University Of South Carolina At Columbia

NIH Research Projects · FY 2025 · 2021-09

Project Summary Each year, approximately 400 million people are infected with an arboviral disease from the bite of an Aedes spp mosquito. Aedes spp. mosquitoes are a leading public health threat due to their high competency to vector multiple pathogens, their preference to bite humans, and their ability to adapt to new domestic environments. In the US, reintroduction and establishment of Aedes aegypti and Aedes albopictus mosquito populations has resulted in local epidemics of Zika, dengue and chikungunya in the past decade. Unfortunately, mosquito control programs in the US generally operate with limited budgets, forcing the majority of insecticide spraying to be conducted in reaction to population exposure instead of targeted prevention, which has also contributed to considerable growth of insecticide resistant populations, yielding a widening gap of infrastructure vulnerability. Our current proposal aims to leverage existing technologies from non-health disciplines to advance mosquito detection and abatement. We propose to validate the use of technology-driven mosquito traps that allow for high- throughput identification and counting of Aedes mosquitos at various life stages to inform decision making when selecting areas for insecticide spraying and abatement. Additionally, we propose to develop rigorous remote sensing workflows for identification of neighborhood-level Aedes abundance risk and rapid detection of individual Aedes mosquito breeding habitats on a household-level. This innovative proposal uses multi-year and real-world mosquito data from two different metropolitan areas to statistically adjust for variances in geographic ecologies, urban microclimates, seasonal climate patterns, and annual weather events. Our study will result in low-cost tools immediately ready for broad distribution and integration by vector control agencies nationally. The outcomes of our study have promise to directly impact vector control agency’s decision-making processes for mosquito trapping site selection, inform preventative abetment protocols, and shorten the time required for mosquito collection and identification. Further, integration of our proposed technology traps and informed site selection maps will increase overall collection volumes while preserving scarce resources for local vector control agencies. This proposal has the potential to create a paradigm shift in how we approach vector control globally, with a targeted intervention resulting in significant economic, environmental, and clinical benefits.

NIH Research Projects · FY 2025 · 2021-09

People living in rural regions are more likely to be at increased risk of morbidity and premature mortality because of underlying chronic diseases such as diabetes, hypertension, and cardiovascular disease. Additionally, various stressors (e.g., limited health care access, lack of social support, social isolation and economic instability) experienced within rural communities may further complicate the management of chronic diseases, thus undermining the mental and physical health not only of the patient but carepartners who provide critical support. This study tests the efficacy of a telehealth-enhanced, RN-Community Health Worker (CHW) delivered dyad intervention, ICINGS FAM (Integrating Community-based Intervention Under Nurse Guidance with Families), on quality of life (QoL), and health-related outcomes in rural dwelling adults with preexisting chronic illness and their informal carepartners (IC). Adapted from our previous WISSDOM CINGs model tested in adult stroke patients, key features of this intervention include a) strategies to address various forms of stress perceived by patients and ICs; and b) incorporation of the patient/IC dyad as a unit of analysis to better understand how interpersonal and interdependent relationships impact health and health related outcomes for both partners. We hypothesize that patient/IC dyads receiving the intervention (i.e., coaching related to health promotion, chronic disease management information, and assistance navigating the health care system) will demonstrate improved QoL and health-related secondary outcomes compared to the attention control arm receiving monthly general health promotion. The objective of iCINGS FAM is to strengthen the efficacy and agency of the dyad to manage illness behaviors as an integrated unit, termed "dyad illness management. In Aim 1, we will conduct interviews and focus groups with key community stakeholders to refine iCINGS FAM components to the individual, interpersonal, community, social environment, and other health-related social needs for dyad illness management. In Aim 2, we will employ an RCT design to test intervention efficacy on QoL of adult patients and ICs (250 dyads) with pre-existing chronic health conditions. Intervention effects on symptoms, dyadic confidence, and social support will also be investigated (Aim 2.1). In Aim 3, we will identify individual - and family - level determinants of health (e.g. economic stability, education, food security social support and social isolation)and family illness management behaviors associated with reduced/improved QoL and health outcomes on a subset of dyads (n=50). Finally, to further contextualize study findings, in Exploratory Aim 4 we will examine associations between outcomes and community-level risk and protective factors influence on dyad health and QOL. This intervention has the potential to reduce poor health outcomes and increase understanding of determinants of health that affect QoL and dyadic illness management behaviors in rural patients living with chronic diseases.

NIH Research Projects · FY 2025 · 2021-09

Project Summary This project responds to NIH Directors TRA RFA-RM-20-013 and will test the hypothesis that homeostatic restoration of small GTPase signaling to modify Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) pathogenesis is a game-changing therapeutic approach compared to unidirectional targeting. If proven, this new and innovative paradigm will have far-reaching and transformative impact for targeting other chronic diseases and disorders such as autism spectrum disorder, schizophrenia, and drug addiction. The predominant and conventional therapeutic strategies in treating human diseases are unidirectionally inhibiting or stimulating affected biological processes. However, in many chronic diseases such as AD and ALS, complete inhibition or activation of the affected signaling events may themselves promote diseases. Disease progression can also be spatiotemporal, with initial activation followed by inhibition or vice versa, as well as activation versus inhibition at different brain regions. Thus, simple unidirectional targeting may itself be a major reason that no drugs have successfully prevented, reversed or even modified the disease course for such neurodegenerative disorders. To overcome this formidable challenge, new therapeutic paradigms must be investigated. One approach is to restore homeostatic balance instead of completely inhibiting or activating the affected signaling pathways. This approach is largely untested for AD and ALS but is broadly significant because many other complex diseases also exhibit homeostatic imbalance and spatiotemporal dysregulation of signaling pathways, making the use of inhibitors or activators ineffective if used inappropriately. This TRA project proposes to restore the homeostatic balance of Rho and Rab family small GTPase signaling, which is spatiotemporally dysregulated in AD and ALS. The classical Rho GTPases include RhoA, Rac1, and Cdc42, in which RhoA often acts in opposition to Rac1 and Cdc42 to control protein processing and trafficking as well as synaptic remodeling. Rab GTPases additionally control ER stress and protein aggregation. Our project will apply innovative dual function small molecules to investigate this antagonism for restoring their homeostatic balance. We will determine the effects of their modulation on AD and ALS hallmark proteins and pathogenesis in mouse models. If successful, this project will deliver novel first-in-class drug leads, and the new therapeutic paradigm will transform the entire AD and ALS drug development landscape and beyond. In summary, our proposal provides a strong rationale for the transformative impact of establishing homeostatic targeting at defective signaling processes in AD and ALS. With a multi-institution and multi- disciplinary approach, this project will lead to novel and significant insights into whether targeting homeostatic balances of defective signaling can modify AD and ALS disease course, providing a pioneering example of applying the same approach for future targeting of other chronic and slow progression diseases.

