University Of South Carolina At Columbia

NIH Research Projects · FY 2025 · 2022-09

Project Summary Patients recovering from painful surgical procedures commonly receive opioids during their inpatient and post- operative periods to help manage pain and initiate the recovery process. Nonetheless, access to opioids after surgery puts patients at increased risk of becoming a chronic user. Over 80% of surgical patients receive opioids after low-risk surgery with many patients receiving opioids more than the amount needed to control pain. Overprescribing increases the risk of diversion and misuse. Conversely, under-prescribing may leave many patients open to uncontrolled pain and subsequent emergency care. Current opioid discharge clinical practice guidelines (CPGs) involve lowering maximum discharge defaults, high level warnings, defaults pegged to procedures received by patients, or warnings based on prior opioid utilization. However, research suggests that post-surgery pain management should be tailored to each patient based on individual pain experience and pain tolerance. These insights suggest that a patient- centered CPG for post-operative pain management is needed. However, patient-centered CPGs are cumbersome and time consuming to implement by hand from hospital electronic health records (EHR) at discharge. A 2020 National Academies of Sciences, Engineering, and Medicine document emphasized the need to find patient-centered opioid prescribing CPG for acute pain. A clinical decision support (CDS) tool is needed to quickly synthesize patient-specific data from the EHR to promote the use of patient-centered opioid discharge CPGs. Toward this goal, three recent studies provide a strong clinical rationale that inpatient opioid use the day before discharge affords a sound proxy for individual pain experience and pain tolerance at discharge to guide patient- centered post-discharge opioid prescribing. Surgeons in the General Surgery department at Prisma Health in South Carolina used this rationale to develop a patient-centered opioid discharge CPG that was implemented in their department in March 2018. The percentage of patients with CPG-compliant opioid discharge prescriptions increased from 10% to 25.8% after implementation,59 the department-wide average opioid discharge level fell, and the General Surgeons anecdotally found little negative patient response from these reductions. Despite these positive results, General Surgeons reported that the extra time required to apply the CPG within a busy practice limited its broader use which reflects findings in the literature. Currently, the patient-centered CPG requires providers to perform a detailed analysis of patient charts by hand that can add 5-10 minutes per patient to the discharge process. In addition, with only anecdote available, the evidence on patient outcomes from use of the patient-centered CPG is not definitive. We believe that a patient-centered opioid prescribing tool (PCOPT) that immediately incorporates patient- specific information from EHR into the discharge process will significantly increase compliance with the patient- centered opioid discharge CPG. In addition, we will implement the PCOPT using an effectiveness-implementation hybrid Type II study design to yield definitive evidence on the effects of the patient-centered CPG on patient outcomes on outcomes using orthopaedic trauma patients with a lower- extremity fracture. Our proposal is in response to the Special Emphasis Notice (SEN): AHRQ Announces Interest in Health Services Research to Address the Opioids Crisis (NOT-HS-18-015).

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT Timely well visits are essential to ensure the wellbeing of children in their first year of life as they provide opportunities for delivery of preventive health interventions as well as growth monitoring. Prior studies show high rates of gaps and delays in the delivery of preventive health interventions, indicative of gaps in well visits, and reflective of broader health system and community-level barriers. For example, in Tanzania, only 68% of children receive key recommended preventive health interventions within their first year of life. Utilizing community-based health workforce capacity and leveraging rapidly evolving digital health innovations hold great potential to mitigate gaps in service delivery, healthcare access, and caregiver knowledge in this context. Our multidisciplinary study team recently completed a project that demonstrated the feasibility and efficacy of mobile phone-based reminders and conditional financial incentives for improving rates and timeliness of routine preventive health interventions recommended for children. Our team has also shown that using community health workers (CHWs) is an acceptable approach for addressing caregivers’ knowledge gaps. Building on this prior work, we propose to develop and evaluate a machine learning approach that allows for the proactive identification of children who are most likely to experience missed or delayed child well visits. Early identification could allow for these children to be supported by our integrated, community-based, digital intervention to improve uptake and timeliness of recommended child well visits. This intervention, called “Huduma Kwa Wakati”, facilitates timely well visits through a CHW-led outreach and educational intervention that is supported by a combination of low-cost digital strategies (autonomous mobile phone-based child health protocols, reminders, clinic operations notifications; conditional incentive offers for adherence to visit schedules). To optimize the implementation and efficiency of Huduma Kwa Wakati, we propose the following specific aims: In Aim 1, we will initially collect retrospective data on the characteristics and child well visits of 800 children in their first year of life. Mothers with children ages 12-23 months will be enrolled from 40 geographic clusters in the catchment areas of 40 health facilities in four rural districts in Mwanza and Shinyanga regions of Tanzania. In Year 4, 800 pregnant women in their last trimester of pregnancy will be enrolled into a parallel two-arm clusterrandomized trial. Women will be enrolled from 80 geographic clusters in the catchment areas of the same 40 health facilities. 40 clusters will be randomized into the intervention arm; 40 clusters will be randomized into the control arm. Women will be followed for up to 15 months, until the child reaches 1 year of age. Child well visit dates will be documented using government-issued clinic cards. Concurrently, data on all child well visits in each catchment area since 2019 will be extracted from facility logbooks. In Aim 2, we will characterize the implementation context for our integrated, community-based intervention to improve rates and timeliness of child well visits, assess factors associated with its acceptability among mothers and key stakeholders, develop a training and implementation blueprint, and characterize the cost of the intervention. In Aim 3, we will evaluate the feasibility and potential efficacy of a machine learning approach for proactively identifying children who are most likely to experience missed or delayed child well visits and validate predictive models using data gathered in aim 1. Child well visits extracted from facility logbooks will serve as training data. Well visit data collected from the 800 study children will serve as validation data. Study findings will inform models and interventions to identify children who are most likely to experience missed or delayed well visits and the relevance and implementation of Huduma Kwa Wakati across a wide range of rural and low-resource community settings.

