Wake Forest University Health Sciences

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.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY: The breakdown of hydroxyproline, a component of collagen within our bodies and in the meat that we consume, is a significant contributor to glyoxylate and oxalate levels. We have shown in normal individuals and patients with primary hyperoxaluria (PH) that hydroxyproline is converted to oxalate (18% for PH1, 47% for PH3, and 33% for PH3). These values are the largest known contribution to oxalate formation for any metabolite studied to date. We hypothesize that blocking the hydroxyproline pathway with a drug will significantly lower the glyoxylate and oxalate burden of PH2 and PH3 patients, for which there are no available therapies. The target of this study is the first enzyme in the hydroxyproline degradation pathway, hydroxyproline dehydrogenase (HYPDH). A drug that blocks HYPDH activity would prevent the formation of downstream metabolites that contribute to oxalate levels. This strategy is supported by the observation that individuals that are deficient in HYPDH are normal and safely excrete the excess hydroxyproline into their urine. Our team has made the HYPDH knockout mouse (Prodh2 gene) and shown that the mice are healthy and not affected by HYPDH deficiency. Moreover, we have shown that the HYPDH knockout in the PH2 mouse model protects the mice from oxalate production from hydroxyproline. Thus, inhibition of HYPDH shows promise for the prevention and treatment of PH. Our team has already performed high throughput screening assays and identified potent inhibitors of HYPDH. These inhibitors require further optimization to improve potency, selectivity, and drug-like properties. The proposed research program will combine our biochemical, cellular, structural biology, computational, and medicinal chemistry expertise to optimize the compounds. The following specific aims illustrate the iterative compound progression plan that will be employed: (Aim 1) to design and synthesize compounds that will explore the structure-activity-relationship (SAR) properties of HYPDH inhibitor scaffolds; (Aim 2) to determine the biochemical and cellular properties of HYPDH inhibitors; (Aim 3) to apply computational and structural biology approaches to determine the binding mode of HYPDH inhibitors to inform compound design and synthesis; and (Aim 4) to determine the efficacy of HYPDH inhibitors in a variety of PH mouse models.

NIH Research Projects · FY 2025 · 2024-08

Summary Preeclampsia (PE) is a hypertensive disorder of pregnancy that occurs in 5-7% of all pregnancies. Women exposed to PE are more likely to develop cardiovascular and subclinical cerebrovascular events later in life. Recent studies suggest an alarming trend that women with a history of PE often experience pronounced subjective cognitive and psychological dysfunction that significantly alters their quality of life. Although the exact mechanisms of this subclinical disease are not well understood, endothelial dysfunction and inflammation are implicated in the pathogenesis of the cerebrovascular and cognitive syndrome after PE. The apelinergic system, consisting of apelin, elabela (ELA), and the apelin receptor (APJ), is a novel therapeutic pathway in preeclampsia. Our studies demonstrated that apelin has anti-hypertensive and reno-protective effects. However, apelin also reduces brain edema, inflammation and oxidative stress in models of transient model of focal cerebral ischemia, ischemia-reperfusion, and stroke suggesting its potential as neuroprotector. Studies proposed in this application are based on the clinical evidence suggesting a link between preeclampsia and vascular dementia- like syndrome experienced by women years after the exposure to PE. Our studies will establish the neuroprotective actions of apelinergic axis on long-term cerebrovascular consequences of preeclampsia. The established and well-characterized models of normal pregnancy and preeclampsia are readily available in our laboratory and will be used for this project. These studies will improve our understanding of the protective role of apelin/APJ axis in preeclampsia.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT Flavor is perhaps the most important determinant of eating habits—we eat foods that taste good and avoid foods that taste bad. Because eating habits are directly linked to nutrition and health, altering flavor perception is a prime target for interventions aimed at steering people toward heathier food choice. Flavor includes well-understood gustatory qualities (sweet, bitter, sour, salty, umami). However, a substantial portion of flavor constitutes olfactory (smell) qualities (try taking a sip of wine or eating a jellybean candy while pinching your nose). The gustatory and olfactory sensory systems that contribute to flavor each have unique characteristics. Hedonic perception of gustatory signals is innate and relatively stable (e.g., from birth into adulthood, sweet is liked, bitter disliked). In contrast, olfactory processing tends to be highly plastic, suggesting a strong opportunity to alter flavor perception through interventions. This proposal will gain basic understanding of the relationship between flavor-related odor perception and eating habits. I focus on children 4-6 years of age, because this constitutes a developmental period during which eating habits are formed for life, making it a particularly promising target for interventions. In Specific Aim 1, I will characterize the contribution of olfaction to multiple aspects of flavor perception in children and adults using a novel adaptation of a simple, non-verbal rating procedure, as well as analysis of video recordings of facial expressions. Preliminary data suggest that perception of olfactory flavor components (but not gustatory flavor components) undergoes substantial developmental changes. I will determine the extent to which differences in smell perception between children and adults can be explained by exposure to specific foods, as measured by a modified food frequency questionnaire and a non-verbal identification task. In Specific Aim 2, I will determine how individual differences in flavor perception among children relate to weight status. In order to development effective nutritional interventions, we must consider the relationship between weight status and flavor perception. Although this relationship has not been examined among young children, there is substantial evidence that overweight/obesity is associated with impairments in flavor sensitivity among adults. By conducting a regression analyses between BMI-for-age and perceptual measures for taste and smell, I will be able to determine whether this relationship emerges as early as ages 4-6. The results will provide novel mechanistic insight into how sensory processing interacts with flavor exposure and weight status during early childhood.