NIH Research Projects · FY 2025 · 2021-09

Abstract Big Data Science (BDS) offers powerful tools to advance biomedical, behavioral, and clinical research through the integration of electronic health records, mobile and wearable technologies, genomic and geospatial data, and computational methods such as machine learning and artificial intelligence. These resources create unprecedented opportunities to address pressing challenges in infectious disease research, particularly in areas of high relevance to NIAID like HIV/AIDS and other infectious diseases. To cultivate a thriving and talented pipeline of next generation scientist workforce capable of leveraging these approaches, we propose the Big Data Health Science Scholar Program for Infectious Diseases, a 10-week short-term summer research training program for predoctoral students in quantitative and/or physical sciences (e.g., biomedical engineering, information technology, chemistry, mathematics, statistics etc) from across South Carolina (SC) and the United States (US). Each year, 8 students (40 total over the project period) will be competitively selected to engage in hands-on research, mentored by experienced faculty, while receiving structured academic training and professional development. Objective 1: Create a summer big data science training pipeline for qualified predoctoral students by exposing them to relevant courses/training for competency development in the application of BDS to infectious disease research. Objective 2: Engage trainees in hands-on research using infectious disease data. Objective 3: Provide trainees with rich research mentoring experience in BDS research and professional development for at least one year (summer included).The program will leverage the infrastructure of the University of South Carolina’s Big Data Health Science Center (BDHSC), which integrates five research cores (EHR, geospatial, genomic, social media, and AI for sensing and Diagnosis) and two supporting hubs (business/entrepreneurship and technology) with participation from 40+ faculty across 10 colleges. Trainees will complete structured training, participate in mentored research, and develop at least one scholarly product. By engaging students from non-healthcare disciplines early in their careers, this program will expand the pipeline of investigators prepared to apply BDS methods to infectious disease research, thereby advancing the NIH mission.

NIH Research Projects · FY 2024 · 2021-09

Project Summary/Abstract: Cardiac contractility is regulated by Ca2+ release form the sarcoplasmic reticulum through ryanodine receptor (RyR2), a protein with multiple regulatory domains for Ca2+, Mg2+, protein kinase, caffeine and FKBP12.6. Since a number of RyR2 missense mutations associate with lethal cardiomyopathies, a detailed understanding of regulatory mechanisms of RyR2 is essential for treatment of these pathologies. Two strategies of heterologous expression of recombinant RyR2 mutants in HEK293 cells and transgenic mouse models, have been used to study structure/function relationship of RyR2 and the functional consequences of disease-linked RyR2 mutations. Although these approaches have provided new insights into RyR2 regulatory mechanisms, they have inherent drawbacks of cells with non-cardiac genetic background and differences in human and mice hearts. We have therefore established an alternate research platform where RyR2 mutations are introduced in human induced pluripotent stem cells (hiPSCs)-derived cardiomyocytes (CMs) using CRISPR/Cas9 gene-editing. Mutant myocytes are then cultured in media that matures them structurally and functionally toward adult cardiomyocyte state. Using this human myocyte platform, we propose to examine molecular mechanisms underlying Ca2+, caffeine, and FKBP regulation of RyR2 associated with CPVT1 pathology. Specifically we aim: 1) To compare Ca2+-signaling consequences of domain specific CPVT1-associated RyR2 mutations expressed in “mature” hiPSC-CMs , rescue their phenotype by back-mutagenesis, and determine their drug specificity; 2) To characterize the functional consequence of mutating the RyR2 Ca2+ and caffeine binding sites, predicted from near atomic structure and determine their interaction; and 3) To characterize mechanisms underlying loss-of-function CPVT1-associated RyR2 mutations and identify the difference between Ca2+ leaky and non-leaky mutations. To accomplish these aims we propose to create multiple mutant lines of our more mature hiPSC-CMs carrying the different RyR2 mutations and examine their Ca2+ signaling aberrancies. Membrane currents and intracellular Ca2+ signals of wild type and mutant hiPSC- derived cardiomyocytes will be quantified in patch-clamped myocytes imaged by confocal/TIRF microscopy using genetically encoded Ca2+ probes targeted to various nodes of Ca2+ signaling pathway. We will also use [3H]ryanodine binding assay, to determine possible alterations in affinities of Ca2+, caffeine and accessory proteins. To assure the reliability of our hiPSC-platform, we will compare the Ca2+ signaling aberrancies of mutagenesis in hiPSC-CMs with in vivo knock-in of RyR2 mutations in mouse models. We hope that our novel approach will make it possible to systematically characterize the phenotype of the CPVT1 mutants, as well as non-CPVT1 mutants with implication to atomic structure of RyR2, in human myocardium, thus providing a novel and synergistic human platform for studies of RyR2 regulation.

NIH Research Projects · FY 2025 · 2021-08

The proposed project establishes an annual conference entitled, “Promoting High-Impact Alzheimer’s Disease Research.” The specific aims of the conference series are to: 1) Provide a forum for all interested researchers, community members, policy makers and other stakeholders to learn about and engage with current research projects and initiatives addressing Alzheimer’s disease and related dementias (ADRD); 2) Provide a mechanism to support ongoing networking among researchers, community members, policy makers, and other stakeholders; and 3) Conduct process and outcome evaluations of the program, making modifications as needed. The proposed conference series leverages the MPIs’ successful leadership in providing mentoring to faculty and students through several active NIA-supported mechanisms. Similarly to our NIA-funded projects, the conference series will extend our statewide collaborations with Clemson University, Medical University of South Carolina (MUSC), Claflin University, Allen University, and South Carolina State University. Additional partners include the only other active statewide AD registries in the United States (US), which are located in Georgia, West Virginia, and South Carolina (the last of which is housed within an office that was co-directed by MPI Friedman). Additional NIA-funded partners include researchers affiliated with the UCLA RCMAR Coordinating Center, University of Southern California (USC) AD-RCMAR, and USC/UCLA Center on Biodemography and Population Health. The conference series will contribute to our ultimate goal of increasing the research workforce in aging and advancing the science on ADRD.