NIH Research Projects · FY 2025 · 2022-09

Project Summary The Coronavirus disease 2019 (COVID-19) pandemic has caused significant social, healthcare, and economic devastation in the United States (US), potentially exacerbating the maternal health disparities facing rural women and women of color. Telehealth represents a promising opportunity to reducing disparities in maternal health access, quality, and outcomes, given its substantial range of opportunities, including audiovisual synchronous and asynchronous encounters between patients and providers, remote patient monitoring, facilitating visual communication of evidence-based practice, and supporting clinical decision-making. Yet, multilevel barriers might hinder some underserved women from fully benefiting from telehealth. Expanded federal and state-level telehealth coverage through the Coronavirus Aid, Relief, and Economic Security (CARES) Act and state policies may be mitigating the detrimental effects of this unprecedented pandemic by reducing gaps in access to telehealth and quality maternity care. Although self-reported data indicated abrupt increases in telehealth uptake during the pandemic, limited real-world data are available regarding the role of perinatal telehealth uptake on the pandemic’s effects and the role of state level policy in telehealth adaptation during COVID-19. This longitudinal, real-world data study will use recurring national electronic health records (EHR) data [National COVID Cohort Collaborative (N3C)] and integrated statewide population-based data in South Carolina and Florida which complement the overrepresentation of urban populations in N3C. With multiple innovative approaches using common data modeling, multi-level imputation for missingness, and Bayesian statistics simulation methods, this study aims to: 1) investigate the impact of the COVID-19 pandemic on maternal care access, quality, and maternal and birth outcomes by maternal race/ethnicity and rural/urban residence; 2) examine whether perinatal telehealth uptake mitigates the pandemic's effects on disparities in maternal care access, quality, and outcomes by maternal race/ethnicity and rural/urban residence; and 3) assess how state-level telehealth policies (relaxation for originating sites, reimbursements for store-and- forward services, remote patient monitoring, and provider expansion) – relate to perinatal telehealth uptake by race-ethnicity and rural/urban residence. We will also 4) develop a stochastic simulation model to predict long-term changes in maternal care access, quality, outcomes, and expenditures of maternity care, with and without each respective state telehealth policy. Our overarching goal is to advance the understanding of the three-way intersections among the COVID-19 pandemic, state telehealth policy, and perinatal telehealth uptake on health disparities facing vulnerable maternal populations – rural and racial/ethnic minority women. We have formed a multidisciplinary team of investigators, including maternal health services researchers, health policy analysts, telehealth experts, senior clinical researchers, perinatal epidemiologists, rural health advocates, health psychologist, big data analysts, and machine learning experts to conduct this study.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY/ABSTRACT Despite extensive evidence that friendships play an integral role in adolescent development, we know relatively little about the friendships of maltreated adolescents, a group that is at significantly elevated risk for experiencing future adverse outcomes. The existing literature regarding the influence of friendships on maltreated youth’s development is highly conflicting and limited by investigations that do not account for the full complexity of friendship experiences. Thus, there is a critical need to study how maltreated adolescents’ friendships might mitigate or exacerbate their risk for proceeding on negative developmental trajectories. The overall objective of this project is to investigate how the friendship experiences of maltreated and non-maltreated adolescents differ, and understand how these experiences influence risk for adverse outcomes. There are three specific aims. During the K99 phase, this proposal will (1) use data from two prospective longitudinal studies to identify how maltreated and non-maltreated adolescents’ friendships differ, and (2) use data from both studies and results from Aim 1 to test for the potential mediating effects of multiple friendship experiences on the relationship between maltreatment and psychopathology/peer victimization. Aim 3 will be completed during the R00 phase and use clinical trial methodology to pilot a procedure to assess maltreated adolescents’ friendships using observational and multi-reporter methods, and investigate how they influence psychophysiological reactivity to a laboratory stressor and later psychopathology/peer victimization. This project is innovative because it represents a substantive improvement upon existing research by considering the influence of a range of friendship experiences on the adjustment outcomes of maltreated adolescents using longitudinal data and multi-reporter and observational methodology. This contribution will be significant because it will help to delineate whether friendship can offer the same health and social benefits and/or risks for some of our most vulnerable adolescents, as they provide for normative/low-risk populations. This proposal will greatly enhance the PI’s career development and enable her to advance toward her long-term goal of becoming an independent investigator at a research institution. Penn State College of Medicine provides an optimal environment for training with a wealth of resources for career development and several interdisciplinary faculty who study child maltreatment and are actively engaged in mentoring the next generation of maltreatment researchers. Training and mentorship will be provided to develop expertise in the study of friendships; acquire skills in longitudinal data collection and analysis; learn new multi-reporter, multi- level, and observational techniques; and gain clinical trial experience. Furthermore, the PI will be engaged in training activities that foster her transition to independence, including grant writing, publishing, presenting, and preparing for the academic job market. These skills and activities, combined with the proposed research, will prepare the PI to compete for future R01 funding.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY Diversity enhances creativity and innovation in research, but biomedical research institutions have generally failed to effectively incorporate minoritized groups, such as individuals who identify as people of color, women, and lesbian, gay, bisexual, transgender, or queer/questioning (LGBTQ) persons. Earlier diversity efforts focused exclusively on intensified recruitment of minoritized faculty, mentoring, and training, but many institutions did not sustain their success because of insufficient change in institutional environments, systems, and culture. Over the past two years, the leadership of the University of South Carolina (UofSC) has been intentional about transforming the institutional culture to one that embraces and expects a climate of diversity, equity, and inclusion (DEI). UofSC’s Strategic Plan, released in 2020, includes eight priorities which were developed, vetted, and revised with intense participation of the campus community. The priorities include Strategic Priority #2 “Assemble and cultivate a world class faculty and staff” and #4 “Cultivate a more diverse, equitable and inclusive campus culture.” UofSC has demonstrated increased commitment to diversity in multiple ways, including hiring UofSC’s first Black/African American Provost and elevating the Chief Diversity Officer to the level of a Vice President. These efforts reflect UofSC’s campaign to identify and remove factors supporting systemic racism and gender-bias across all campus endeavors. In response to RFA-RM-21-025, we have developed the Faculty Initiative for Improved Recruitment, Retention & Experience (FIIRRE) using a systems science informed multi-level approach. FIIRRE aims to: (1) Develop, cultivate, and implement institutional programs and practices that become self-reinforcing in promoting inclusive excellence; (2) Achieve significant and sustainable institutional culture change that supports inclusive excellence; (3) Recruit, nurture, and retain a cohort of ten new tenure-track Assistant Professors who are committed to inclusive excellence; and (4) Collaborate with other FIRST awardees and the FIRST Coordination and Evaluation Center in this multi-center initiative. The 10 tenure-track faculty will constitute the FIRST cohort at UofSC and will be recruited as a cluster hire within the area of health disparities and equity research. The FIIRRE Administrative Core, Faculty Development Core, and the Evaluation Core serve complementary purposes in support of these overarching aims. Initiated by two of UofSC’s leading health science units, the Arnold School of Public Health and the College of Nursing, FIIRRE will serve as an incubator and facilitator of institutional change. FIIRRE leadership is varied in race/ethnicity, academic rank, nationality, and institutional history, with over a decade of experience working together in research and administrative capacities, helping to ensure FIIRRE’s success. Strong existing connections with established diversity initiatives on campus will help complement and bolster FIIRRE goals, as will the unwavering institutional commitment to inclusive excellence by UofSC’s leadership.

