state and task-based functional MRI; (2) Evaluate the effects of ARTEMIS on transcriptional control pathways and downstream markers of peripheral inflammation; and (3) Test whether reductions in proinflammatory markers have positive feedback on reward functioning and stimulant use. To achieve these specific aims, we will enroll 189 PWH who currently use stimulants and have suppressed HIV viral load. Participants will be randomly assigned on a 2:1 ratio to receive ARTEMIS or a wait-list control. To support durable HIV viral suppression throughout the trial, all participants will receive smartphone-based contingency management for ART adherence. Assessments at 3- and 6-month follow-ups will characterize changes in neural functioning and leukocyte signaling as plausible mediators of ARTEMIS effects on behavioral outcomes. Our innovative and clinically important proposal is highly responsive to RFA-DA-24-005 and will advance our basic understanding of the neuroimmune pathways underlying psychological resilience to social stress that may mitigate substance use and depression in PWH. This proposal provides a scientifically rigorous model for examining the causal associations amongst these prevalent comorbidities in a population that is critical to ending the HIV epidemic, while also providing participants with the benefit of an evidence-based intervention with a transdiagnostic target. The results of this mechanistic trial will identify preclinical targets for novel pharmacotherapies linked to reward circuitry.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Type 2 diabetes (T2D) involves derangement in multiple tissues, yet the physiological drivers of disease will vary and are difficult to discern for a given individual. This variability in T2D pathophysiology contributes to heterogeneity in T2D complications and in which treatment strategy will offer optimum benefit. Together, these pose challenges for clinical decisions on the optimal intervention. We and others have helped disentangle this heterogeneity by advancing subclassification of T2D and identifying subtypes with different clinical risk, genetic susceptibility, and response to interventions. However, multiple clinical gaps remain before T2D subtypes can be used in routine clinical care, including a lack of racial/ethnic diversity in study populations, understanding of T2D subtypes across the age spectrum, and integration of multiple different data types to provide comprehensive understanding of the physiological drivers of heterogeneity in T2D. This application is in response to RFA-DK- 23-019, which seeks to establish a consortium to bring together investigative teams to improve classification of T2D. We propose to contribute to this consortium and provide data from the Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Diabetes Heart Study (DHS), African American DHS, Hispanic Community Health Study/Study of Latinos, Insulin Resistance Atherosclerosis Study (IRAS), IRAS Family Study, Action for Health in Diabetes Trial, Multi-Ethnic Study of Atherosclerosis, and SEARCH for Diabetes in Youth. These 10 populations total 55,766 individuals (25% prevalent T2D, 8% incident T2D) and reflect the diversity of the US population at risk for and with T2D, spanning ages 10 to 86 years at enrollment, and include large numbers of females (57%), Black (21%), and Hispanic (37%) individuals. We have a multidisciplinary team with expertise in biostatistics, clinical diabetes care, data science, epidemiology, genetics, metabolomics, and physiology. We have led developments in diabetes subgrouping and novel computational methods to estimate missing data that will be used as a framework for broader application in this proposal. Aim 1 will assemble, harmonize, and integrate clinical, genetic, metabolomic, social determinants of health (SDoH), and disease outcomes data across these cohorts. Aim 2 will build and cross-validate data-type distinct and aggregate models for classification of T2D subtypes based on clinical, genetic, and metabolomics data. Aim 3 will assess T2D subtypes with risk for cardiovascular disease (and subtypes coronary heart disease, cerebrovascular disease, and heart failure), chronic kidney disease, retinopathy, and mortality. We will also assess the influence of SDoH on these relationships. Successful completion of this proposal will generate evidence needed to establish physiological drivers of and precise definitions for T2D subtypes. This work furthers our long-term goal of developing more efficient precision medicine-based prevention and treatment strategies for T2D that maximize benefits and minimize risk for adverse outcomes.