NIH Research Projects · FY 2025 · 2021-08

The multiple, massive, and rich Big Data streams in healthcare (e.g., electronic health records [EHR], mobile technologies, wearable devices, genomic data) and the emergence of advanced information and computational technologies (e.g., machine learning and artificial intelligence [AI]) offer an invaluable opportunity for applying innovative data science research in NIAID focus areas of infectious diseases such as HIV and COVID-19. Data science has the potential to identify high-risk individuals and communities and prioritize them for early biomedical or public health interventions, predict long-term clinical outcomes and disease progression, and evaluate public health policy impact. Key to addressing these complexities is a critical mass of health researchers with adequate knowledge, competencies, and skills to unlock important answers from Big Data to better understand, treat, and ultimately prevent these diseases and related comorbidities. However, there is a nationwide shortage of talent with such knowledge, competencies, and skills, especially in traditional academic settings. While junior faculty, as part of the generations of digital learners, have the greatest potential to develop their Big Data health science (BDHS) research, many face multiple structural barriers to conduct Big Data research. Such barriers include a lack of protected time to initiate new Big Data research, lack of opportunity to participate in funded Big Data research, and a lack of adequate mentoring. To address these gaps, we propose developing a “Big Data Heath Science Fellow” program for junior faculty (i.e., assistant professors) at the University of South Carolina (USC). Specifically, we plan to recruit 4 USC junior faculty per year and provide them with protected time (25%) to participate in comprehensive training, including: 1) courses for competency and skill development; 2) hands-on research and grant proposal development; and 3) interdisciplinary mentoring in Big Data research and professional development. The proposed training program will be implemented with the support of the existing infrastructure of the USC Big Data Health Science Center (BDHSC). With a mission to promote and support BDHS research at USC and across SC through capacity development, academic training, professional development, community engagement, and methodological advancement, BDHSC contains 5 content cores (EHR, geospatial, genomic, social media, and AI for sensing and diagnosis) and 2 supporting hubs (technology and business/entrepreneurship) with the involvement of 50 faculty from 10 USC college/schools. The proposed training will be an integral component of the BDHSC professional development mission. Upon the accomplishment of the proposed training, each trainee will be expected to: 1) obtain hands-on mentored research experience on an NIAID-funded project; 2) develop at least one Big Data-related manuscript on HIV or COVID-19; and 3) submit one grant application to NIAID or other appropriate funding source. The training program will foster a research environment to encourage individuals from all backgrounds to pursue further BDHS research in HIV, COVID-19, and other NIAID focus areas.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY Complex phenotypes are suites of adaptive traits that contribute to a shared function. An important challenge is understanding how such phenotypes evolve and are maintained in populations. Theory predicts that the evolution of complex traits and their preservation in the face of homogenizing gene flow will depend on the genetic architecture of trait divergence, the types and sources of genetic variation, and the presence of reproductive isolating barriers. However, we lack empirical systems to rigorously test these theoretical expectations. While investigations into the genetic basis of repeated phenotypic evolution in emerging model taxa provide an opportunity whether, and how often, evolution proceeds through similar genetic processes, studies of repeated evolution have often involved comparison of only two or three lineages, and rarely have studied complex traits. My research group will bridge these gaps by investigating evolutionary genetics of floral pollination syndrome, a complex adaptation, in the plant genus Penstemon. In this genus, a novel syndrome phenotype has evolved at least 20 independent times. My group will initiate research directions aimed at systematically quantifying genetic and genomic features governing the evolution and maintenance of complex trait diversity, leveraging the exceptional parallelism in Penstemon. We will examine the genetic and genomic architecture of adaptive divergence using replicate QTL analyses, determine which elements of complex traits display genetic parallelism, assess whether standing variation or gene flow act as a source of genetic variation, and examine how complex trait variation is maintained in recently diverged species using population genomic data. This integrative work will contribute to the development of a general framework for understanding whether, and through what mechanisms, phenotypic evolution is constrained by genetic mechanisms. In other words, such data will illuminate the inherent flexibility and limits of an organism's genome to adapt to novel environmental challenges.

NIH Research Projects · FY 2024 · 2021-08

PROJECT SUMMARY The United States (US) and Mexico have the highest prevalence of obesity in the world. In the US, Latinxs, who comprise the largest ethnic minority group, have disproportionately high rates of poor diet quality, obesity, and diet-related health outcomes. Food labeling is a low-cost, wide-reaching intervention for communicating nutrition information to consumers so they can make more informed, healthier food choices. Between 2020 and 2021, the US is changing the Nutrition Facts Label (NFL) on pre-packaged foods, which will increase the visibility of calorie amounts and serving sizes while introducing information on added sugar. NFLs have been criticized, however, for their complexity and location on the back of packaging. Front-of-package (FOP) nutrition labels provide more visible and simplified information on the nutritional value of foods, enabling consumers to easily compare options at the point of product selection. Between 2020 and 2021, Mexico will implement mandatory FOP warnings in the form of prominent “stop signs” on packaged foods that are high in calories, sodium, sugar, saturated fat, or trans fats, as well as products with added caffeine or non-caloric sweeteners. To evaluate the relative effectiveness of these new US and Mexican policies, the current proposal leverages data from the International Food Policy Study (IFPS), which has annually surveyed approximately 4000 US and 4000 Mexican adults since 2018. Funding for Mexico ends in 2020, though funding is secured for the US through 2024. Mexicans and US Latinxs with lower educational attainment – key groups with disproportionately high obesity rates and for whom the FOP warnings may be most effective – have been under-represented in IFPS surveys. The proposed study will continue annual surveys of Mexican consumers through 2024 (n=4000/year) while providing an oversample of US Mexican Americans (MAs; n=2000/year) who comprise approximately two-thirds of all US Latinxs. We will recruit additional samples of Mexicans (n=1500/year) and MAs (n=1500/year) with lower education. This pre/post study will compare within- and between-countries over time to address two aims. Aim 1 will evaluate the impact of the mandatory FOP warnings in Mexico relative to NFL changes in the US. We hypothesize that increases in awareness/use of nutrition labels, nutrition knowledge, and healthy dietary behaviors will be greater in Mexico than in the US, including US MAs. Aim 2 will evaluate disparities in the effects of these nutrition labeling policies. We hypothesize that awareness and use of FOP warnings, nutrition knowledge, and healthy dietary behaviors will increase more from pre- to post-policy among disadvantaged groups in Mexico than in the US due to the greater prominence and simplicity of the Mexican FOP warnings. Finally, we expect that post-implementation trends in labeling effects among disadvantaged groups will favor the Mexican over US policy. The results from this study will inform policy development in the US and globally, as well as communication theories that guide product labeling to promote healthy behaviors.

NIH Research Projects · FY 2024 · 2021-07

Overweight and obesity are linked to a number of chronic diseases, including type 2 diabetes mellitus (T2DM). Weight loss has been shown to help with the prevention of T2DM. Behavioral weight loss programs that provide, encourage, or facilitate social support are associated with greater adherence to treatment. Social support can also help to encourage consistent dietary self-monitoring, which is considered the cornerstone of weight loss treatment and an important component of interventions targeting T2DM prevention and management. Few studies have focused specifically on ways to target areas of social support that have proven to be effective in face-to-face delivery settings. The Social Pounds Off Digitally (Social POD) study was a three-month randomized weight loss intervention with content delivered remotely via twice-weekly podcasts (same for both intervention arms). Overweight adults (N=51) were recruited and randomly assigned to either the experimental group (n= 26; Social POD app that received points for self-monitoring and social support)) or the comparison group (n=25; standard diet tracking app with no points). Social POD group participants lost significantly more weight (-5.3 kg; 95%CI: -7.5, -3.0) than those in the standard app group (-2.2 kg; 95%CI: -3.6, -1.0; p=0.02) and total points earned significantly predicted % weight loss (B=-0.02, p=0.01). This study, with 39% of the participants being African American, represents one of the more diverse study samples for a digital weight loss intervention. The goal of the present proposal is to examine the Social POD intervention in a longer-term study (12 months) to ensure that use of social gaming leads to sustainable behavior changes and continued weight loss. Our study has the following aims: Aim 1) Determine if the Social POD app plus points intervention (SocialPOD+points; points for provision and receipt of social support) produces significantly more weight loss at 12 months than the Social POD without points (SocialPOD-) among 240 adults with overweight or obesity and ≥3 T2DM risk factors. Hypothesis: The SocialPOD+points group will lose more weight than the SocialPOD- group. Aim 2) Examine the differences in social support provision and receipt between groups at 12 months. Hypothesis: That the SocialPOD+points group will have greater levels of social support provision and receipt than the SocialPOD-. Secondary Aims) Examine usage patterns over time [e.g., do points sustain engagement and promote weight loss maintenance?], potential mediators and moderators [engagement (e.g., frequency of self-monitoring)], demographic factors (e.g., sex, race, age)], the usability and acceptability of the interventions, and the association of social support provision/receipt and psychosocial factors (e.g., motivation, enjoyment) with weight loss. This approach has considerable public health appeal since, if the social gaming approach proves to be successful in promoting and maintaining weight loss, it could be greatly scaled up for widespread dissemination.