NIH Research Projects · FY 2024 · 2022-08

PROJECT SUMMARY Recent work suggests that mothers of children with disabilities are at increased risk for accelerated cognitive aging. Mothers of children with autism spectrum disorder (ASD), in particular, may be especially susceptible to atypical aging given their elevated rates of key risk factors for dementia relative to mothers of typically developing children or children with other neurodevelopmental disorders. ASD is also a heritable condition, and emerging research indicates similar effects of tauopathy in ASD and Alzheimer’s disease. Though it is not known if mothers of children with ASD also have tauopathy as a result of their genetic liability, this possibility may have an impact on atypical cognitive aging in this group. The theoretical framework from this research is based on the Diathesis-Stress model, which posits that environmental or psychosocial factors (e.g., stress) moderate the gene-phenotype relationship. Understanding risk for atypical cognitive decline in mothers of children with ASD is important given the high prevalence of ASD in the population (1 in 54 children). Moreover, a significant number of mothers of children with ASD (up to 65%) continue to be caregivers for their adult children, resulting in increased stress, depression, loneliness, reduced social support, and poor sleep, all of which are risk factors for dementia-related disease. This project will address gaps in the literature on cognitive decline in mothers of children with ASD and associated risk factors. Aim 1 will compare the neuropsychological profiles of mothers of children with ASD and mothers of typically developing children, as well as age effects, using a comprehensive battery. Aim 2 will examine the effects of risk factors (i.e., stress, depression, loneliness, reduced social support, and poor sleep quality) on neuropsychological test performance within mothers of children with ASD. This project will provide insight into atypical cognitive aging among mothers of children with ASD, which may have broader consequences on their children who continue to live at home and depend on their parents as caregivers after high school. This research will be implemented in an ideal training environment with a strong infrastructure for aging research at the University of South Carolina and with the support of an experienced mentorship team with expertise in aging, neuropsychological assessments, and Alzheimer’s and other dementia-related diseases. The training plan focuses on the development of the trainee in: (1) theories, measurement, and interpretation of neuropsychological assessments, (2) trajectories of typical aging and aging in dementia-related disease, and (3) professional development. The proposed study and training plan will help the trainee pursue a line of research on the risk for dementia-related disease in mothers of children with ASD.

NIH Research Projects · FY 2025 · 2022-08

This U01 project leverages our expertise in the epidemiology of colorectal cancer (CRC); disparities; obesity; metabolic dysregulation, an important manifestation of inflammation; the microbiome; animal CRC models; and lifestyle intervention trials to address the growing problem of Early-Onset CRC (EOCRC) (i.e., <50 years). Adiposity and diet drive metabolic dysregulation. So, understanding the interaction between diet and adiposity are key to understanding the genesis of EOCRC – and an array of other obesity-related cancers). This project will address the absence of critical clinical trials and mechanistic studies involving lifestyle interventions for EOCRC. We intend to address this gap; and have the transdisciplinary team representing complementary backgrounds to do so. We focus on dietary modulation of gut microbes to reduce metaflammation and subsequent metabolic dysfunction in obesity, with a goal of preventing EOCRC. We will perform 1) an anti- inflammatory dietary intervention trial in dyads of adults and children at elevated risk for CRC. We also will conduct a complementary mechanistic animal study that builds on and leverages our expertise in mechanistic studies on obesity and CRC. This work is supported by infrastructure that we have built over the past decades in two key centers at the University of South Carolina (UofSC): (1) Center for Colon Cancer Research (CCCR, 2002 - present – which specializes in mouse models of CRC); and (2) the Cancer Prevention and Control Program (CPCP, 2000 - present – which specializes in the epidemiology of cancer and lifestyle intervention trials for cancer, with a focus on cancer disparities. The two projects that comprise the proposed grant address two Specific Aims that are represented by the human study and laboratory animal experiment: i.e. ,1: To establish the metabolic protective effects of an anti-inflammatory diet in obese, high-risk African- American (AA) and European-American (EA) adults and children in reducing inflammation as indicated by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), IGF-1, Tumor Necrosis Factor alpha (TNFα), Interleukin 6 (IL-6), and C-Reactive Protein (CRP), and a creating more favorable microbiome signature; 2: To establish gut microbes as mediators between anti-inflammatory dietary input and reversal of metabolic dysfunction and associated CRC risk. This complements the human study by carrying out pre-clinical murine model studies with similar inputs (diet), intermediate endpoints (inflammation, microbiome), and outcomes (CRC-related). We hypothesize that an anti-inflammatory dietary intervention will reduce metabolic dysfunction and metainflammation through regulatory effects on gut microbiota. Results from this work will address the role of metabolic dysregulation in relation to factors that are known to be important in carcinogenesis, that therefore could have profound effects on EOCRC, have implications for other obesity-related cancers, and have great promise for moving the field forward by addressing mechanisms that drive large health-related disparities that consistently disfavor African Americans.

NIH Research Projects · FY 2024 · 2022-08

PROJECT SUMMARY/ABSTRACT Autism spectrum disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are two of the most common neurodevelopmental disorders and affect approximately 1 in 54 and 1 in 11 children in the U.S. respectively with a surprisingly high comorbidity rate of up to 70%. Growing literature suggests that early intervention can ameliorate symptoms and reduce burden of suffering for children affected by these disorders and their families. In order for early intervention to be successful, identification of infants at the highest risk for later challenges is necessary. Social communication deficits, atypical attention, and motor skills challenges have been implicated in the development of both ASD and ADHD. However, little is known about the specificity of these features as unique mechanisms related to the development of ASD and ADHD in infancy. Characterizing the profiles of social communication, attention, and motor skills across infants at an elevated genetic likelihood for ASD, infants at an elevated genetic likelihood for ADHD, and infants at a low genetic likelihood for both disorders can provide important information about disorder-specific symptoms of ASD and ADHD. Understanding transdiagnostic and disorder-specific features of ASD and ADHD will lead to improved screening tools and tailored interventions. Thus, the present study leverages a prospective, longitudinal design to study trajectories of social communication, attention, and motor skills and their relation to ASD and ADHD symptomology throughout the first three years of life. Consistent with NIMH’s Research Domain Criteria (RDoC) approach to investigation of mental disorders, this study will use physiological and behavioral measures to assess these constructs. Further, ASD and ADHD symptoms will be assessed on a dimensional basis. Specific Aim 1 will provide novel information about three phenotypes of ASD and ADHD – communication, attention, motor skills – in infants at genetic risk to provide an early profile of infant skills across three groups. Results from this study will provide information about symptoms associated with genetic risk for ASD and ADHD. Specific Aim 2 will investigate a physiological measure of attention as a predictor of ASD and ADHD symptomology. Notably, this aim will address a gap in current literature concerning the association between attention measured physiologically and symptoms of ADHD. Finally, Specific Aim 3 will explore trajectories of social communication, attention, and motor development as predictors for ASD and ADHD symptomology. These research aims will inform the complex mechanisms implicated in the development of ASD and ADHD symptoms.