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Each of the 4-5 quick eye movements (saccades) that we generate every second is the result of a target selection process that combines perceptual and motor planning signals modulated by attention mechanisms, which prioritize the potential targets. The overarching goal of this project is to reveal how these attention mechanisms are instantiated in the activity of the frontal eye field (FEF), a key oculomotor area. Specifically, I propose to record neuronal activity from recognized neuronal types in FEF while monkeys perform two novel visuomotor tasks. Many studies have investigated how oculomotor neurons contribute to visuomotor choices. However, most have relied on serialized tasks where a perceptual judgment is made first and a motor report is made subsequently, and given this structure, the resulting behavioral metrics (accuracy and RT) confound the contributions of perceptual, motor, and attentional processes to each choice. An effective solution to this limitation is to impose urgency which, in essence, means that motor plans are always initiated first, before the task-relevant sensory cue is evaluated. Time pressure yields a novel psychophysical curve, the “tachometric curve”, which is unique in its ability to resolve the contributions of distinct perceptual signals to the saccadic choice process as it unfolds in time. Each of my two Specific Aims implements a novel, urgent decision-making paradigm. In both cases the general strategy is to record FEF activity and, using the time-resolved behavioral information provided by the tachometric curve, compare the neuronal responses evoked before and after perceptual information arrives to the circuit. In Aim 1, I plan to use an urgent version of the classic random dot motion (RDM) discrimination task to determine whether the spatially selective activity in FEF represents the location where attention is deployed or, alternatively, the amount of sensory evidence that has accumulated in favor of a choice toward that location. These two functions, attentional deployment and evidence accumulation, represent entirely distinct theoretical constructs — but are readily confounded in standard, non-urgent tasks. The proposed dissociation would represent a key conceptual advance. In Aim 2, I plan to use SpotChase, a gamified, dynamic urgent task, to investigate how visuomotor performance depends on selection history effects. It is now well established that visuomotor choices are determined not only by ongoing stimulus-driven and goal-driven signals, but also by past events (stimuli, actions, rewards, etc.) recently experienced. However, the impact of such selection histories is likely to be much stronger under natural viewing conditions than in trial-based laboratory tasks. Because SpotChase is highly dynamic but still permits rigorous behavioral quantification (specifically, construction of tachometric curves), it will afford a much more comprehensive characterization of the neural basis of selection history effects under more relevant behavioral conditions. Preliminary data promise significant advances in both Aims.

NIH Research Projects · FY 2025 · 2024-09

Project Summary In 2021, there was an estimated 29.5 million people that were diagnosed with alcohol use disorder (AUD), resulting in an estimated annual cost of $249 billion to the US economy. AUD is an ongoing, severe health crisis that requires further research to identify therapeutic targets. Stress can drive initial and sustained drug use, as well as trigger relapse during abstinence, however the mechanisms that drive this effect are under active research. The insula is a highly interconnected brain region that has been implicated in multiple disorders, including AUD. Interestingly, fMRI studies have shown that alcohol-dependent individuals have reduced insular cortex volumes, which was correlated with self-reports of impulsivity. PTSD patients have increased connectivity between the insula and the bed nucleus of the stria terminalis (BNST), suggesting this pathway is recruited by salient negative affective states. We have shown that the insula-BNST pathway drives negative affect-like behavior during abstinence, however the molecular mechanisms involved in this pathway are not understood. Nicotinic acetylcholine receptors (nAChRs) have been repeatedly shown to play an important role in reward and stress involved with drug misuse, however further research is needed to understand circuit specific nAChRs in these behaviors. Ethanol (EtOH) acts on nAChRs in a subunit specific manner. Multiple nAChR subunits have been implicated in AUD, one of the most prominent being α4β2, which are highly expressed throughout the brain. Moreover, multiple compounds acting on α4β2 nAChRs reduced binge-like EtOH consumption. Chronic alcohol exposure in rhesus monkeys resulted in decreased α4β2 nAChRs in the insular cortex, suggesting a role for these receptors in driving AUD associated behaviors. The overarching goal of this proposal is to characterize the role of α4β2 nAChRs expressed in mid-insulaBNST neurons in modulating compulsive-like EtOH consumption and abstinence-induced negative affect-like behavior. We will use whole-cell electrophysiology and calcium imaging in Aim 1 to determine the changes in sensitivity to α4β2 nAChRs expressed in insula-BNST neurons following binge-like EtOH drinking, aversion- resistant drinking and abstinence from alcohol. In aim 2, we will use bidirectional genetic manipulation of β2 nAChRs in this specific cell population to determine whether these receptors are sufficient and necessary for binge-like drinking and abstinence-induced negative affect. These studies will highlight the potential for nAChRs expressed in the insula-BNST pathway as a potential therapeutic target for AUD.