NIH Research Projects · FY 2025 · 2021-07

Total knee replacement (TKR) utilization continues to increase, placing substantial burden on the economy. As patients live longer with TKR, it is essential to identify strategies that will maximize long-term functional outcomes and promote health-related quality of life and independence as adults age after surgery. The majority of TKR patients meet criteria for overweight/obesity and remain physically inactive after surgery, both of which heighten the risk of poor functional outcomes and disability. Further, most patients will actually gain weight within two years after surgery. Patients after TKR are also at an increased risk of death from cardiovascular and mental diseases. Promoting weight management may be an effective strategy to improve long-term functional and physical activity outcomes after TKR, reduce the risk of disability and death from cardiovascular and mental diseases, and improve the value of the costly surgery. We propose to examine the effectiveness of a Patient-Centered (PACE) weight loss program in adults after TKR in a fully-powered, two-arm randomized controlled trial. Patients (n=250) will be randomized to receive either (1) PACE weight loss program or (2) Chronic Disease Self-Management (CDSM) control group. PACE participants will start the patient-centered program 12 weeks after TKR and continue for 12 months. PACE is tailored to the patients’ needs and unique barriers to diet and physical activity. PACE focuses on reducing caloric intake and increasing physical activity (aerobic and resistance) to facilitate a weight loss of at least 7% of initial body weight. Coaching calls with a trained behavioral interventionist will occur weekly during months 1-4, biweekly during months 5-6, and monthly during months 7-12. No coaching will occur during the maintenance phase (months 13-18). CDSM will receive a self-directed version of the program and monthly calls on topics not related to study outcomes. Data collection will occur at baseline (12 weeks after surgery), 6 months (end of intensive intervention), 12 months (end of treatment), and 18 months (maintenance). Assessments will include measures of weight, secondary outcomes (e.g., physical activity, pain, function), and potential mediators from our conceptual model (e.g., adherence, self-efficacy, autonomy, competence). Data related to the cost of implementing the PACE weight loss intervention relative to Control will also be collected to examine the cost-effectiveness of reducing weight on patient outcomes. The primary outcome is weight change at 6 months. The expected outcome from this study is to determine the effectiveness and long-term maintenance of a refined patient-centered weight loss program tailored specifically for adults after TKR. If PACE is effective at improving short- and long-term outcomes, and is found to be cost-effective, orthopedic centers and/or insurance companies could consider offering this program to TKR patients, offering significant benefits to the rising number of adults underdoing TKR.

NIH Research Projects · FY 2024 · 2021-07

PROJECT SUMMARY As the nation continues to grapple with a rapidly changing epidemic of opioid overdose and mortality, there has been increasing public attention devoted to expanding access to opioid use disorder (OUD) treatment. While Medicaid is positioned to be a key policy lever to improve access to OUD treatment and reduce mortality among vulnerable populations, many state Medicaid programs do not cover the full continuum of OUD treatment and use utilization management parameters that may restrict access. Moreover, most state Medicaid programs contract with managed care organizations (MCOs). While over 70% of all Medicaid enrollees participate in MCO plans, little is known about how these plans cover OUD treatment. To fill this gap in the scientific evidence, we will conduct the first multi-state study of the effects of Medicaid MCO coverage and utilization management design on OUD treatment receipt and outcomes. The study will break new ground by encompassing all MCO plans, across multiple states, for the full continuum of treatment. We also propose to make use of innovative random auto-assignment methods in two state Medicaid programs. Our specific aims will include: estimating how state Medicaid program contractual regulations and oversight are associated with MCO plan level coverage and utilization design; estimating how MCO plans’ coverage and utilization management design are associated with progression through the Cascade of Care (diagnosis, engagement, medication initiation, and retention); and estimating how MCO plans’ coverage and utilization management parameters are associated with opioid-related emergency department visits, hospitalizations, and mortality. The proposed study will be the first comprehensive investigation of the effects of MCO coverage for OUD treatment services and medications on treatment receipt and outcomes – evidence without which the care of a large fraction of the OUD population is compromised. The study will also produce new insight into how states are regulating and monitoring MCO plan coverage and utilization management design. In the midst of the deadliest drug epidemic in the nation’s history, evidence regarding the impact of Medicaid MCO coverage for OUD treatment is urgently needed. This research will equip policymakers with evidence-based guidance on how to structure MCO contractual arrangements to ensure appropriate and efficient access to OUD treatment.

NIH Research Projects · FY 2025 · 2021-06

Abstract Viral suppression is the final stage of the HIV treatment cascade, which serves as the framework for UNAIDS’ 90-90-90 goals. Sustained viral suppression is one of four strategic areas of the “Ending the HIV Epidemic (EtHE): A Plan for America” federal campaign, launched in February 2019, which aims for the reduction of new HIV infections in the United States (US) by 75% and 90% by 2025 and 2030, respectively. The EtHE campaign focuses on 48 US counties and 7 states, including South Carolina (SC). Given the importance of viral suppression in ending the US HIV epidemic, an optimal predictive model of viral status can help clinicians identify those at risk of poor viral control and inform clinical improvements in HIV treatment and care. Various indicators to characterize the longitudinal virologic outcomes have been proposed in the literature such as sustained viral suppression, viral rebound, low-level viraemia (LLV), persistent LLV, and virologic blips. However, some critical gaps still exist in our efforts to develop an optimal predictive model of viral suppression. These gaps include the use of limited indicators of virologic outcomes, limited duration of follow-up, limited data sources, lack of consideration of structural and socioenvironmental data, small or unrepresentative samples of people living with HIV (PLWH), and limited efforts to translate research findings into service-ready tools for clinical use. With NIH support (R01AI127203) since 2017, we have utilized a Big Data approach to examine treatment gaps (e.g., missed opportunities for diagnosis and linkage to care) among a statewide cohort of PLWH in SC. This ongoing research extracted longitudinal electronic health records data from six state agencies and then linked the patient-level data with county-level data (e.g., socioeconomic indicators, number of health care professionals, hospitals, and health care facilities) from multiple publicly available data sources. The resultant integrated database has enabled us to successfully “track” 11,470 patients who were diagnosed with HIV from 2005 to 2016 in SC and identify the gaps in HIV treatment linkage and retention. Based on the experience and accomplishment of the R01AI127203, we submit this application to examine the longitudinal dynamic pattern of viral suppression, develop optimal predictive models of various viral suppression indicators, and translate the models to service-ready tools for clinical use. In the proposed research, we will: 1) continue to “follow” our cohort for another five years (and also expand the cohort by adding PLWH diagnosed between 2016-2020); 2) expand our database to include additional data on critical predictors of viral suppression (e.g., treatment and laboratory data, alcohol and substance use data) from two newly participating statewide data sources; 3) employ artificial intelligence (AI)-based modeling to understand the dynamic viral load patterns and their predictors; and 4) develop and pilot-test a multifactorial decision system for clinical use. The results will enable the identification of PLWH with poor viral control and suggest “when” and “how” to help those PLWH achieve and maintain viral suppression. The proposed research will improve our understanding of the longitudinal dynamics of viral suppression and inform tailored HIV care management among PLWH in SC and beyond.