NIH Research Projects · FY 2025 · 2022-08

UNAIDS set for 2030 the ambitious 95-95-95 target: diagnosing 95% of all persons living with HIV (PWH), initiating antiretroviral therapy for 95% of those diagnosed, and achieving viral suppression for 95% of those treated. In Tanzania, a PEPFAR strategy country with an adult HIV prevalence of 4.8%, only 83% of PWH are aware of their status. More than 200,000 undiagnosed PWH need to test in order to reach the “first 95”. With the cost-effectiveness of traditional HIV testing approaches declining, we propose to evaluate a novel application of mobile health (mHealth) technology that leverages the ubiquity of mobile phones and the reach of social networks to increase rates of HIV testing, especially among higher-risk individuals. Specifically, we will evaluate the acceptability, efficacy, and cost-effectiveness of automated, confidential, SMS-based HIV testing referrals, as a means of ‘nudging’ individuals to test. We hypothesize that an automated, confidential referral system, developed and deployed in the Kilimanjaro Region of Tanzania, will be acceptable to both index clients and their referrals and that it will be cost-effective for increasing HIV testing rates. Building on existing relationships with all 25 HIV counseling and testing (HCT) providers in the study area, including 8 HIV care and treatment centers (CTCs), and using an open-source, low-code, and highly versatile mobile phone-based appointment reminder and incentive system (mParis), this study will address the following specific aims: R21 Phase: Aim 1 will conduct qualitative, formative work with (1) HCT providers, (2) HCT clients, (3) PWH who are in care at CTCs, and (4) social network contacts of HCT and CTC clients, to identify desirable provider- and client-side characteristics of an SMS-based HIV testing referral system. Aim 2 will adapt our mParis system to receive phone numbers of HIV testing referrals identified by index clients and autonomously send confidential HIV testing invitations. Aim 3 will pilot-test the Confidential Social Network Referrals for HIV Testing (CONSORT) system to collect preliminary data on the system’s acceptability, performance, and potential efficacy. R33 Phase: Aim 4 will evaluate the acceptability and efficacy of CONSORT in a pragmatic randomized controlled trial with 400 HCT clients and 200 HIV-infected CTC patients. Arm 1 participants will be offered confidential SMS referrals and physical invitation cards (“card referrals”) to extend to any of their network contacts. Arm 2 participants will be offered card referrals alone. The primary outcome will be uptake of HIV testing. Secondary outcomes include the number of new HIV diagnoses, and the risk correlation within referral networks. Aim 5 will evaluate the incremental cost-effectiveness of CONSORT+card referrals vs. card referrals alone. The study will provide estimates of the acceptability, efficacy, and cost-effectiveness of an exceptionally low-cost intervention for increasing the uptake of HIV testing. More broadly it will develop analytic and mHealth capacity in Tanzania and inform the development of mobile phone-based chain-referral interventions that can reach key social networks, are transferrable to other technologies, and can be extended beyond HIV testing.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY Ovarian cancer is the fifth most common cause of cancer-related deaths in women and results in more deaths than any other cancer of the female reproductive system. The primary reason for the high death rate of ovarian cancer is multidrug-resistance. Since conventional anticancer drugs cannot kill drug-resistant cells while causing systemic toxicity to deteriorate patient health condition, a novel effective and safe treatment for ovarian cancer is urgently needed. Our preliminary study has discovered a novel polymer-metal combination which uniquely induces a lysosomal copper elevation initiated intrinsic apoptosis pathway. Consequently, this combination is highly selectively in killing cancer cells, including drug-resistant ovarian cancer cells, while not damaging healthy cells. The objective of this research is to develop a polymer-metal nano-complex (PMC) for safe and effective ovarian cancer therapy through a cancer cell selective apoptosis mechanism. Our project has three specific aims. In Aim 1, we will identify the mechanism of cancer cell killing effect of PMC. Aim 2 will identify the cancer selective killing mechanism of PMC and optimize its formulation to achieve the highest selectivity for cancer cells. Aim 3 will investigate the pharmacokinetic properties, examine the biodistribution of PMC, and evaluate its tumor growth inhibitory effect, immune response, and systemic toxicity. In summary, the unique anticancer mechanism of PMC and its simple formulation will provide clinicians a safe and effective tool to control advanced ovarian cancer and benefit ovarian cancer patients.

NIH Research Projects · FY 2024 · 2022-08

Modified Project Summary/Abstract Section Over 70% of Americans have a body mass index (BMI) classified as overweight or obesity. Weight-related stressors (e.g., negative perceptions and treatment based on body size) are experienced more frequently by certain groups and those with higher BMIs, and can contribute to unhealthy behaviors, and increased disease risk, making the study of these experiences essential to improving health outcomes across the broader population. Sexual minority women (SMW; i.e., women with sexual orientations other than heterosexual) are up to twice as likely to live in larger bodies and experience weight-related stressors compared to men and heterosexual women. Weight-related stressors, the NIMHD research framework, and the minority stress model, which posits that some groups, such as SMW, are at increased risk for stress due to multi-level contextual stressors, can be applied to help delineate risk and protective factors associated with population-level variability in obesity. Greater knowledge of these factors, particularly for at-risk groups like SMW, can offer insight into broader mechanisms influencing obesity risk and enhance public health strategies for population-based health. Research on obesity among women or the primary behavioral drivers of overweight/obesity (i.e., energy-balance behaviors, unhealthy weight-control behaviors, physical inactivity) has given little attention to weight-related and contextual stressors and little consideration of belonging to multiple disparity populations, often grouping individuals analytically that obscure important differences. Among the research on weight-related stressors, energy-balance behaviors, or their health correlates (e.g., disordered eating), there is an overreliance on cross-sectional, retrospective self-report, or semi-annual longitudinal designs. These studies provide knowledge foundation, but are limited in the data they can provide. Experience sampling methods (ESM) can advance our understanding by identifying temporally proximal risk factors for behavioral health disparities and disentangling risk factors from correlates. This exploratory sequential mixed methods study aims to delineate factors and mechanisms that may be associated with behavioral risk among women with non-heterosexual orientation and belonging to a racial/ethnic minority population to inform a more comprehensive understanding of population-level variability in weight-related health. Aim 1 utilizes a qualitative life history approach to identify preliminary barriers and facilitators to health cognitions and behaviors. Aim 2 uses ESM to test the preliminary model identified in Aim 1 and examine relationships between contextual and weight-related stressors and behaviors in real time in the natural environment among SMW. These aims support my training plan with expert mentors and training in: multi-level contextual influences on behavioral health (Training Aim 1); mixed methods data collection and analysis (Training Aim 2); ESM and advanced statistics for ESM data (Training Aim 3); and career development (Training Aim 4). Results will inform a multi-level model of contextual and weight-related stress among SMW to inform broader mechanisms for the promotion of health and well-being for all individuals.