NIH Research Projects · FY 2025 · 2024-08

Recent trends highlight the importance of championing a genomics research workforce that is well-prepared to support genomics research. Offering training to the entry-level workforce such as Community Health Workers (CHWs) can support genomics research more broadly by ensuring the entry-level workforce fully understands the genomics aspects of the research in which they are engaged. The CHW workforce has witnessed unprecedented growth, with an anticipated 15% increase in the number of CHWs in the US by 2029. Although CHWs are familiar with the communities they serve, regularly interact with a broad range of populations, and have expressed interest in receiving training in genomics and related competencies, CHWs have yet to be provided with appropriate training in genomics. Thus, CHWs are an obvious but not well-equipped potential entry-level genomics research workforce. To address the unmet need of developing a trained network of CHWs with genomics competencies, we propose the PaRtnEring to build understanding oF gEnomics Responsibly (PREFER) CHW Genomics Research Education Program (PREFER CHW). Through this program we will work closely with five partner sites in the Southeast United States (The Center for Community Health Alignment, North Carolina CHW Association, South Carolina State University, Southern Mississippi University, and the Tennessee CHW Association). The CHW workforce is highly active in the Southeast, with over 10,000 CHWs engaged in the region and over 3,000 CHWs in the four states (South Carolina, North Carolina, Mississippi, and Tennessee) that are participating in PREFER CHW. Specifically, we will: 1) refine and finalize an educational curriculum (PREFER CHW) focused on 10 key genomic competencies, 2) implement the program among 150 CHWs using online asynchronous and synchronous methods, 3) equip partner sites to continue delivering PREFER CHW, and 4) assess the content and program goals of PREFER CHW. Our approach builds from the substantial strengths of the lead site faculty (Wake Forest University Health Sciences) in genomics education and history of collaboration with partner sites. PREFER CHW offers a viable, sustainable solution of training CHWs in genomics competencies to help enhance the capacity of the entry-level genomics research workforce and leverages the existing network of CHWs to improve engagement in genomics research.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY/ABSTRACT A critical barrier to realizing the promise of prevention in the academic Learning Health System (aLHS) is the insufficient number of investigators with the skills to cross the research-practice chasm and create health systems in which new knowledge is integrated into clinical practice, not just for treatment but to prevent disease and improve population health. We propose to develop clinician prevention scientists – who are grounded in several rapidly evolving, but infrequently integrated focus areas and competencies, including: 1) health equity and health disparities research (including measurement of disparities; stakeholder engagement; leadership and research management; systems science and organizational change; and addressing social determinants of health and promoting health equity); 2) development and implementation of prevention interventions (including research questions and standards of scientific evidence; ethics of research and implementation in health systems and the community; and study design and development of multi-level interventions); and 3) methodological and statistical approaches (including implementation science methods; health system research methods; biomedical informatics; biostatistics and data science; and scientific communication). We propose an innovative academic Learning Health System Preventions for PRomoting Health Equity (aLHS-PRE) T32 program to provide the next generation of clinician prevention scientists with the methodological and professional skills to conduct rigorous research in complex multi-level environments across multiple domains, including health systems, and to disseminate and implement findings from research into practice, utilizing a framework to reduce health disparities and promote health equity through: (1) building competency in the above focus areas, (2) building skills in team science and leading interdisciplinary, diverse research teams; and (3) preparing trainees for productive research careers. The aLHS-PRE will target outstanding predoctoral candidates who are underrepresented in prevention research who are currently pursuing doctoral-level clinical training in health professions. We will have a cohort of five trainees who will pursue an established MS degree in LHS science with a curriculum designed around the competencies above; trainees will conduct a mentored research project guided by diverse mentoring teams consisting of experienced and committed subject-matter experts, health system leaders, and “step ahead” faculty, all of whom are well-grounded in the principles of effective mentoring. Mentors will complete the Clinical and Translational Science Institute (CTSI) Mentor Academy that addresses core mentoring competencies. The aLHS-PRE will be part of an integrated educational infrastructure at Wake Forest (WF) CTSI that includes a postdoctoral TL1 program in aLHS; trainees will utilize CTSI resources, attend professional development seminars, and build networks with other WF T32 trainees. This unique training experience will prepare trainees for future careers as clinicial prevention scientists leading integration of preventive care in the health system.

NIH Research Projects · FY 2025 · 2024-07

There is a critical need to generate age- and sex-specific survival curves to characterize chronological aging and develop new biochemical and omic methods to describe biological age consistently across NHPs used in biomedical research. Without accurate measures of chronological and biological aging, it is impossible to make inferences into genetic, demographic, or physiological variables driving differences in NHP lifespan. The Nonhuman Primate Lifespan Project (NPLP) now includes data on >110,000 individual NHPs from 59 species across 15 research institutions that will be leveraged to identify demographic, clinical, and molecular biomarkers of aging and lifespan. The first aim of this proposal will generate the most accurate and comprehensive characterization of sex-specific lifespan and age-at-death distributions to date for 11 biomedically-relevant species, including chimpanzees, baboons, vervets, four species of macaques, marmosets, tamarins, titi monkeys, and squirrel monkeys. It will test the influence of energetic trade-offs including body size, age at reproductive maturity, and number of offspring (in females) on lifespan across species. Aim 2 will identify shared and species-specific patterns of biological aging across 15,000 NHP lifespans based on a deficit accumulation index (DAI) generated from clinical blood chemistries collected annually to test if longer lifespans within and between species are associated with increased physiological disruption later in life and a slower pace of biological aging as characterized by a lower trajectory of deficit accumulation. This aim will focus on the most used species for translational human aging studies: baboons, vervets, rhesus macaques, and marmosets. With the lifespan and healthspan data generated in the first two aims, animals will be selected showing contrasting patterns of pace of biological aging and lifespan. Aim 3 will identify omic biomarkers that differentiate exceptionally long-lived animals to characterize pathways mediating health and lifespan differences within and between species. This will leverage existing sequence data in 2700 pedigreed NHPs to identify rare and common genetic variants associated with lifespan, healthspan, and pace of aging within species. Evolutionary conservation of the implicated genes across 77 primate species, including humans, will identify genes selected for longevity in each clade. Finally, longitudinal untargeted plasma proteomic data will be generated in 48 animals with extreme or median longevity from each of the four species (a total of 576 plasma proteomes). This data will be used to identify the underlying biology driving differences in longevity within and between species including pace of aging as characterized in Aim 2. It is hypothesized that while individual genomic and proteomic variants driving longevity may be specific to one species or clade, when taken together, the variants will coalesce to highlight a limited number of biological pathways for potential intervention. Collectively, these aims will identify energetic burdens (growth, reproduction), physiological maintenance (biological aging, proteomics), and innate risk (genomics) that drive differences in longevity across NHP clades.