NIH Research Projects · FY 2025 · 2021-06

K23 Abstract DESCRIPTION: Nearly one third of individuals with substance use disorders are women of childbearing age. Life-threatening infant complications from maternal opioid use disorders (OUD) include neonatal withdrawal syndrome, acute and chronic developmental and behavioral challenges, increased risks of infection through maternal transmission (i.e. HIV, Syphilis), and death. Mothers with OUD must negotiate micro and macro level challenges that impact parenting and recovery management, including reluctance to disclose drug use for fear of legal issues, child custody and domestic disputes, stigma, financial, and transportation barriers. There are few proven interventions that support long-term recovery management and parenting for addicted new mothers embedded within this unique context. Using a community based participatory research (CBPR) approach, we will determine the feasibility and preliminary effects of a customized evidence-based digital technology self-management recovery program for women with OUD during the pregnancy and postpartum period. Based on our preliminary data, our central hypothesis is that once tailored strategies are identified by primary stakeholders, an evidence-based program that uses digital technology can be delivered to pregnant and parenting women with OUD to expand accessibility to evidence-based parenting and recovery resources. The specific aims of this study include: (1) Customize eRecovery technology integrating preferred parenting resources and recovery supports in collaboration with a community advisory board (CAB) and new mothers in early recovery from substance use disorders; (2) Evaluate the feasibility of using the customized eRecovery technology for pregnant and postpartum women in early recovery from OUD to determine use and usefulness based on participant perceptions, engagement and retention in care, drug abstinence, and parenting outcomes. The results from this proof-of-concept study will provide strong pilot data to guide development of a full-scale trial in a future RO1 application in Year 4 of this award. The career development award will provide Dr. Raynor the mentoring and training needed to develop knowledge and skills in rural health disparities, CBPR methods, digital intervention development and program evaluation, population health interventions and advanced research training. At the close of the award, she will be positioned to design, implement, and evaluate research that will significantly improve the health outcomes of pregnant and parenting women with OUD and their vulnerable newborn infants living in a rural Southeastern state.

NIH Research Projects · FY 2025 · 2021-05

Project Summary T-cell-dependent (TD) immunoglobulin A (IgA) responses regulate the composition of the gut microbiota. How B-cell-intrinsic MHCII signaling, which is central to the development of TD IgA responses, influences host- microbiota interactions is unknown. MHCII is widely assumed to promote clonal diversity in effector lymphocyte populations, but this has not been tested. Here, we present evidence in support of the argument that B cell- intrinsic MHCII signaling controls GC dynamics, IgA repertoire diversity, and microbiota composition. Additionally, evidence from our experiments also indicate that both B-cell-intrinsic ablation of MHCII and specific MHC genotypes are associated with enhanced bacterial dissemination from the gut. Based on these observations and previous work by Dr. Kubinak, this R01 seeks to address the hypothesis that B-cell-intrinsic MHCII signaling is a diversifying force of selection promoting clonal diversity in IgA plasma cell pools and individuality in microbiota composition. The objective of Specific Aim #1 is to define the B-cell-intrinsic role of MHCII during GC reactions in the gut; specifically focusing on its role in shaping plasma cell repertoire diversity. A 'Confetti' mouse model will be used to visually demonstrate the effect of MHCII ablation on GC B cell clonal diversity in the gut. IgH sequencing will be used to determine the effect of MHCII polymorphisms and MHC heterozygosity on IgA repertoire diversity in the gut. scRNA sequencing will be used to determine how MHCII influences overlap in clonal diversity between mucosal and systemic plasma cell pools. RAG1-/- bone marrow (BM) chimeras will be used to quantify the effect of MHCII on cross-seeding of gut-derived plasma cells into the BM. Reciprocal BM chimeras will be used to determine the necessity/sufficiency of defects in B-cell-intrinsic MHCII in regulating bacterial dissemination from the gut. The objective of Specific Aim #2 is to test that microbiota composition is an MHCII-dependent phenotype. RAG1-/- and RAG1-/-IL7R-/- BM chimeras will be used to determine the role gut peyer's patches play in driving MHCII-mediated IgA selection in the gut. Microbial colonization experiments in germfree GF RAG1-/- BM chimeras will determine the effect of B-cell-intrinsic MHCII on IgA-targeting of commensal bacteria. A RAG1-/- adoptive transfer model will be used to determine if MHCII surface density influences IgA-mediated targeting of commensals and microbiota composition. Finally, a novel germfree MHC congenic model will be used to explicitly define the role IgA plays in driving individuality in microbiota composition. Results from these studies will address the B-cell-intrinsic role of MHCII in regulating mucosal IgA responses, microbiota composition, and host health. This is a critical gap in our knowledge that is highly relevant to human health. IgA deficiency is the most common form of antibody-deficiency in humans, is strongly linked to genetic variation in MHCII genes, and has been shown to result in dysbiosis that is associated with chronic inflammation. Experiments outlined here are the first to address how MHC genotype influences microbiota composition and bacterial leakage from the gut, a potent driver of chronic immune activation.

NIH Research Projects · FY 2025 · 2021-05

Health promotion efforts among African American men have produced limited results. African American men have lower health-related quality of life (HRQoL; i.e., a comprehensive indicator of health consisting of physical, psychological, and social functioning) than any other ethnic-sex group in the United States. HRQoL is a measure of population health that is associated with mortality and morbidity. HRQoL is exacerbated by stress, depression, low levels of physical activity, and poor diet – contributors to adverse health often experienced by African American men. There is an urgent need to develop a health promotion program to improve HRQoL among these men. The success of such a program hinges on its ability to recruit and retain these men – African American men constitute fewer than 10% of participants enrolled in clinical trials and are underrepresented in health research. A health promotion program that is culturally relevant to the lived experiences of these men and implemented through a peer-to-peer model can improve engagement, minimize attrition, and promote HRQoL. Thus, a community-informed, peer-to-peer intervention to improve the HRQoL among African American men will be developed. The development of this intervention will be informed by the Social Ecological Model of Health, Social Cognitive Theory, Community-Based Participatory Research, and a community advisory board consisting of African American men. It is hypothesized that the theoretically-based intervention will be effective in recruiting and retaining these men, in addition to improving their HRQoL. The specific aims of the study are (1) to determine the individual, social, and environmental characteristics that impact stress, depression, physical activity, and diet among African American men; (2) to assess the feasibility and acceptability of a community-informed, peer-to- peer intervention to improve the HRQoL among African American men; and (3) to evaluate the efficacy of a pilot randomized wait-list control trial to determine the preliminary impacts of the community-informed intervention on HRQoL among African American men. This research will inform recruitment and retention efforts of African American men in health promotion programs, in addition to strategies to improve HRQoL. The candidate’s mentorship team consists of renowned experts in the development of tailored health promotion interventions, the health of men of color, qualitative and quantitative research, Community-Based Participatory Research, and technology-enhanced interventions for African American men. The training plan involves coursework, seminars, and mentored research experiences to develop expertise in (1) qualitative, quantitative, and mixed-methods research, (2) implementation and dissemination science, (3) behavioral randomized controlled trials, (4) grant- writing, (5) health promotion and disparities among minority communities, and (6) mHealth. The research and training proposed in this K23 Career Development Award will support the candidate’s long-term goal of becoming an independent scientist and leading investigator in developing and testing innovative interventions to improve the HRQoL among underserved and at-risk communities.