NIH Research Projects · FY 2026 · 2022-08

SUMMARY/ABSTRACT As one of the most abundant anions in the human body, chloride plays a crucial role in human health. Chloride homeostasis is maintained inside the cell while the chloride level is varied based on the function of organelles. Dysregulation of chloride homeostasis caused by the mutation of chloride channels results in various human diseases such as cystic fibrosis (CFTR, >70,000 people worldwide), proteinuria and kidney stones (ClC-5, 39 million people in US), Osteoporosis (ClC-7, 10 million people in US, 43 million people in the risk group). Although five FDA-approved chloride channel modulators have been reported, they only target plasma membrane chloride channels due to the technical barrier. There is no FDA-approved or clinical trial drug that targets organellar chloride channel. The field of chloride channel-targeted therapy is still under-studied (5 FDA-approved drugs, 2 clinical trial) compared to other channels such as calcium, potassium, and sodium. The lack of understanding of the physiological role of organellar chloride and the well-characterized chloride channel are the biggest roadblocks for the development of chloride channel-targeted therapy. Therefore, suitable research tools with a high resolving ability to examine the organelle chloride in live cells is a highly urgent need, which is essential to elucidate the physiological role of organellar chloride and characterize the chloride channel. However, the current chloride measurement with one-dimensional analysis only shows the average ion level. It cannot observe the chloride level change in a minor subset of organelles triggered by the cellular pathway such as STING and autophagy. Furthermore, the typical fluorescence measurement can only tell the variation of the average chloride level (increase, decrease, and no significant change) in certain conditions. The current methods significantly hinder the identification of deactivated cell pathways or protein based on the chloride level measurement. The proposed research integrate organelle selective dual reporters, single organelle measurement, sub- cellular imaging, and the three-dimensional analysis, to fingerprint the chemotype of organelles along with STING pathway, autophagy, and mitochondrial respiration. Completion of the proposed study will find out the physiological role of organellar chloride which shed light on the chloride channel-targeted therapy. The development of the organelle chemotype fingerprinting technique will also provide tools to characterize chloride channels, evaluate chloride channel modulators and identify the deactivated cell pathways or proteins.

NIH Research Projects · FY 2025 · 2022-08

Cancer drug resistance is driven in part by the plasticity of tumor cells that allows for therapy-induced adaptation of their transcriptional program. This adaptive drug resistance is associated with the acquisition of various phenotypic changes that promote tumor growth, metastasis and resistance to other therapies. Experimental drugs targeting CDK8/19 Mediator kinase that regulates transcriptional reprogramming were found to suppress the development of resistance to different classes of targeted and conventional anticancer agents. We hypothesize that the emergence of adaptive drug resistance in vitro and in vivo, with concurrent acquisition of tumor-promoting phenotypes, can be prevented by inhibiting Mediator kinase. We will test this hypothesis in HER2-positive breast cancers by analyzing the effects of Mediator kinase inhibition on the emergence of resistance to a HER2-targeting drug (lapatinib) and a conventional drug (paclitaxel). We will pursue the following Specific Aims. (1) The effect of Mediator kinase deficiency on the development of adaptive drug resistance in vitro will be analyzed by generating derivatives of HER2-positive human breast cancer cell lines that will express wild-type or kinase-dead Mediator kinase and by analyzing the effects of Mediator kinase mutagenesis or treatment with selective CDK8/19 inhibitors on the emergence of adaptive resistance to lapatinib or paclitaxel. Comprehensive phenotypic, genomic and transcriptomic analyses will be used to evaluate the effect of drug adaptation and Mediator kinase inhibition on the acquisition of tumor-promoting phenotypes and to identify signal transduction pathways, inhibitors of which could be combined with CDK8/19 inhibitors to enhance the prevention of resistance. (2) HER2-positive human cell lines with different Mediator kinase status and a panel of HER2- positive breast cancer patient-derived xenografts (PDX) will be selected for lapatinib and paclitaxel resistance in vivo, to compare the resistance-preventing effects of Mediator kinase deficiency in tumor cells alone and with the effects of its pharmacological inhibition in both tumor and stromal cells. Transcriptomic and phenotypic analysis will be used to delineate the effects of drug selection and Mediator kinase inhibition on gene expression in tumor and stromal cells. Whole exome sequencing of PDX tumors will reveal if Mediator kinase inhibition prevents the emergence of new drug-resistant tumor lineages or suppresses the growth of drug-resistant cells that may pre-exist in heterogeneous PDXs. (3) The effects of Mediator kinase on the emergence of drug resistance will also be investigated in a murine Her2/Neu-driven mouse mammary carcinoma cells adapted for syngeneic growth, both in vitro (as in Aim 1) and in vivo using both immunocompetent and immunodeficient hosts. This analysis will elucidate the effect of the host immune system on drug adaptation and the role of Mediator kinase in this effect. The proposed program will delineate the roles of Mediator kinase in tumor adaptation to treatment, in vitro and in vivo, and will indicate whether Mediator kinase-inhibiting drugs may be able to extend the duration of remission induced by cancer therapy.

NIH Research Projects · FY 2026 · 2022-07

PROJECT SUMMARY/ABSTRACT About 1 in 151 women in the US are carriers of a genetic abnormality called the FMR1 premutation (FXpm). Mothers who carry the FXpm are at risk for passing the mutated gene to their children, which may result in fragile X syndrome. The FXpm is also associated with substantially increased risk for disease, including neurodegenerative disease, premature menopause, psychiatric involvement, and executive and social deficits. New evidence suggests that FXpm carrier mothers may experience premature age-related decline across multiple symptom domains. The aging expression of FXpm phenotype is particularly concerning when applied within the context of fragile X families because these symptoms impact not only the carrier mother, but also her ability to care and advocate for her children with fragile X syndrome. However, almost all evidence of age- related decline in this group has been gleaned from cross-sectional data that are insufficient for drawing robust longitudinal trajectories. This represents a substantial barrier to effective clinical management, as we lack the data needed to understand the long-term effects of the FXpm genotype and its implications for families. This proposal seeks to determine the stability of key FXpm phenotypes (mental health, executive, social) across midlife and early old age in FXpm carrier mothers compared to healthy controls (Aim 1); investigate autonomic and molecular-genetic factors associated with age-related symptom expression and their interface with parenting stress (Aim 2); and evaluate functional limitations associated with FXpm symptoms across age (Aim 3). We will accomplish these aims by adopting an accelerated longitudinal design to track age-related change occurring across 45-80 years in 75 FXpm carrier mothers compared to 75 control mothers. The over- arching goal is to inform the critical age periods and risk factors in age-related decline, as well as to lay the groundwork for future mechanistic studies. This work is necessary to develop strategies to ameliorate FXpm symptoms, which will improve outcomes for both FXpm carrier mothers and their children with fragile X syndrome.

NIH Research Projects · FY 2026 · 2022-07

PROJECT SUMMARY/ABSTRACT Despite the impairment in fragile X syndrome (FXS) and the fragile X premutation (FXpm), surprisingly little research has examined the underpinnings of these impairments. One potential factor that contributes to impairment is autonomic nervous system (ANS) dysfunction. Elevated physiological arousal, reflecting ANS dysfunction, has long been implicated as contributing to learning impairments and atypical behavior in FXS. While ANS dysfunction has been linked to impairment in both FXS and FXpm, research has not examined the presence, onset, developmental trajectory, or developmental consequences of ANS dysfunction or how molecular-genetic factors are associated. This project addresses these critical gaps with the following specific aims: (1) Identify the onset and developmental trajectory of baseline ANS dysfunction through prospective longitudinal assessment at 6, 9, 12, and 24 months in FXS (n=30 males) and FXpm (n=30; 15 males and 15 females) contrasted to typical controls (n=45; 30 males and 15 females); (2) Determine how molecular-genetic variation relates to the onset and/or developmental trajectory of ANS dysfunction in FXS and FXpm; (3) Characterize behavioral and ANS reactivity to sensory stimuli through prospective longitudinal assessment at 6, 9, 12, and 24 months in FXS and FXpm; and (4) Document the consequences of ANS dysfunction across infancy on sensory processing impairments, adaptive skills, ASD symptoms, and social communication, concurrently and at 24 months in FXS and FXpm. This work will have tremendous impact by greatly expanding information on the mechanistic underpinnings, biological pathways, and timing of symptom progression, which is essential to identify targets and timing of treatment to reduce symptom severity in FXS and FXpm. Our focus on infancy is critical, as evidence has documented that intervention provided early in life has the potential to accelerate development and improve developmental trajectories over time in a multi-dimensional manner.