NIH Research Projects · FY 2025 · 2024-07

A critical barrier to realizing the promise of the Academic Learning Health System (aLHS) is the insufficient number of investigators with the skills to cross the research-practice chasm and create health systems in which new knowledge is integrated into clinical practice. The realization of the aLHS requires a new translational workforce phenotype – the aLHS Translational Scientist – who is grounded in several rapidly evolving, but infrequently integrated knowledge domains, including: 1) system science and organizational change management; 2) research questions and standards of scientific evidence; 3) health systems research methods; 4) biomedical informatics; 5) ethics of research and implementation in health systems; 6) improvement and implementation science; and 7) stakeholder engagement, leadership, and research management. This T32 application proposes an innovative two-year Academic Learning Health System Scholars Program (aLHSSP) to provide the next generation of translational scientists with the methodologic and professional skills to conduct rigorous research in the complex environments of health systems and to disseminate and implement findings from such research into practice through: (1) building competency in the above domains, (2) building skills in team science and leading effective interdisciplinary research teams of engaged stakeholders; (3) preparing scholars for productive research careers in LHS science; and (4) further developing scientific communication skills. The aLHSSP will target outstanding candidates with doctoral-level clinical training in medicine and other health professions, or PhD-prepared scientists who wish to conduct aLHS research. We will have a cohort of four trainees, two of which will be NCATS supported. All trainees will participate in a two-year program, pursuing an established Master of Science degree in LHS Science with a curriculum designed around the knowledge domains listed above to prepare them to conduct research in an aLHS and to lead teams. Scholars will conduct a mentored research project that addresses a pressing health system issue guided by mentoring teams consisting of experienced and committed subject-matter experts, health system leaders, and near peer faculty, all of whom are well-grounded in the principles of effective mentoring. Mentors will complete a 20-hr training via the Clinical and Translational Science Institute (CTSI) Mentor Academy that addresses core mentoring competencies, and participate in multi-CTSA hub Mentorship Symposia. The aLHSSP will be part of an integrated educational infrastructure at Wake Forest (WF) that includes the Workforce Development Program; trainees will utilize CTSI resources, attend professional development seminars, build networks with other WF T32 trainees and nationally with other CTSA hubs; they will have access to extensive support services. This unique training experience will prepare scholars for future careers as learning health system scientists who lead evidence based integration of knowledge into clinical practice.

NIH Research Projects · FY 2025 · 2024-07

The Wake Forest (WF) Clinical and Translational Science Institute (CTSI) joined the CTSA consortium in 2015 with the goal of catalyzing our health system’s transformation into an exemplary Learning Health System (LHS). Since then, we have extended this LHS framework by integrating traditional academic goals of T0-T4 translation, scholarship, and education while also promoting health for all people and the vitality of the communities we serve. We call this evolved vision the Academic Learning Health System (aLHS). Achieving this vision requires scientists with a deep understanding of the translational science process that moves from data to evidence to practice and policy in a continuous cycle. To develop this critical workforce, the CTSI K12 Program will provide a rigorous training program for outstanding and carefully selected interdisciplinary early-career faculty that develops expertise in seven LHS science competency domains identified by the AHRQ/PCORI LHS Learning Collaborative. These competencies support the traits of translational scientists as outlined by the international Translation Together collaborative. The K12 Program builds on our highly successful KL2 Program, which to date has trained 28 translational scientists who received 55 subsequently funded awards and published 539 manuscripts; many of them have advanced to become leaders in our CTSI. We will retain those training elements proven to be highly effective and add new initiatives in response to rigorous programmatic evaluations. Our growing healthcare system serves nearly 6 million patients in 1,167 sites of care, offering an ideal laboratory for K12 Scholars to work across the full translational spectrum, from pre-clinical discoveries to testing clinical interventions to implementation. Notably, WF serves as the academic core of this new health system, and our aLHS serves as a guiding framework for advancing care delivery throughout the system.

NIH Research Projects · FY 2025 · 2024-07

Project Summary Adolescent and young adult cancer survivors (AYAs; ages 15-39 years) are an important underserved group at risk for significant financial hardship. There are nearly 90,000 new diagnoses of cancer annually in AYAs, and nearly 680,000 AYA cancer survivors living in the United States. Five-year survival rates among AYAs are high (>80%) and AYAs have approximately 35 to 59 years of life expectancy remaining, including 25 to 40 years of productive employment in the paid workforce. Unfortunately, AYAs with cancer may have inadequate insurance coverage, limited financial assets, and experience significant work interruption, leading to greater financial hardship during and after treatment. Thus, AYA cancer survivors are at greater risk of financial hardship than AYAs without a history of cancer. Interventions to address financial hardship exist, but few address AYAs’ unique needs, and, to our knowledge, none address determinants of financial hardship, which lie at multiple levels. At the individual level, AYAs lack financial and health insurance literacy. At the organizational level, assessment of AYAs’ eligibility for financial support resources is haphazard, and access to financial assistance programs is uncoordinated. CHAT (“Let’s CHAT about health insurance”) is a program designed to educate AYAs about health insurance; Lessening the Impact of Financial Toxicity (LIFT) was designed to systematically assess cancer patients’ eligibility and coordinate access to financial support resources. To address multilevel determinants of financial hardship among AYAs, LIFT must be combined with CHAT. Combining CHAT with LIFT may also facilitate implementation in community-based settings, where most AYAs receive cancer care, yet resources required to implement new interventions are limited. This proposal responds to the National Cancer Institute’s call “to develop and/or test interventional approaches to prevent and/or mitigate financial hardship in individuals diagnosed with cancer” by assessing the influence of a multilevel financial hardship intervention on AYAs’ health insurance literacy and financial hardship. We propose the following specific aims: (1) To synthesize CHAT and LIFT to create FinFit, an intervention to address the unique, multilevel determinants of financial hardship among AYAs treated in community oncology practices; (2) to conduct a randomized controlled trial (RCT) of FinFit, a multilevel intervention, to address financial hardship among AYAs (n=408); and (3) to develop guidance for implementing FinFit to be tested in a future hybrid effectiveness- implementation trial. This study will be the first, real world efficacy trial of a multilevel intervention to reduce financial hardship among a representative, geographically diverse sample of AYAs treated in community oncology practices. Study results will guide future efforts to scale up FinFit to the diverse settings where AYA cancer survivors are served.