NIH Research Projects · FY 2025 · 2021-04

Project Summary/Abstract The U.S. Dietary Guidelines (USDG) form the basis of federal nutrition programs and policy and provide valuable guidance to health initiatives and industries. The updated 2015 USDG moved away from a focus on individual nutrients to a greater focus on dietary patterns. The USDG state that healthy eating goals can be met through a variety of dietary patterns, but present healthy diet in three main ways: 1) Healthy U.S.- Style Eating Pattern, 2) Healthy Mediterranean-Style Eating Pattern, and 3) Healthy Vegetarian Eating Pattern. Currently, US adults are falling short of the nutrition recommendations (fruit/vegetable intake, greens/beans, whole grains, etc.) set forth by the USDG and measured by the Healthy Eating Index (HEI). While the USDG are the basis of nutrition guidelines, the research informing these dietary pattern recommendations has largely been drawn from observational studies among mostly white populations. In addition, there has been very limited cultural-tailoring of these dietary patterns that would ensure that these diets are acceptable to diverse populations, in particular, African Americans (AAs) living in the south, who experience a disproportionate burden of chronic disease, especially type 2 diabetes (T2DM). Currently, US adults are not meeting nutrition recommendations (fruit/vegetable, whole grains, etc.) set forth by the USDG and measured by the Healthy Eating Index (HEI). For this study, AA adult participants with overweight/obesity and ≥three T2DM risk factors will be recruited to participate in the following aims: Aim 1: Conduct a 3-month randomized trial among AAs comparing adoption of the 3 dietary patterns [1) US, 2) Med, or 3) Veg] using existing materials from the USDG and examine differences in diet quality (HEI) and T2DM risk factors (weight, HgbA1c). Aim 2: Drawing on participants’ experiences in Aim 1, conduct qualitative work to refine and culturally tailor the dietary pattern intervention for an AA audience. Aim 3: Based on the findings of Aim 2, conduct a one-year intervention using revised culturally tailored materials to examine differences in HEI and T2DM risk factors among participants (n=198) randomized to one of the 3 dietary patterns. This will result in community-based strategies around presenting dietary guidelines in a way to effectively meet nutrition recommendations leading to significant impacts on health among AA adults.

NIH Research Projects · FY 2025 · 2021-02

Interventions promoting physical activity among cancer survivors improve their functioning, reduce fatigue and offer other benefits in cancer recovery and risk reduction for future cancer. There is a need for interventions that can be implemented on a wider-scale than in research settings. Our 12-week theory-based exercise intervention that was delivered by research staff by telephone was efficacious in improving fitness, and increasing moderate-to-vigorous physical activity (MVPA) among breast, colorectal and endometrial cancer survivors. To widen the intervention’s reach, we trained peer coaches in the American Cancer Society’s Reach to Recovery program to deliver the same MVPA intervention called Moving Forward Together (MFT) to other breast cancer survivors. In a randomized controlled trial, MFT significantly increased MVPA and provided psychosocial benefits for these survivors (Pinto, Stein & Dunsiger, 2015). Now, our goal is to prepare for wider implementation of MFT by automating key resource-intensive components such as matching survivors with a coach by using a web-based peer mentoring platform and to collect key indices to prepare for large scale implementation. InquistHealth’s web platform (Mentor1to1™) has demonstrated to be effective in peer mentoring for chronic disease management (e.g., diabetes). We will partner with InquisitHealth to adapt their web platform for MFT. The aim is to streamline intervention delivery, assure fidelity and improve survivor outcomes. There will be two phases in this 4-year R01 application: in Phase 1, we will work with 6 peer coaches who have already delivered MFT (our original evidence-based MVPA intervention) in prior work. Using iterative user-centered design principles, we will modify the web platform for MFT, creating webMFT. In Phase 2, we will conduct a randomized controlled trial in which 10-12 peer coaches will deliver webMFT to 56 breast cancer survivors who will be randomized to receive either webMFT or MVPA Tracking. We will recruit and train coaches naïve to MFT from three cancer care organizations with peer mentoring programs. We will collect feasibility and acceptability data about webMFT from the coaches. We will examine survivor outcomes (objectively measured MVPA and self-reported fatigue, quality of life, physical functioning and mood) by using mixed effects regression models to compare groups at 12 weeks. We will obtain survivors’ feedback on their experience with webMFT. Based on the RE-AIM framework and PRISM, we will collect data on implementation indices at the organizational level by conducting key multi-level stakeholder interviews. Using newer technologies for enhanced intervention delivery, program management and automated data collection has the exciting promise of facilitating effective implementation by organizations with limited resources. Adapting evidence-based MFT to a customized web platform and collecting data at multiple-levels (coaches, survivors and organizations) along with costs will provide a strong foundation for a robust multi-site implementation trial to increase MVPA (and its benefits) among many more breast cancer survivors.

NIH Research Projects · FY 2025 · 2021-01

PROJECT SUMMARY WENCESLAU, CAMILLA F. One of the major pathophysiological characteristics of hypertension is the presence of vascular remodeling. Accordingly, it has been shown that 100% hypertensive subjects present small artery remodeling. However, there is a gap in the literature in understanding the exact trigger that leads to vascular remodeling, and this may limit our ability to adequately treat and prevent hypertension. Recent evidence implicates immune mechanisms in the pathophysiology of hypertension. Formyl peptide receptor (FPR)-1 is a pattern recognition receptor which plays a crucial role in the function of the innate immune system. In fact, one of the most powerful signaling pathways that induces actin polymerization and neutrophil movement is mediated by FPR-1. Recently, we observed that this receptor is expressed in arteries. Therefore, we questioned why a receptor that is crucial for immune defense and cell motility in leukocytes, would be expressed and functional in arteries? We observed that activation of FPR-1 in arteries is important for the temporal reorganization of actin, which rapidly induces actin polymerization. FPR-1 is a G-protein-coupled receptor that can bind N-formyl peptides produced by bacterial degradation. Interestingly, mitochondria carry hallmarks of their bacterial ancestry. Consequently, both mitochondrial and bacterial-derived peptides have a formyl group at their N-terminus. Therefore, N-formyl peptides (NFPs), regardless of origin, are recognized by FPR-1 as pathogens and thus play a role in the initiation of inflammation. Here, we observed for the first time that NFPs are present in the circulation of hypertensive animals and humans. Therefore, it is plausible to suggest that synergistic action of leaky gut-derived bacteria NFPs and cell damage-derived mitochondria NFPs lead to FPR-1 activation. Consequently, FPR-1 activation maybe the trigger to induce vascular remodeling, via actin polymerization, and subsequently, hypertension. This planned research is uniquely suited to the NHLBI Early Stage Investigator (ESI)-Research Project Grant (R01). It is innovative and has a strong, translational and multi-disciplinary research team of collaborators that have the capabilities and expertise to make this project successful. As an independent ESI, my short-term goal is to use state-of-art approaches, including culture-pressure myographs, genetic-engineering technologies, and arteries from humans and animals to explore a major driving force behind vascular-immune network dysfunction in hypertension.