NIH Research Projects · FY 2025 · 2022-05

ABSTRACT Mitochondrial diseases are respiratory chain disorders in which the mitochondria are no longer operating efficiently to produce ATP, usually due to a problem with one or more components of the oxidative phosphorylation machinery. Mitochondrial diseases manifesting as encephalopathies occur at a rate of 1 in 5000 live births and are often fatal in the first few years of life. The genetic cause and clinical course of these encephalopathies, e.g., Complex I deficient Leigh Syndrome, are well-described. The effective treatment of these diseases is limited by our lack of mechanistic understanding of pathomechanisms that drive neuronal decline, beyond the known Complex-I bioenergetic deficit. We have previously described the reaction of the citric acid cycle metabolite fumarate with protein cysteine residues to generate an irreversible modification, 2-succinocysteine (2SC), also known as protein succination. Fumarate and protein succination increase in the Ndufs4 knockout mouse model of mitochondrial Complex I deficiency. We demonstrate that the succination of a component of the α-ketoglutarate dehydrogenase (α- KGDH) complex impairs the enzymatic activity of this complex. This results in decreased succinyl CoA production, and impaired substrate level phosphorylation to produce much needed GTP/ATP. We hypothesize that metabolic acidosis derived from the Complex I loss redirects α-KG toward 2-hydroxyglutarate production. We predict that this influences the epigenetic landscape in the affected neurons. The citric acid cycle of other non-neuronal cells are also impacted in the Ndufs4 knockout mouse. We show preliminary data to demonstrate an impaired ability to produce itaconate, an important anti-inflammatory metabolite. This is significant given the accumulation of microglia in the center of neuropathological lesions. Our novel hypotheses link specific citric acid cycle perturbations to the chemical modifications of proteins that may accelerate the biochemical damage within the regions most affected by pathology. To address these specific pathomechanisms we outline targeted therapeutic approaches that should reduce the drivers of neuropathology.

NIH Research Projects · FY 2025 · 2022-05

PROJECT SUMMARY Erectile dysfunction (ED) is one of the most prevalent and impactful complications of diabetes mellitus (DM). The combination of diabetes and sexual dysfunction affects family planning and overall quality of life, and ED is now considered an early marker for cardiovascular diseases and consequently could predate the development of a life-threatening condition. Hyperglycemia, hyperlipidemia and inflammation are all associated with DM and induce the generation of vascular reactive oxygen species (ROS). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) is the main source of ROS in the vasculature and ROS activate intracellular signaling pathways that induce constriction of the penile vasculature. In vascular smooth muscle cells (VSMCs), this signaling cascade begins with extracellular superoxide (O2-•) production by Nox1 at the plasma membrane. Extracellular O2-• from Nox1 can alter vascular tone by inactivating endothelium-derived nitric oxide (NO). But O2-• also triggers activation of RhoA/Rho-kinase signaling to cause constriction of the penile vasculature. In diabetes, activation of RhoA/Rho-kinase signaling is exaggerated leading to ED. We have demonstrated functional and structural inter-dependence between Nox1 and volume-regulated anion channels (VRACs) composed of leucine-rich repeat-containing 8 (LRRC8) family proteins. LRRC8A is required for all VRACs and combines with one of four closely related LRRC8 isoforms (LRRC8B through E) to produce channels with unique biophysical properties. We speculate and provide preliminary data that VRACs provide O2-• access to the cytoplasm. Our preliminary data demonstrate that LRRC8 knockout (KO) or channel inhibition enhances dilator function (or reduces constriction) in control blood vessels and null mice are protected against impairment of vasodilation by TNFα in vitro and angiotensin II (AngII) in vivo. This proposal will provide a structural framework to understand how extracellular O2-• produces intracellular signals that lead to contraction of the penile vasculature. We hypothesize that in diabetes, erectile dysfunction is partly due to the entry of extracellular O2-• from Nox1 via LRRC8 anion channels to activate RhoA/Rho-kinase resulting in vascular contraction. Three aims address this central hypothesis: 1) to test the hypothesis that in diabetes, ED is caused by excess Nox1 and LRRC8A-dependent production of extracellular O2-• which then enters VSMCs via LRRC8A anion channels, activates RhoA/Rho kinase and increases vascular tone; 2) to test the hypothesis that diabetic mice that lack the LRRC8 channel in the vasculature will not develop ED; and 3) to test the hypothesis that drugs that selectively inhibit LRRC8 channels will be novel therapeutic agents for the treatment of ED in diabetes. This work will provide a comprehensive approach to understanding the role of LRRC8/VRACs, O2-• and RhoA in the etiology and development of ED in diabetic males and provide a novel therapeutic approach for treatment of the disorder.

NIH Research Projects · FY 2026 · 2022-04

Project Summary/Abstract African Americans (AAs) are disproportionately affected by cardiovascular disease (CVD) and obesity. AA vegetarians/vegans have significantly lower risks of hypertension and diabetes as compared to AA omnivores. Vegan soul food restaurants have emerged as a potential community partner for introducing patrons to healthy versions of familiar soul food cuisine. To explore the potential impact of this intervention on AAs with overweight or obesity who were not already following vegan diets, we conducted the Nutritious Eating with Soul intervention (NEW Soul; R01HL135220), delivered in a university setting in Columbia, SC (n=159 AAs; vegan vs. low-fat omnivorous diet, both focused on soul food). We completed 3-month assessments with high retention rates (88%) and significant weight loss (vegan -2.2±2.8 kgs; omnivorous -1.2±2.7 kgs; p=0.03). We propose to examine the effectiveness and implementation of a remotely-delivered, 3-month NEW Soul program. We will work with two vegan soul food restaurants (see letters of support). We have the following aims: Aim 1: Evaluate the effectiveness of the 3-month NEW Soul restaurant-delivered program on two important factors in the development of CVD (body weight and diet quality) among AAs with overweight or obesity. Participants (n=228) will be randomized to one of two conditions: 1. Remotely delivered live weekly classes with restaurant vouchers (intervention) or 2. restaurant voucher-only (active control). Aim 2: Conduct a cost-effectiveness analysis of delivering the online intervention plus voucher vs. voucher- only with the outcome of cost/change in weight, HEI and quality adjusted life year (QALY). This includes estimating costs of the intervention itself (e.g., training, delivery, infrastructure). Aim 3a: Examine the implementation of the NEW Soul study. Guided by the implementation outcome framework by Proctor, et. al., and the implementation strategies described by Waltz, et. al., we will examine the feasibility and utility of the NEW Soul implementation strategies (e.g., provide iterative assistance, provide ongoing training and consultation, centralize technical assistance) in restaurant settings. We will employ qualitative (semi-structured interviews with intervention staff and focus groups with participants), and quantitative (surveys with participants) research methods, which will be guided by CFIR domains (intervention characteristics, inner setting, outer setting, characteristics of individuals, and process). Aim 3b: Building on the findings from Aims 1-3a, we will conduct key informant interviews with intervention and restaurant staff to identify areas to prepare the intervention for widespread adoption by vegan soul food restaurants across the southeast. We will focus on the design quality and packaging, part of the CFIR “intervention characteristics” domain.