NIH Research Projects · FY 2025 · 2024-07

The emergence of large integrated health systems linked by common informatics platforms offers an unprecedented opportunity to study the impact of new therapies and healthcare delivery models in real world settings. Such integrated systems also offer opportunities to test approaches to implement and scale evidence-based practices, to address gaps in translational science, and to become Learning Health Systems (LHS). The Wake Forest (WF) Clinical and Translational Science Institute (CTSI) has pioneered the integration of the academic mission into the LHS framework including T0-T4 translation, scholarship, and education while also promoting the vitality of communities we serve. WF leads as the academic core of Advocate Health – the nation’s third largest not-for-profit health system serving nearly 6 million patients across the Southeast and Midwest United Sates. The aLHS is Advocate Health’s guiding vision, and the WF CTSI is its central resource for supporting translational science across the entire system. The size of the health system offers a unique opportunity to develop, demonstrate, and disseminate novel care models in a wide range of settings. With this funding, the WF CTSI will drive the realization of the full potential of an aLHS and create a model for advancing translational science in a large academic health system. The need for such a model is urgent, given the ongoing consolidation of academic and non-academic health systems in the United States and the challenges in conducting research in busy practice settings. All activities and initiatives to advance translational science will be grounded in a culture of accountability to improve the health of our patients. WF CTSI’s vision will be achieved through the four specific aims: 1) Support a highly effective governance structure that promotes a culture of continuous quality improvement, enables timely response to regional and national health emergencies, supports proactive dissemination and implementation, and enables active participation in CTSA-sponsored trials; 2) Recruit and train a highly competent aLHS workforce and engage the full range of patient and community stakeholders who are essential to improving health; 3) Provide resources to promote innovative pragmatic study designs, support pilot studies that address key translational roadblocks, and satisfy the needs of the aLHS research community for timely access to data from electronic health records, population surveys, omics analyses, and other sources; and 4) Enhance translational efficiency through projects testing novel methods (e.g., respondent driven sampling to improve patient recruitment, integrating patient generated data into the EHR). Innovations made in achieving these aims will be shared through and beyond the CTSA national network.

NIH Research Projects · FY 2025 · 2024-07

An excess of circulating lipids in conjunction with dysregulated retinal de novo lipogenesis results in retinal lipotoxicity which can lead to retinal inflammation and apoptosis contributing to the pathogenesis of diabetic retinopathy (DR). The nuclear retinoid X receptor (RXR), shown to be diminished in human and mouse diabetic retinas, is of particular interest for therapeutic intervention due to its binding and activation of PPAR and LXR that regulate the expressions of lipid metabolism-associated and inflammation-related genes. Recently we synthesized two small molecules, the RXR agonists (rexinoids) UAB30 and UAB126 which demonstrated marked efficacy in reducing DR progression when given systemically; however these agents reduced hyperglycemia and thus the beneficial effect of rexinoids on DR could be directly due to improvement in diabetes management. In the proposed studies, we directed our efforts towards developing retinal delivery of rexinoids to remove the confounding effect on glucose regulation and establish whether this targeted delivery could beneficially impact retinal lipid metabolism and reduce retinal inflammation directly. Our overarching hypothesis is that intravitreal (IVT) delivery of rexinoids as sustainable released microparticles (UAB126-MP and UAB30-MP) will activate RXR, provide a long-term therapy for DR, and enhance the pool of RXR homodimers available to partner with the PPARs and LXRs to both prevent and reverse DR. Therefore, we propose that rexinoids act through the stabilization of the RXR/PPAR and RXR/LXR complexes leading to the normalization of lipid metabolism and correction of neurovascular defects typically seen in DR. We will test our hypothesis using IVT formulations of UAB126 and UAB30 and two diabetic mouse models, as well as ex vivo retinal models, primary human retinal microvascular endothelial and human retinal pigment epithelial cell cultures, and a diverse set of molecular biological applications. In Aim#1, we proposed to determine the physiological effect of RXR-based therapy in diabetic retinas by assessing the pharmacokinetics of UAB126- MP and UAB30-MP and the therapeutic impact of IVT rexinoids to prevent and reverse DR. In Aim#2, we will investigate the cellular mechanism of RXR-based therapy by examining the control of RXR on retinal lipid profile and reveal the retinal cell type most vulnerable to RXR deficiency in diabetes. In Aim#3, we will focus on molecular mechanisms of RXR-based therapy by investigating the requirement of PPAR and/or LXR as binding partners of RXR in the retina and the gene expression network regulated by PPAR and LXR responsive elements as consequences of IVT rexinoid delivery. This proposed study is highly innovative and has marked translational significance by targeting retinal lipotoxicity and retinal inflammation and could be tested not only as a monotherapy but also in combination with existing therapies for DR. Our interdisciplinary team has expertise in drug discovery, ocular drug delivery, cell biology, biochemistry, and metabolism of the diabetic retina and thus we have all the tools necessary to successfully accomplish this translational research.

NIH Research Projects · FY 2026 · 2024-06

Summary Hepatitis B virus (HBV) is a common cause of liver diseases such as acute and chronic hepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HBV infection continues to pose a major threat to global public health, affecting more than 250 million people worldwide. Although licensed vaccines can effectively prevent new HBV infection, they do not offer therapeutic benefits to the hundreds of million people already infected with HBV. The biggest challenge to cure chronic hepatitis B is the lack of therapeutics to eliminate HBV covalently closed circular DNA (cccDNA), which is responsible for HBV persistence. Current standard antiviral therapies consisting of interferon and/or nucleoside analogs can suppress HBV replication but do not significantly affect the level of HBV cccDNA. Thus, there is an urgent need to discover and develop new classes of antiviral drugs capable of eliminating HBV infection. Over the years, the search for a cure of chronic hepatitis B has been hampered by the lack of robust cell culture systems of HBV propagation and small animal models of HBV infection and replication. The discovery of sodium taurocholate cotransporting polypeptide (NTCP) as an HBV receptor has made it possible to develop cell culture models of HBV infection. However, NTCP per se does not confer HBV susceptibility in transgenic mice, suggesting other co-receptors that may be needed for more efficient HBV infection in vivo. Through preliminary studies, we have found that human apolipoprotein E (apoE) and apoE-binding receptors such as heparan sulfate proteoglycans (HSPGs) and the low-density lipoprotein receptor (LDLR) family proteins promote HBV infection. More significantly, our preliminary data suggest that co-expression of NTCP with human apoE and LDLR in the proprotein convertase subtilisin/kexin type 9 (PCSK9)-deficient mice could confer HBV susceptibility. Strikingly, inoculation of NTCP/apoE3/LDLR/PCSK9-/- mice with HBV derived from HBV-transgenic mice expressing human apoE3 resulted in a high HBV viremia (~106 genome copy equivalents/mL) in the mouse sera after one week of HBV inoculation. We hypothesize that the cell tropism of HBV is not only determined by its receptor NTCP but also by host factors promoting HBV infection, transcription, and replication. The overall goal of this application is to develop robust mouse models of HBV infection and replication for investigation of HBV infection, transcription, replication, pathogenesis, and host immune response to HBV infection as well as for evaluation of HBV-specific antiviral drugs and therapeutic strategies in vivo. Our specific aims are: 1) to develop an immunocompetent mouse model of HBV infection and replication; 2) to construct novel mouse models of HBV persistence; and 3) to develop an immunodeficient mouse model of HBV infection and to determine host immune control of HBV infection. The successful completion of this application will have a profound impact on HBV research by providing novel mouse models of HBV infection and replication and new therapeutic strategies towards the ultimate cure of chronic hepatitis B.