NIH Research Projects · FY 2024 · 2020-11

PROJECT SUMMARY Anxiety and risky behaviors are the most prevalent mental health concerns facing adolescents. The adolescent brain is characterized by a high degree of neural plasticity in which circuit-level formation is very responsive to environmental changes. There is increasing evidence that most psychiatric disorders have a developmental origin that is the result of early disturbances in this complex process. Adolescence is a period in which exposure to altered environmental lighting is decidedly common, as 50% of adolescents in the USA reported using computers, smartphones, and tablets before bedtime. This intensity of artificial light and the duration of exposure past sunset is unprecedented in human history. Despite the widespread exposure to night-time light in adolescents, our knowledge of the mechanisms by which our brain adapts to irregular environmental lighting is still incomplete. The medial amygdala (MeA) plays a key role in processing emotions and is also one of the regions, among others, that receives and processes light information. Thus, artificial changes in light exposure levels, timing, and regularity might generate confusing signals in this region, affecting neuroplasticity and emotional responses. To study whether light affects neuroplasticity in the MeA, thereby increasing vulnerability to anxiety and risk-decision making in adolescent mice, I developed a new aberrant light protocol designed to mimic human adolescent light exposure. This Pathway to Independence Award will provide the opportunity to build on my expertise in neurobiology and behavioral neuroscience while developing my abilities in fiber photometry and RNA-sequencing. Aim 1 is built upon our preliminary data showing that aberrant light exposure alters neurotransmitter plasticity in the MeA of adolescent mice, and that such neuroplasticity contributes to their vulnerability to anxiety and risky behaviors. Under the supervision of Dr. Barnes and Dr. Young, I will use the Iowa Gambling Task to test whether aberrant light exposure alters risk-taking behaviors differently in adolescent and adult mice. With additional mentorship from Dr. Ramanathan in the K99 phase, I will explore whether aberrant light affects neural activity in selected MeA neurons using fiber photometry-based calcium recording in behaving mice. In Aim 2, under the supervision of Dr. Preissl, I will investigate whether aberrant light exposure affects gene expression in MeA neurons and its target regions participating in anxiety and risky choice behaviors, such as the central amygdala and the bed nucleus of the stria terminalis. These experiments will prepare me for the R00 phase in which I will study the role of amygdala circuitry in light-mediated anxiety and risky behavior by combining pharmacological manipulation of amygdalar neurons, fiber photometry, and translational mouse models (Aim 3). Because the amygdala is a well-conserved structure, the proposed research will be translationally relevant for understanding the effect of altered environmental lighting during pubertal development and for the design of appropriate integrative interventions to promote emotional well-being in adolescents.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY Between 2001 and 2009, the multi-site SEARCH for Diabetes in Youth study documented marked increases in the incidence and prevalence of type 1 diabetes (T1D) and type 2 diabetes (T2D) among youth. These trends were largely driven by increased incidence rates in racial and ethnic minorities. Ongoing surveillance of diabetes diagnosed in youth is essential to inform health care systems and generate testable hypotheses related to the natural history of diabetes in youth, but it cannot be accomplished through existing national survey-based surveillance efforts because of the rarity of diabetes in youth. Therefore, in response to RFA-DP- 20-001, Component A, we propose the South Carolina DiCAYA Youth study, which will ascertain newly- diagnosed incident diabetes cases statewide throughout the study period. Our approach is informed by almost 20 years of experience in South Carolina that allows us to conduct diabetes surveillance work in youth in a highly efficient manner, relying on a novel 2-step approach developed by our team which builds on electronic health record (EHR) data. Our specific aims are: Aim 1: To ascertain newly-diagnosed cases of incident diabetes in youth < 18 years of age in 2020 - 2024 in order to describe diabetes incidence in South Carolina, by age, sex, race/ethnicity, and diabetes type. Aim 2: To provide annual estimates of the prevalence of diabetes in youth < 18 years, by age, sex, race/ethnicity, and diabetes type, using mathematical modeling and the ascertained incidence data. South Carolina is uniquely positioned to contribute to the DiCAYA surveillance effort by employing our well-established surveillance infrastructure that has been refined for optimal efficiency while maintaining our exceptional levels of scientific rigor and ascertainment completeness. Moreover, we are comprised of a highly-experienced, collaborative and multi-disciplinary investigative team. Last but not least, South Carolina’s location in the South Atlantic census division and high proportion of non- Hispanic black residents will be critical to guaranteeing the representativeness of the overall DiCAYA surveillance effort, as South Carolina has contributed 21% of all incident T1D cases (48% of non-Hispanic black T1D) and 32% of all incident T2D cases (70% of non-Hispanic black T2D) to surveillance conducted by SEARCH. Thus, the well- established and highly- productive South Carolina team is uniquely positioned to provide critical information on the prevalence and incidence of diabetes in youth.

NIH Research Projects · FY 2024 · 2020-09

Abstract: Racial and ethnic disparities in maternal adverse outcomes remain a significant public health problem. Studies conducted in New York City (NYC) hospitals have shown that minority women are more likely to deliver in low-quality hospitals and that they are also at a higher within-hospital risk of severe maternal morbidity (SMM) than white women, even after accounting for type of insurance. Although these studies represent important pointers in our understanding of SMM disparities, there are still many open questions about how quality of delivery hospitals drives the higher rates in adverse outcomes observed for minority women. First, it is unknown whether racial/ethnic differences in delivery hospital quality (between and within) exist in cities or regions other than NYC, especially in rural areas. Second, there is little information on the reasons for differences in where women of different racial/ethnic status deliver. Third, previous efforts examining racial disparities in healthcare delivery have mainly focused on individual-level factors overlooking the broader macro-level societal and structural conditions (e.g., structural racism) that may be at play. Finally, it is unknown how important policies such as Medicaid expansion have impacted obstetric hospital quality, especially minority- and rural-serving hospitals. Research studies investigating higher level factors that transcend individual-level factors to explain racial/ethnic disparities in maternal outcomes are urgently needed to design effective interventions. Thus, the proposed study will address the following: 1) Determine the contribution of delivery hospital quality to racial/ethnic disparities in maternal mortality and SMM; 2) Examine within-hospital racial/ethnic disparities in risk-adjusted maternal mortality and severe morbidity and identify whether these disparities are associated with types of medical insurance and broader societal and structural conditions; 3) Determine societal- and individual-level maternal factors associated with using versus bypassing high-quality hospitals; 4) Identify the impact of expanded Medicaid income eligibility to adults earning up to 138% federal poverty level on: (Aim 4a) hospital quality (especially safety-net and rural-serving hospitals); and (Aim 4b) the incidence of maternal mortality and SMM, either overall or by race/ethnicity and socioeconomic status. We will use birth certificate data linked to hospital discharge data and supplemented by other datasets from eight U.S. states from 2000-2019 to develop a risk-adjusted maternal mortality and SMM composite outcome which will allow us to rank hospitals. We will subsequently use hospital ranking to examine the contribution of hospital quality to racial/ethnic disparities. The aim on Medicaid expansion will make use of a natural experiment framework and difference-in-difference analysis resulting in comparing each state to itself, before and after Medicaid expansion. At the end of the study, we will have a better understanding of racial/ethnic disparities in the health care system among all mothers in eight states and will identify potential areas for improvement that can have profound implications on reducing disparities.