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The progression of recreational drinking to alcohol use disorder (AUD) is characterized by increased seeking behavior and loss of intake control, with individuals continuing to use alcohol despite experiencing negative consequences. While one operant paradigm has been developed to assess operant alcohol self-administration in a manner that can procedurally separate the appetitive (seeking) vs. consummatory facets of behavior, no studies have yet leveraged this model to investigate these independent aspects of alcohol self-administration in the presence of an alternative reinforcer, an astonishing gap in the literature given that six of the eleven diagnostic criteria of AUD are related to the individual allocating behavior towards alcohol compared to alternative reinforcers. The paucity of translational models of operant alcohol choice self-administration may contribute to the continued mystery of the circuitry underlying maladaptive alcohol seeking, precluding the discovery of therapeutic targets. The present study proposes a novel operant self-administration choice paradigm which will be used to assess the role that the ventral subiculum of the hippocampus to the nucleus accumbens shell projection (vSub-NAc) has on alcohol seeking. Preliminary findings from our lab demonstrate that chemogenetic inhibition of the vSub-NAc produces a uniform reduction in alcohol seeking with minimal effects on consumption without altering seeking or intake of a sucrose solution in a separate cohort of animals. Both our lab and others have additionally shown that chronic intermittent ethanol (CIE) not only produces heightened excitability in vSub, but also results in escalation of seeking and intake. Despite these advances, it remains unknown how the vSub-NAc projection modulates operant choice behavior when a subject can respond for ethanol and an alternative reinforcer, whether the behavioral outcome of vSub-NAc inhibition would differ between CIE-exposed subjects vs. AIR controls, and how sex as a biological variable might mediate these synaptic and behavioral consequences. Therefore, the overarching goal of this proposal is to implement a multidisciplinary approach to test the hypotheses that CIE results in reallocation of behavior towards alcohol and away from an alternative reinforcer via hyperexcitation of the vSub-NAc projection, suggesting that inhibition of this projection will redirect operant choice behavior towards an alternative reinforcer. Aim 1 will employ optogenetic techniques to selectively activate or inhibit the vSub-NAc during alcohol vs. sucrose operant choice self-administration. In Aim 2, we will use CIE as a model of alcohol dependence coupled with optogenetic circuit manipulations to determine if this circuit has unique behavioral effects when assessed in alcohol dependent vs. non-dependent subjects. These studies may identify a novel behavioral mechanism through which the vSub-NAc exerts control over alcohol self-administration, with the potential to provide further evidence that targeting this circuit may have therapeutic value in treating AUD.

NIH Research Projects · FY 2024 · 2024-09

Abstract GPR39 is a G-protein coupled receptor (GPCR) activated by zinc (Zn2+) and implicated in several neurodegenerative symptoms of Alzheimer’s disease (AD), including dyshomeostasis, oxidative stress, microtubule destabilization, and tau phosphorylation. In AD brains, Zn2+ binding to amyloid beta (Aβ) disrupts the zincergic GPR39 signaling cascade, leading to down regulation of critical neuroprotective pathways and poor cognitive function. Targeting GPR39 agonists could inform development of novel drugs to ameliorate AD symptoms, but we have no reliable, noninvasive methods to quantify GPR39 levels. This project will evaluate the first positron emission tomography (PET) radiotracer to accurately measure GPR39 in vivo in rodent and human brain tissues of AD. This PET imaging strategy will significantly advance our understanding of Zn2+ GPR39-mediated dyshomeostasis pathways in AD brains beyond, currently available through terminal ex vivo studies. PET imaging of GPR39 will provide a valuable tool to assess the real-time distribution, target engagement, and dose occupancy of novel GPR39 agonist drugs. Our group has developed [11C]TM-N1324, the first brain-penetrant, PET radiotracer for imaging GPR39 and tested it in rodents. The proposed proof-of-concept R21 project is designed to establish the efficacy of two exciting approaches. First, we will investigate the imaging utility of [11C]TM-N1324 in two rodent models and compare the results in (a) mice that overexpress or do not express GPR39 along age-matched healthy controls (n=8/sex/group); and (b) Aβ-overexpressing APP/PS1 transgenic and age-matched wildtype littermates (n=8/sex/group). We will correlate the PET outcome with associated GPR39 levels via western blot and Aβ levels via immunohistochemical analyses. Second, we will characterize and evaluate binding and pharmacokinetic parameters of [11C]TM-N1324 in the Aβ-overexpressing APP/PS1 transgenic and age- matched wildtype mice and postmortem human AD and age-matched cognitively normal brain tissues (n=8/sex/group) using biodistribution, autoradiography, and metabolite studies. The proposed project will be the first to systematically examine in vivo imaging of GPR39 in rodent models of AD and validate in postmortem human brain AD tissues. Results will inform future imaging studies examining GPR39 modulations in AD pathogenesis and advance the therapeutic potential of GPR39 agonists to ameliorate AD symptoms.