NIH Research Projects · FY 2025 · 2024-06

Abstract Epigenetic variation, especially DNA methylation, has been associated with numerous complex diseases. Epigenetic age is a fairly recent measurement that is associated with an individual’s biological age, and has recently been shown to contribute to general mortality, specifically with cardiovascular disease. Abundant evidence demonstrates that specific interventions (e.g., exercise, diet, smoking cessation) can alter, and more importantly improve, an individual’s epigenetic age acceleration. Although research has addressed attitudes and uptake of specific genetic tests, we do not know whether patients would want information about their epigenetic age or, among those who want their results, how they would respond to receipt of results. Furthermore, we are becoming increasingly aware of the importance of understanding perspectives held by underrepresented populations about the use and implementation of genomic technology. However, such knowledge is often limited. To address this gap in knowledge and to ensure that perspectives of underserved minorities are not overlooked, we will conduct semi-structured, in-depth interviews with 40 1st and 2nd generation Mexican immigrant adults for whom their existing epigenetic age has already been determined as part of a currently funded grant (# R01 MD017006). The interviewer will elicit detailed responses from the participants about perceived benefits and drawbacks of being informed about their epigenetic age, and ask whether they want to receive their epigenetic age test result. Those who opt to receive their epigenetic age will receive them, and then will immediately be asked to briefly respond to a few open-ended questions. Three months later, all participants will engage in a final semi-structured, in-depth interview about the perceived benefits and drawbacks of being able to receive one’s epigenetic age. Through systematic analysis of interview transcripts, we will (1) delineate the perceived benefits and drawbacks to receiving results of epigenetic age test results reported by 1st and 2nd generation Mexican immigrant adults prior to receipt of test results, and (2) identify and delineate the perceived benefits and drawbacks to receiving results of epigenetic age test results reported by 1st and 2nd generation Mexican immigrant adults immediately, and three months after, receipt of test results. We will also determine if responses vary by the difference between each participant’s biological and chronological age.

NIH Research Projects · FY 2025 · 2024-06

Project Summary/Abstract Medical misinformation is a global health problem with 73% of US adults having been exposed to false health information and 87% expressing concern about it. Health misinformation can hijack a patient’s typical discernment faculties and can lead to poor health outcomes. Evidence shows that elderly patients are disproportionately affected by health misinformation and are more likely to believe and spread misinformation, and suffer negative consequences. Engaging physicians has been touted as a promising and plausible means to mitigate misinformation because they are highly trusted, routinely provide reliable medical information, and are effective at influencing sustainable behavior change. Yet there is virtually no empirical data about physician misinformation corrective practices. Physician practices to correct patient misinformation is likely to depend on their political and religious beliefs as seen in other health areas, familiarity with the topic, correction and communication skills, self-efficacy, and environmental (e.g., time) and interpersonal factors (e.g., exhaustion). Prior to developing scalable and evidence-based physician communication interventions, a rich assessment of factors that facilitate or impede physician corrective practices is needed. We use a mixed-methods approach to identify factors and the strength of association among barriers/facilitators and physician willingness to correct misinformation through three specific aims using two divergent cases: unproven stem cell therapies and Covid- 19 vaccination. In Aim 1, we will interview primary care physicians to assess knowledge, experience, attitudes, and beliefs about correcting misinformation. In Aim 2, we will create a novel Determinants of Willingness to Correct Misinformation (DWCM) measure based on Aim 1 qualitative data, expert review, cognitive interviews, and psychometrically evaluate dimensionality and internal consistency. A national survey of physicians using the validated DWCM instrument will be conducted to measure determinants that impact physician corrective practices and attitudes towards adopting a priori correction strategies in their practice. In Aim 3, we will conduct online asynchronous focus groups with elderly patients across the US to assess receptivity towards corrective information from physicians, communication comprehension, channel preferences, and affect towards receiving corrective information and the use of specific terminology. Upon completing this research, we will have (i) identified major factors and their association with physician misinformation corrective practices and their attitudes towards adopting corrective strategies; (ii) created a valid DWCM climate instrument that can be deployed in different health care environments; (iii) offered data into patient receptivity towards receiving corrective information from physicians, including modes of exchange and appropriate language, and (iv) be well-positioned to develop and test the efficacy of a misinformation correction toolkit for physicians in future research.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY Obesity is a common, serious, and costly condition among older adults. Weight loss (WL) is an effective strategy to combat obesity-related comorbidities; however, the safety of WL interventions for older adults remains controversial due to potential exacerbation of age-related muscle and bone loss that increases fracture risk. Mechanical stimuli, such as resistance training (RT), can be effective in mitigating WL-associated bone loss, but there are many barriers to success of RT programs for older adults, including low adherence and accessibility. In response, our group has proposed that a weighted vest may serve as an alternative for maintaining mechanical stress during intentional WL, but it is unclear whether this vest will have similar preservation effects on bone when compared to RT. Therefore, our ongoing 12-month WL trial of 150 older adults living with obesity, INVEST in Bone Health (NCT04076618) is exploring the effects of WL alone versus WL plus weighted vest use or WL plus RT on indicators of bone health and fracture risk, with the primary outcome being 12-month change in total hip volumetric (vBMD) as measured by computed tomography (CT). This F31 proposal enhances the parent study by adding new analyses of the CT scans acquired for this study to investigate indicators of muscle health. As WL-associated muscle loss often precedes bone loss, preserving muscle health may also have clinical relevance to the reduction of fracture risk. Aim 1 will develop an automated image analysis platform to process baseline, 6- and 12-month participant CT scans to measure muscle quantity and quality and assess intervention effects. Aim 2 will utilize CT data for development of subject-specific finite element models to assess longitudinal bone strength and muscle-bone associations in response to WL. Taken together, completion of these aims will provide automated techniques to support future large-scale research projects and opportunistic CT assessments of muscle in clinical care, while also furthering our understanding of the mechanistic relationship between WL- associated changes in muscle and bone. In addition to augmenting the suite of musculoskeletal outcomes in the INVEST trial, this fellowship will provide the predoctoral principal investigator (PI) with valuable training from an experienced mentorship team in the areas of: 1) aging and clinical trials, 2) data management, interpretation, and biostatistics, 3) muscle and bone epidemiology, 4) machine learning and imaging informatics, and 5) computational biomechanics. This research will be conducted at Wake Forest University as an interdisciplinary collaboration between the Departments of Biomedical Engineering, Health and Exercise Science, Radiology, and Statistical Sciences. Together, this collaborative environment and an expert team of mentors will support the PI’s training to achieve independency in her research career while successfully completing her doctoral dissertation. This project, as an extension of the PI’s ongoing work with the INVEST trial, will refine her technical engineering and professional skillsets, and launch her career as an independent bioengineering researcher focused on developing and applying advanced image analyses to study musculoskeletal health in aging.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY Tobacco dependence represents a major public health challenge, and novel treatment approaches are urgently needed. Nicotinic acetylcholine receptors (nAChRs) are known to mediate the addictive action of nicotine, but it has been difficult to know which aspects of nAChR function are involved in the behavioral and physiological response to nicotine. In particular, the contribution of nAChR activation vs. desensitization to the establishment and maintenance of nicotine reinforcement has remained unclear. We will leverage our unique experience with nAChR molecular pharmacology and self-administration assays to address this issue. In Aim 1, we will design, produce, and validate AAV vectors for expression of desensitization-resistant β2 and β4 nAChR subunits. We will test several β2 and β4 variants with specific mutations at a conserved leucine residue in the 2nd transmembrane ⍺-helix (i.e. the “pore-forming” ⍺-helix). Patch clamp electrophysiology will be used to characterize the biophysical change induced by the mutation, and 2-photon laser scanning microscopy and nicotine uncaging will verify proper trafficking of variant subunits in neurons. In Aim 2, we will study how removal of β2 desensitization in VTA impacts nicotine self-administration and dopamine release. We will test the hypothesis that a lack of desensitization will fundamentally alter nicotine's action as a reinforcer. We will also determine how removal of desensitization from VTA β2* nAChRs impacts evoked dopamine release using electrochemical methods. Together, these Aims will 1) produce/validate novel tools for nAChR research and 2) help us understand how nAChR desensitization normally modulates nicotine reinforcement and associated DA release. These vectors and their characterization in behavioral assays will lay the groundwork for future projects related to nAChR physiology and pharmacology, and may also facilitate the development of novel tobacco cessation treatments.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY/ABSTRACT By 2050, the estimated cost of Alzheimer’s disease and related dementias (ADRD) in the US is estimated at 1.6 trillion dollars. Thus, it is crucial to understand the factors contributing to the development of ADRD to identify strategies for prevention or intervention. Stress is a multidimensional construct that can occur at various points across the life course (early and later-life), either accumulating gradually over time or manifesting suddenly with an immediate impact. Although stress has been associated with the risk of cardiovascular disease, there is limited research on the potential association between stress and the risk of cognitive decline and ADRD, or on biomarkers of ADRD pathology. Moreover, few studies have assessed sex differences even though both stress and ADRD differ by sex. In this proposal, stress will be defined as occurring across the life-course as well as an individual's perception of psychological stress. The overarching goal of this proposal is to examine the associations of early and later-life stress on later-life cognition and plasma biomarkers of ADRD pathology including Abeta 40 [Aβ40], Abeta 42 [Aβ42], Glial Fibrillary Acidic Protein [GFAP], and Neurofilament light [NfL], phosphorylated tau181 (p-tau181), and phosphorylated tau217 (p-tau217), and whether associations are modified by sex. To examine these associations, we will cross-sectionally examine the relationship between life course stress and cognition (Aim 1) or plasma biomarkers of ADRD pathology (Aim 2). We will also assess whether sex modifies the association. Moreover, we will examine these associations among participants without dementia, recruited into the Wake Forest Alzheimer’s Disease Research Center (ADRC). The ADRC consists of community-dwelling individuals, who are clinically well-characterized, have completed seven different stress questionnaires, and provided a blood sample. The applicant will receive training in advanced methods in epidemiology, biostatistics, sex differences, and how life course stress impacts health. Additionally, they will also develop an understanding of ADRD clinical diagnosis and cognitive outcomes, while acquiring the necessary skills to interpret plasma ADRD biomarkers – all of which are essential for achieving the proposed aims. Mentorship will be provided by a multidisciplinary team of researchers and physicians at Wake Forest University School of Medicine. The team will provide the applicant with feedback regarding project implementation, data collection and analysis, and manuscript preparation. The proposed aims have the potential to provide essential insight into the impact of life course stress on later-life cognition and by understanding which measures of stress influence ADRD markers. Future interventions can be targeted towards those at highest risk.