NIH Research Projects · FY 2026 · 2022-04

Accurate measurement of free-living physical activity (PA), energy expenditure (EE), and sleep of children (5-12yrs) is complex, with no single method free of limitations. Validation studies of PA, EE, and sleep have demonstrated that combining HR and accelerometry data (e.g., steps, counts, raw signal) provides the most accurate estimate of PA, EE, and sleep. Unfortunately, the simultaneous collection of HR and accelerometry over routine monitoring timeframes (e.g., 7 days) has been limited because historically measuring HR has relied on uncomfortable chest strap telemetry. Advancements in wearable technology have eliminated this issue by incorporating the noninvasive assessment of HR via photoplethysmography in widely-available consumer wearable devices (e.g., FitBits, Garmin) that also include accelerometry. Studies have shown that HR estimates from consumer wearables are comparable to those collected via ECG or chest strap telemetry. However, validation studies of consumer wearables have focused almost exclusively on proprietary activity output (e.g., steps) and have mostly been conducted on healthy adults, older adults, or clinical populations (e.g., people with neuromuscular or gait abnormalities). Consumer wearables hold promise for collecting PA, EE, and sleep data with children 5 to 12yrs, yet no studies have been conducted to establish their validity and utility/feasibility in this population. The objectives of the proposed project are to conduct a series of studies that include both laboratory and field-based protocols to evaluate the reliability, validity and utility/feasibility of consumer wearables for measuring children’s PA, EE, and sleep in free-living conditions. We will evaluate the different features of the devices (e.g., PA, HR) in the lab and in real-world conditions. In addition, we will evaluate the utility/feasibility of consumer wearables for multi-day wear compliance. We will accomplish the following aims. Aim 1. Develop and validate open- source equations to estimate PAEE and time spent physically active using the activity and HR data from consumer wearables compared to the PAEE output from the consumer wearables’ proprietary processing algorithms and a criterion measure of PAEE (i.e., indirect calorimetry). Aim 2. Develop and validate open-source equations to estimate total sleep time, sleep efficiency, and timing from consumer wearables using their activity and HR data compared to the sleep output from the consumer wearables’ proprietary processing algorithms and a criterion measure of sleep (i.e., PSG and actigraphy). Aim 3. Evaluate the validity of the PAEE and sleep equation estimates from the algorithms created in Aim 1 & 2 against a criterion (i.e., Actiheart) under free-living conditions. This project is significant because it will be among the first to establish the validity of consumer wearables for PAEE and sleep monitoring of children. This project is innovative as it will use advanced statistical modeling techniques, including machine learning, to systematically test the validity and utility/feasibility of consumer wearables for children. Our vision is to leverage the biometric data collected across consumer wearables to produce estimates of PAEE and sleep in children. This will allow practitioners and researchers alike to more accurately measure 24-hour movement behaviors in children.

NIH Research Projects · FY 2025 · 2022-02

PROJECT SUMMARY/ABSTRACT The virus, SARS-CoV-2 has caused COVID-19 and claimed the lives of over 240,000 Americans and 1,270,000 people worldwide. Severe cases of the disease leads to Acute Respiratory Distress Syndrome (ARDS), sepsis and can be fatal due to pulmonary inflammation and destruction of the epithelial and endothelial cell lining. Understanding the mechanisms behind these diseases is vital to develop effective preventive and therapeutic strategies. Staphylococcus enterotoxin B (SEB)-induced ARDS mimics the cytokine storm, sepsis and multiple organ failure presented in patients with severe COVID-19. It has been shown that the superantigen structure and sequence associated with the spike protein of the SARS-CoV-2 is similar to that of SEB. This SEB-induced ARDS model also results in various presentations of severity of illness in mice of different genetic backgrounds, as does COVID- 19 in humans. When C3H/HeJ mice are treated with SEB, their survival rate drops to 0%. In our study, we found that Cannabidiol (CBD) administration following SEB treatment, led to 100% survival indefinitely. Initial evaluation of whole single cell sequencing data comparing lungs from naïve with SEB-induced ARDS mice illustrated that there was an increase in neutrophils, inflammatory macrophages and pro-inflammatory cytokines (IL-1β and TNF-α) as well as a loss in lung epithelial cells. To characterize the mechanism by which CBD treatment led to amelioration of the inflammatory response, microRNA expression analysis was done that showed a significant decrease in expression of miR-124-3p in SEB-treated group which is directly associated with upregulation of TNF-α and IL-1β expression as well as macrophage activation gene, Cebp. We hypothesized that CBD attenuates SEB- induced ARDS by miRNA dysregulation in lung-infiltrating cells, specifically by inducing miR-124-3p which downregulates Cebp expression resulting in reduced activation of macrophages. Aim 1 will elucidate the role of resident and monocyte-derived macrophages in disease and the effect CBD on those subpopulations. Aim 2 will elucidate whether CBD affects Cebp expression and the effects that miR-124-3p has on manifestation of disease. Aim 3 will determine the epigenetic factors regulating expression of miR-124-3p. This study will explore CBD as a potential therapeutic for ARDS and/or sepsis induced not only by SEB but other pathogens such as SARS-CoV-2. The K99R00 will provide opportunities associated with Career Development and training in –omics approaches and biostatistics. Taken together, my mentors, advisory committee, consultant, and research environment at the University of South Carolina will nurture my successful transition to an Independent Investigator.