NIH Research Projects · FY 2025 · 2024-09

An estimated 6.7 million Americans are living with Alzheimer’s disease (AD) dementia in 2023, with more than 55 million people living with AD worldwide. However, stark differences exist in the prevalence of AD with older adults with multidimensional poverty being more than twice as likely to develop dementia during their lifetime. Resources, opportunities, and the environment where you live, work, play, and age have been proposed as significant predictors of numerous risk factors associated with dementia. This proposal will investigate the influence of a novel social factor, neighborhood disadvantage, on (1) cardiovascular and metabolic risk factors, brain imaging biomarkers, and (2) cognitive function associated with AD and related dementias (ADRD). This project will utilize data from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core Cohort to conduct analyses investigating these relationships. Training will take place at the Wake Forest University School of Medicine in the Molecular Medicine and Translational Science (MMTS) and Medical programs as a part of the M.D./Ph.D. dual-degree program. The applicant will receive training in the foundational knowledge necessary to conduct research using rigorous statistical methodology and analytical design, along with scientific writing and communication to accomplish the proposed aims. Mentorship for the proposal includes a multidisciplinary team with individuals in the ADRC, along with faculty in the Internal Medicine and Neurology departments. This team will provide the applicant with feedback every step along the way, regarding data analysis, interpretation of findings, and manuscript preparation. The proposed aims have the potential to provide new insights into the effects of one’s neighborhood-level disadvantage on various factors of risk associated with ADRD and further elucidate the influence of social factors on risk of dementia.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Early-stage development of medical countermeasures (MCMs) for hazardous chemicals can be complicated by several factors, including limited expertise in working with highly toxic and restricted chemicals and a diverse array of experimental models of varying relevance. We propose to establish the Wake Forest University Vesicant Exposure Resource and Coordination Core (Vesicant ExRC) to provide a comprehensive suite of experimental models, innovative analytical methods and interactive study design protocols to support CCRP investigators. Dr. McNutt will serve as the overall Director of the Vesicant ExRC. He will be joined by a multidisciplinary scientific team with extensive expertise in vesicant studies and an administrative team with proven experience in managing large, multi-institutional programs under BARDA, NIH and DoD funding. The overall goal of the Vesicant ExRC is to take advantage of our established expertise studying vesicant injury in vivo and in vitro to develop a state-of-the-art facility that accelerates and enhances fundamental and translational studies. Our approach is enabled by the established repertoire of well-characterized experimental models used at Wake Forest to study fundamental effects of vesicants on ocular, dermal and pulmonary tissues. The experimental methods will focus on three primary models; in vivo studies using mouse and rabbit preclinical models of corneal injury; ex vivo exposures using commercially procured eyes for acute and mechanistic studies; and in vitro studies using phenotypically mature, full-thickness upper airway and skin microphysiological models. The Vesicant ExRC will be organized and executed through five specific aims: (1) Establish the Vesicant ExRC as a collaborative vesicant research resource; (2) Enhance collaborative studies through advanced analytical methods; (3) Ensure effective communication and coordination between Vesicant ExRC and stakeholders; (4) Develop resources to education stakeholders and disseminate standardized methods and findings; and (5) transition the Vesicant ExRC to become a sustainable resource. These aims will be achieved through the development and coordination of an Administrative Core, Coordination Core and Research Support Core to manage ExRC operations; establishment of a Steering Committee and External Advisory Committee to provide strategic guidance; implementation of facility website for scheduling, marketing and communications; and education of stakeholders and the broader CCRP Network in experimental approaches. The ability of the Vesicant ExRC to rapidly develop, standardize and disseminate proven methods for the study of highly toxic vesicants is anticipated to directly enhance the CCRP mission by accelerating fundamental studies into toxic mechanisms and improving early-stage MCM development.