NIH Research Projects · FY 2026 · 2024-04

Globally, men at risk of HIV are disproportionately affected by common mental illnesses, including depression and anxiety. The mental health of men at risk of HIV is directly affected by chronic exposure to stressors that uniquely impact them via prejudice events, such as enacted stigma and violence, as well as anticipated and internalized stigma. Behavioral interventions that address the multiple mental and sexual health problems caused by chronic exposure to stress among men at risk of HIV are urgently needed. The goal of this Career Development Award is to expand the candidate’s skillset and prepare him to conduct independent research on scalable behavioral interventions that integrate mental health and HIV services for men at risk of HIV in low resource settings. Through a combination of didactic and applied training and mentorship from leading experts, the candidate will develop expertise in 1) the systematic adaptation of evidence-based interventions; 2) implementation science tools for identifying and evaluating implementation strategies; 3) theory and analysis of mechanisms of change for mental health interventions; and 4) leading culturally appropriate intervention research in low-resource settings. The candidate will apply the knowledge and skills gained through this training to conduct a pilot randomized control trial in collaboration with RAIN, a community-based organization that provides HIV services in Charlotte, NC. Specifically, the candidate will adapt the ESTEEM (Effective Skills to Empower Effective Men) intervention to target pre-exposure prophylaxis (PrEP) uptake for the North Carolina context and to identify implementation strategies (Aim 1). ESTEEM is a skills-building Cognitive Behavioral Therapy intervention that was designed to reduce men’s co-occurring health risks by addressing the underlying cognitive, affective, and behavioral pathways through which stress impairs health; it is effective at improving mental health and HIV-related behaviors among men at risk of HIV in the US. He will then pilot the adapted intervention with 80 men at risk of HIV to assess preliminary effectiveness on depression, anxiety, and PrEP uptake, and explore mechanisms of change (Aim 2). Finally, he will assess acceptability, feasibility, and fidelity of the adapted intervention and implementation strategies for future scale-up in other community clinic settings. Findings from this research will inform the development of an R01 proposal for a hybrid type 1 implementation-effectiveness trial to examine effectiveness and implementation sustainability of the scaled-up, adapted intervention. Together, the training, research, and collaborations outlined in the award will support the testing of a scalable mental health intervention with the potential to improve multiple common mental illnesses and PrEP uptake among men at risk of HIV in low-resource settings, contributing to NIMH’s goal of scaling up interventions for populations with the greatest need.