NIH Research Projects · FY 2024 · 2020-09

Summary The overall objective of the R25 Research Education Program(REP) summer experience is to establish an approach for providing minority students attending USC with the support needed to increase diversity in the field of biomedical science and aging by providing mentorship and research training opportunities for young URM biomedical scientists with unique experiences and perspectives. To accomplish this objective, we will: I) use our already developed and validated innovative strategies to recruit 100 URMs to the different biomedical science disciplines and aging related research experiences at USC. We will attract these students by conducting seminars, workshops, and lectures at the USC campuses throughout the academic year. II) Organize a USC Biomedical Science Forum where 50 URM students from a pool of 100 URMs will be invited for a two-day orientation during the spring semester. These students will visit USC and its biomedical science programs while also obtaining information on the ten-week summer REP. III) Provide a 10-week summer educational mentoring and research opportunity at USC for ten REP students every year for five years. For the summer program, we will,1) match each REP participant with a mentor to initiate the development of an individual development plan(IDP), and organize a weekly mentoring activity, 2) organize professional development workshop training for URMs in aging research, 3) implement a weekly Science/Journal club meeting to discuss publications related to aging research, 4) organize workshop training in professional development to synergize REP students with USC training programs in professional development activities allowing networking with other young colleagues, and 5) provide scientific research for REP students to enhance their research career development in biomedical sciences and promote graduate school aspirations. Beyond the summer REP, we will provide research and mentoring opportunities to continue to synergize REP students with USC training programs. By providing academic support initiatives, including mentoring, professional development activities and training in biomedical science and aging related research opportunities, we will be able to increase diversity in the field of biomedical science and aging related research for young URM biomedical scientists. Continued "mentoring " of REP students will go on until they complete their baccalaureate degree in biomedical science and will even continue finally to their matriculation into graduate programs in biomedical sciences at USC. We expect that 70% of REP students in their senior years will have research experience, evident in publications (manuscripts and conference abstracts). The research experience will prepare them for graduate programs, while the publications will make them competitive for graduate school admission. We plan to increase awareness for at least 60% of URMs, freshman through senior years in different career opportunities in aging research.

NIH Research Projects · FY 2024 · 2020-07

Peripheral nerves spontaneously regenerate but the axon growth rate is abysmally slow, such that complete functional reinnervation of targets is rarely achieved in humans. Axon regeneration in the central nervous system is even worse, such that individuals with spinal cord injury (SCI) almost invariably have permanent lose of sensory and motor functions below the level of the lesion. There is a pressing need to accelerate axon regeneration in the peripheral nervous system and increase axon regeneration in the central nervous system. Our research program focuses on axon intrinsic mechanisms of regeneration. Intra-axonally synthesized proteins support axon growth in developing neurons. We have shown that PNS neurons retain the capacity to synthesize proteins in their axons and these proteins support growth of injured axons. Axons of cultured neurons contain thousands of mRNAs – and several lines of evidence point to complex populations of mRNAs in CNS axons in vivo and spinal cord axons contain mRNAs and translational machinery when encouraged to regenerate with permissive substrates. Despite remarkable advances since the early 2000’s, the molecular mechanisms that determine when and where a specific mRNA is translated in axons remain largely unknown. This level of regulation is critical for regulating axon growth capacity. We have shown that mRNAs are stored in PNS axons in RNA-protein aggregates that contain the stress granule protein G3BP1. G3BP1 protein can drive stress granule aggregation, and G3BP1 phosphorylation blocks stress granule assembly. Unlike the classically defined stress granule, axonal G3PB1 protein shows aggregation in uninjured/functioning PNS axons. These axonal G3BP1 aggregates rapidly increase after axotomy, but decrease to below basal levels shortly thereafter with a corresponding increase in phosphorylated G3BP1. G3BP1 binds to mRNAs in axons and attenuates their translation. We have discovered exogenous agents and endogenous signals that trigger disassembly of axonal G3BP1 aggregates. The exogenous agents specifically increase axonal protein synthesis and accelerate axon growth rates in vitro and in vivo. These observations have led us to hypothesize that physiological aggregation of stress granule proteins in axons attenuates axon growth in the injured PNS and CNS by blocking translation of an axonal mRNA cohort. We will test this hypothesis with the following specific aims: Aim 1 – Promotion of axon growth by inhibition of G3BP1 function. Aim 2 – Endogenous mechanisms for axonal G3BP1 aggregate disassembly. Aim 3 – Mechanisms driving axon growth upon disassembly of axonal G3BP1 aggregates. Functional roles for axonal translation have now come to light and we have solid in vivo evidence that this mechanism can be targeted to accelerate axon growth after acute peripheral nerve injury. Completion of the proposed research will bring new insight into mechanisms for temporal regulation of axonal mRNA translation in axon injury & regeneration and uncover new therapeutic strategies for neural repair.

NIH Research Projects · FY 2024 · 2019-09

ABSTRACT The proposed renewal application seeks a second five years of funding to support the Advancing Diversity in Aging Research (ADAR) Summit (5R13AG066389), which brings together students and principal investigators from the successful NIA-funded MSTEM: Advancing Diversity in Aging Research (ADAR) through Undergraduate Education (R25) programs (PAR-12-016, PAR-17-290, and PAR-20-317). ADAR programs in MSTEM and aging were launched in 2012 with the overarching goal “to support educational activities that encourage individuals from diverse backgrounds, including those from groups underrepresented in the biomedical and behavioral sciences, to pursue further studies or careers in research.” This program is part of NIA’s coordinated effort to a) fill a gap in the pipeline transitioning from undergraduate to graduate education in aging as it relates to medicine and STEM and b) fulfill the objectives of the NIA Health Disparities Strategic Plan. The motivation to hold annual meetings for students participating in the ADAR program is based on extensive research demonstrating the importance of the following in retaining historically underrepresented students in science: a) taking ownership of their research by presenting findings in a safe, non-threatening, and supportive environment; b) creating a supportive community where students have a sense of belonging and are supported in their identify as scientists, c) networking where students are empowered to view themselves as capable learners through the interpersonal validation they receive from URM senior faculty and peers; d) seeing role models of established and peer adjacent URM scholars sharing their path to becoming research scientists; and e) participating in professional development activities. The annual ADAR Summit meets each of these criteria. The ADAR Summit also enables students to engage in the broader scientific community, as the Summit is held immediately before the annual meeting of the Gerontology Society of America (GSA). Partial support from the GSA has enabled ADAR students to participate in the Presidential Symposium Poster Sessions, attend presentations relevant to their field, and visit the Exhibition Hall, where many graduate/professional schools have booths where students can engage with program representatives. The Summit also supports PIs to meet annually. The ultimate goal of the ADAR Summit conference series is to help solidify the identity of ADAR undergraduate students as scientists in MSTEM and aging. The ADAR Summit is an important strategy for the retention of diverse scholars in budding research careers. Ultimately, the goal is to have a research community of scientists that is representative of the overall United States population to more accurately address health issues of the 21st century and beyond.