NIH Research Projects · FY 2026 · 2024-04

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The goal of this Independent Scientist Award (K02) is to seek five years of training and protected time to enable and expand the work of a newly established independent investigator. The candidate’s laboratory, the Access to Behavioral Health for All (ABHA) Lab, is supported by a recent R01 (Parent Study; DA037276; March 2020-2025) that will evaluate the efficacy of a novel digital therapeutic (DTx) for smoking cessation tailored to patients with serious mental illness. The candidate’s research to date has focused on the development of DTx using user-centered design research, and the subsequent testing of their efficacy using clinical trials methodology. However, efficacy trials do not always translate into real-world practice, nor are tested treatments always adopted by all subgroups of a population. This gap is well documented in the implementation science literature. In a recent epidemiological study (N=40,181) we showed differential rates of smoking decline among Americans with serious psychological distress over the last decade. This data accentuates the critical need to develop DTx that have a wider population health impact. Therefore, the five years of protected time provided by this Independent Scientist Award will fundamentally enhance the candidate’s current program of research by providing formal training and contact with expert collaborators in the following key areas: (1) community health and participatory research, (2) implementation science, and (3) DTx’s oversight, marketing, and dissemination. The award will also support a convergent mixed-methods Ancillary Study based on the RE-AIM framework, that will examine community health and implementation science outcomes in the Parent Study. This award will provide the necessary research experience and network of collaborators to scale up widespread dissemination of DTx for individuals with tobacco use disorder and serious mental illness. This award will also establish the conditions to pursue and maintain this program of research in the future by protecting the candidate’s time from clinical responsibilities. In the short term, the award will generate preliminary data to inform the design of a large pragmatic trial that will evaluate the dissemination of DTx for all Americans with tobacco use disorder and serious mental illness. In the long term the award will generate a new body of research rigorously examining social drivers and barriers of health in DTx for addiction treatment, a new model for the widespread implementation and technology transfer of these DTx, and mentoring opportunities for junior scientists that will extend the impact of this work beyond the candidate’s own program of research.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY Necrotizing enterocolitis (NEC) is a devastating intestinal disease affecting the most fragile premature infants, with mortality rates that persist at 20-40%. Accurate and conclusive early diagnosis of NEC remains elusive, with limited diagnostic confidence complicating timely and effective medical management efforts to prevent disease progression to urgent surgical removal of necrotic intestine. As the population of premature infants at the highest risk for NEC continues to rise, a critical need has emerged to develop innovative clinically translatable diagnostic methods to enable early interventional opportunities to combat this disease. Motivated by the significance of the translational potential, clinical need, and extensive promising preliminary data, we propose to investigate the development and use of photoacoustic imaging (PAI), an emerging non-invasive imaging modality, in healthy neonatal intestine and NEC disease, representing a novel first-in-disease preclinical investigation. PAI methods present enormous potential for fundamentally changing current clinical paradigms by non-invasively detecting, diagnosing, and monitoring intestinal pathologies, such as NEC, in premature infants. We hypothesize that PAI can accurately and quantitatively characterize changes in the NEC vascular hallmark of intestinal tissue hypoxia and NEC intestinal functional hallmark of motility to improve the diagnosis and monitoring of intestinal disease in premature infants. The aims of this application reflect a stepwise development and validation study to optimize PAI acquisition and analysis methods to assess early healthy development and NEC disease onset and progression in the neonatal intestine. In Aim 1, we will optimize PAI measurements of neonatal intestinal tissue oxygenation. In Aim 2, we will optimize PAI measurements of functional neonatal intestinal motility. Under each aim, we will compare quantitative characterization of physiological biophysical indicators for neonatal intestinal microvasculature and function from PAI with paired histopathological analysis. This enables our study to uncover the cellular and molecular origins of observed changes on PAI. Combined, the proposed studies will establish PAI as a non-invasive detection and quantitative imaging methodology to detect differences in neonatal intestinal tissue oxygenation and functional motility in the healthy developing infant intestine and in NEC disease onset and progression. The development of new advanced non-invasive imaging methods for neonatal intestinal disease presents significant translational opportunity to improve the quality of care in the NICU. With considerable rationale and strong preliminary data establishing feasibility for the use of PAI to detect changes in intestinal microvasculature and function, this project has a high likelihood of demonstrating success in quantitative characterization of NEC in these proposed first-in-disease studies. Our multi-disciplinary study team is well- positioned to develop these innovative imaging methods specifically designed for feasible clinical translation as a first-in-disease investigation to make a significant impact in intestinal health in premature infants.

NIH Research Projects · FY 2025 · 2024-04

In the U.S., substance use disorders (SUDs) cost more than $820 billion dollars a year and continue to present significant challenges to health and justice systems [1, 2]. Although there are clinically effective pharmacotherapies for numerous drugs of misuse there are currently no FDA-approved treatments for cocaine use disorder (CUD), despite decades of preclinical research. The lack of effective medications for CUD suggests that there are gaps in translatability between preclinical and clinical research. One possible cause of this gap is the fact that most individuals with CUD are using more than one drug at the same time [3]. One substance that is commonly co-used with cocaine is alcohol and estimates suggest that up to 90% of individuals who misuse cocaine also co-use alcohol [4, 5]. While the mechanistic basis of alcohol and cocaine co-use is still poorly understood, research suggests that ethanol may enhance cocaine’s elevation of striatal dopamine concentrations, thus increasing cocaine’s reinforcing effects [6]. It is also important to note that the co-use of cocaine and alcohol is associated with more severe cocaine dependence, higher rates of psychiatric co-morbidities, and poorer treatment outcomes [7-9]. Despite this, the vast majority of substance abuse research has focused on the use of cocaine or alcohol in isolation, which may limit the clinical translatability of research findings. Given this, the aims of this NRSA are to characterize the effects of ethanol on vulnerability to cocaine reinforcement (Aim 1), to examine how ethanol influences maladaptive cocaine choice in the presence of an alternative reinforcer (Aim 2), and to explore a potential pharmacotherapy for cocaine and alcohol co-use (Aim 3) in a translational nonhuman primate model of substance use. I hypothesize that ethanol consumption will enhance the potency of cocaine reinforcement, resulting in greater sensitivity in studies of acquisition and the ability of alternative non-drug reinforcers to decrease cocaine choice. I also hypothesize that a combination of modafinil analog JJC8-091 and naltrexone will reduce both cocaine and ethanol self-administration. These findings will build on other data providing evidence as to why people co-use multiple drugs (e.g., enhance reinforcement) and how the study of pharmacological interventions need to consider these conditions.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY/ABSTRACT Hyperlipidemia (HLD) is a major contributor to atherosclerotic cardiovascular disease (ASCVD), the leading cause of US mortality and morbidity. Nearly 30% of Emergency Department (ED) patients with chest pain have undiagnosed and/or unmanaged HLD, putting them at an increased risk of ASCVD. Although safe and effective HLD treatments exist, the ED traditionally focuses on acute care and does not offer preventive cardiovascular care services or treatment for HLD. This represents a large, missed opportunity to improve cardiovascular health for the millions of Americans evaluated in the ED each year for chest pain who are not receiving appropriate guideline-directed preventive care in the outpatient setting. The overarching research goals of this study are to determine the efficacy of a novel, protocolized, ED-based preventive care intervention for HLD known as EMERALD (Emergency Medicine Cardiovascular Risk Assessment for Lipid Disorders) in lowering cholesterol while also informing our understanding of patient adherence and implementation determinants of ED-based preventive cardiovascular care. To accomplish these goals, I worked with my mentoring team to design a career development plan that blends multidisciplinary research training with an innovative research proposal. Aim 1 will use a randomized, controlled, single center, parallel group trial of 130 ED patients to test the efficacy of EMERALD vs. usual care in lowering cholesterol. Aim 2 will rely on mixed methods to identify patient adherence facilitators and barriers as well as implementation determinants for Emergency Medicine providers. To successfully accomplish these Specific Aims, I will capitalize on the outstanding research environment at the Wake Forest University School of Medicine and my engaged transdisciplinary mentorship team of senior scientists. With support from my mentoring team, I will complete a robust career development program that will provide me with the necessary training in preventive cardiovascular care, clinical trial design and methodology, and qualitative methods that are needed for me to become an independent investigator and national leader with expertise in ED-based preventive cardiovascular care strategies. The proposed K23 Award aligns with NHLBI's objective to “Develop and optimize novel diagnostic and therapeutic strategies to prevent, treat, and cure heart, lung, blood, and sleep diseases,” with position statements from Emergency Medicine and Cardiology professional societies, and with the Department of Health and Human Services “Healthy People 2030” initiative. This proposal will inform our understanding of ED-based preventive cardiovascular care strategies and will help me achieve my long-term goal of becoming an independent investigator focused on ED-based preventive cardiovascular care.

NIH Research Projects · FY 2025 · 2024-03

Project Summary Acute myeloid leukemia (AML) is an aggressive cancer of the bone marrow. There is a well-documented survival disparity with non-Hispanic white (NHW) patients having a better outcome compared to non-Hispanic black (NHB) patients. To date, clinical trials with minimal NHB patient participation are the basis for all approved treatments and risk stratification systems. How ancestral racial backgrounds are reflected in AML that arises in NHB patients is largely unknown. This may have led to treatment practices that are not optimal for NHB patients. Indeed, in contrast to NHWs who have a good prognosis, NHB patients with NPM1 mutations have an adverse prognosis when treated with standard therapies. The lack of preclinical models of NHB origins further exacerbate this lack of knowledge. As a result, there is little to no preclinical or clinical evidence to what extent the current approved therapies in AML are efficacious in NHB patients. This is clearly unacceptable. This proposal seeks to leverage novel approaches to generate preclinical AML models of NHB origins and to compare therapy responses and basic biochemical properties to models generated from NHW patients. This will be accomplished in the 3 aims of this proposal. They are 1) Utilize the Sleeping Beauty (SB) transposon system to generate AML models from CD34+ cells derived from healthy donors of NHB and NHW origins; 2) Characterize racial differences in therapy sensitivity and DNA damage response in AML models; 3) Develop patient derived organoid models from NHW and NHB AML patients; The results from this study will greatly inform the influence of racial ancestry on AML arising from NHB patients. This information will guide new strategies geared specifically towards AML in NHB patients and will inform drug development efforts to ensure future therapies are efficacious for AML patients of all racial backgrounds.

NIH Research Projects · FY 2025 · 2024-03

Summary Antibody-drug conjugates (ADCs) have driven a revolution in the treatment of breast cancer; however, the long-term benefits on patients are still heterogeneous. ADCs induce immunogenic cell death of cancer cells, leading to anticancer immunity, and this plays a key role in antitumor response of ADCs. Therapy-induced anticancer immunity is often limited by immunosuppressive mechanisms posed by the tumor microenvironment (TME). Treatment of breast cancer cells with trastuzumab-emtansine (T-DM1), an ADC, causes extracellular ATP release, which initiates the recruitment of innate immune cells and in the priming of anti‐tumor immunity. However, extracellular ATP in the TME is quickly degraded into immunosuppressive adenosine via the concerted enzymatic activities of CD39 and CD73, dampening anticancer immunity. We hypothesize that ATP-responsive delivery of CD39/CD73 inhibitors with boronic acid (BA)-containing nanoparticles enables complementation of ADCs’ actions and the NP delivery, leading to synergistic anticancer actions at two levels. Firstly, cancer- targeting ADCs generate ATP to trigger the release of CD39/CD73 inhibitors from the NPs only in tumor sites, preventing off-target effects in normal tissues. Thereafter, the released enzyme inhibitors prevent conversion of ATP to Ado, enhancing and prolonging the immunogenic actions by ADCs, leading to durable tumor response. We have prepared BA-containing nanoparticles for ATP-responsive drug delivery. CD39 inhibitor ARL67156 (ARL), a nucleotide analogue, is loaded to the nanoparticles through the interaction with BA. The nucleotide drug can be released from the nanoparticles through replacement with ATP and other nucleotides. In preliminary studies, treatment of breast cancer cells with T-DM1 followed by NP-ARL increased extracellular ATP concentration and reduced the presence of adenosine. Combination therapy with T-DM1 and NP-ARL in EO711/HER2-bearing mice remodeled the TME into an immunostimulatory landscape. This change of immune landscape led to excellent immune-medicated tumor response in this syngeneic mouse model of breast cancer. In this proposal, we will explore the mechanisms for immune activation produced by ATP-responsive drug delivery, and will then enhance anticancer activity of our approach for providing an effective and safe therapy of HER2-low breast cancer. This project can be directly translated into a novel cancer immunotherapy treating BC that is aggressive and highly immune heterogeneous. Studies of this project will test the feasibility of using BA- based nanoparticles as a new delivery system for drug targeting, and thus will open a new research horizon for delivery of nucleotide/nucleoside drugs that can treat various diseases.