NIH Research Projects · FY 2026 · 2022-01

Project Summary/Abstract African American (AA) women experience disproportionately higher rates of chronic diseases compared to White women, including being twice as likely to die from cardiovascular disease. Physical activity (PA) is a key protective factor for reducing risk for chronic diseases, yet only 35% of AA women meet national PA guidelines. Persistent disparities in chronic disease and pre-mature death among African American women across the adult lifespan highlight the need for developing effective interventions for increasing PA among AA women. We propose that community settings hold tremendous promise as an important context for reaching AA women, but the role of social affiliation has been understudied in past community-based interventions as a key mechanism for engaging AA women in long-term PA. A variety of theories have highlighted the importance of social affiliation for health promotion and have defined social affiliation through several distinct but related constructs. Social Cognitive Theory (SCT) proposes that the group context promotes social learning and collective efficacy, while Self-Determination Theory (SDT) and Group Dynamics Theory (GDT) have emphasized the importance of positive interactions between group members in order to promote relatedness, reciprocal support, and group cohesion. Social affiliation within group-based programs may be especially important to AA women, given that collectivism (belief in the importance of advancing the group over the individual) is a prominent cultural value for many AAs. Despite converging evidence highlighting the importance of social affiliation from a motivational and cultural perspective, this factor has been minimally integrated within intervention designs and rarely targeted as a central mechanism for increasing PA. Our investigative team provides strong preliminary data for expanding on previous community-based PA interventions for inactive AA women by targeting social affiliation through a combination of collaborative and competitive strategies. Drawing from SDT, SCT, GDT, and a cultural values framework, The Together Everyone Achieve More Physical Activity (TEAM-PA) trial evaluates the efficacy of a group-based social affiliation intervention (vs. a standard group-delivered PA comparison program) for increasing PA among inactive AA women. Using a group cohort randomized design implemented at community centers across five years, the primary aim of this study is to evaluate the efficacy of the 10-week TEAM-PA group-based intervention (vs. comparison program) on increasing accelerometry-assessed minutes per day of total PA (light to vigorous activities) from baseline to post-intervention and maintenance at a 6-month follow-up [Primary Aim 1]. Additionally, we will evaluate the impact of the TEAM-PA intervention on secondary outcomes (percentage meeting national recommendations for PA, light PA, sedentary behavior, body mass index, blood pressure) [Secondary Aims 1-2] and potential mediators of the intervention effect on changes in PA [Secondary Aim 3].

NIH Research Projects · FY 2025 · 2021-12

ABSTRACT Stigma and discrimination related to HIV and AIDS (“HIV-related stigma”) have been identified worldwide as major barriers to HIV treatment and care, posing challenges to HIV prevention efforts and provision of adequate care, support, and treatment. Despite decades of global efforts to tackle HIV-related stigma, previous interventions designed to reduce stigma have been largely ineffective. The knowledge gaps and challenges for combating HIV-related stigma are partly rooted in the complexity and diversity of the stigma and partly in the limitations in current conceptualization of stigma reduction efforts. Recent research, including our own preliminary data, has shown the promise of resilience approaches that focus on the development of strengths, competencies, resources, and capacities of people living with HIV (PLWH) and those of their real or surrogate family members and healthcare facilities to prevent, reduce, and mitigate the negative effects of stigma. However, the resilience approach, while hypothesized, has not been widely tested in intervention trials. In the current application, we propose to develop, implement, and evaluate a theory-guided, multilevel multimode resilience- based intervention via a stepped wedge randomized trial among 800 PLWH and their real or surrogate family members as well as 320 healthcare providers in Guangxi, China where we have built a strong research infrastructure and community collaboration through NIH-funded research since 2004. The primary outcome will be viral suppression among PLWH, and the intermediate outcomes will include resilience resources at the levels of individuals, the real or surrogate family members, and healthcare facilities as well as chronic stress response and adherence to treatment and care. The proposed study is innovative as it addresses a number of knowledge gaps in HIV-related stigma reduction intervention research based on both a conceptualization of stigma reduction and advancement in intervention research methodology (e.g., multilevel and multi-component intervention modality, a stepped wedge design, addition of biomarkers to assess the effects of stigma, and targeting primary HIV clinical outcomes such as viral suppression). The proposed research is significant as it addresses a critical public health issue in the US and globally. The proposed intervention protocol, if proven efficacious, has the potential to be replicated in other low- and middle-income countries to mitigate the negative impact of stigma on the HIV treatment and care continuum.

NIH Research Projects · FY 2025 · 2021-11

Project Summary / Abstract Repetitive behaviors are commonly observed in disorders such as Obsessive-Compulsive Disorder (OCD), Tourette’s Syndrome (TS), and Autism Spectrum Disorders (ASDs). These behaviors can have profound negative effects on patients’ lives and can impair their ability to learn, carry out social interactions, and adapt to changing environments. While selective serotonin reuptake inhibitors, antipsychotics, and behavioral therapy are moderately effective in treating these symptoms, many patients are refractory to these therapies and there is a critical need to identify better treatment strategies to help patients with these disabling symptoms. The striatum is a brain region that plays a key role in integrating information from numerous brain structures and is essential to modulating habitual and goal-directed behaviors. Converging clinical and preclinical data suggest that hyperactive dopaminergic and glutamatergic neurotransmission through specific circuits in the striatum may represent common mechanistic underpinnings of abnormal repetitive behaviors. Interestingly, extensive studies from our lab and others have found that the M4 subtype of muscarinic acetylcholine receptor can exert powerful modulatory control over striatal dopaminergic and glutamatergic transmission, raising the possibility that selective activators of M4 could reverse pathological changes that may give rise to repetitive behaviors. Here we provide preliminary data demonstrating that M4 PAMs can reduce excessive grooming in SAPAP3 KO mice (a genetic mouse model that displays a repetitive over-grooming phenotype). This could provide a breakthrough in identifying a novel approach for treatment of disabling symptoms that are resistant to available therapies. We hypothesize that repetitive behaviors in multiple animal models displaying repetitive grooming are associated with hyperactive glutamate and dopamine release in the striatum, and that M4 PAM treatment can reduce repetitive behaviors by normalizing these forms of neurotransmission. We will test this hypothesis through a series of electrophysiological and behavioral studies using a combination of genetically modified mice, optogenetic approaches, and novel pharmacological tools. These studies will provide important information regarding the physiological role of M4 receptors in regulating basal ganglia function and will elucidate the therapeutic potential of M4 PAMs in providing relief from repetitive behaviors.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY More than 36 million people worldwide are estimated to be living with HIV infection and more than 1.2 million are in the USA. With the introduction of highly active anti-retroviral therapy, the life span of HIV-infected individuals has increased significantly. However, the quality of life of can be compromised owing to a range of cognitive deficits and memory loss, commonly referred to as HIV-associated neurological disorders (HAND). HIV-infected individuals are more likely to suffer from substance use disorder (SUD), and disproportionately suffer from high all-cause mortality. Drugs of abuse also increase severity of HAND by several potential biological mechanisms. HIV associated cognitive deficiencies in conjunction with SUD decrease engagement in HIV care, which fuels a worsening downward spiral of health status. Despite intensive research, there is no approved therapy for the treatment of HAND and particularly for the combined neurological effects of HIV and drugs of abuse. We have developed and employed MOLIERE and AGATHA, AI-based literature mining systems that discover novel interactions that potentially contribute to HAND. These systems also prioritize mining results to uncover small molecules that can be tested for anti-HAND therapy. Experimental validation of MOLIERE was achieved; four small molecules predicted by MOLIERE were shown to prevent HIV-Tat and cocaine induced neurotoxicity. AGATHA improved MOLIERE results on a massive retroactive validation and is ready to be deployed for wider searches that now include PubChem. In parallel, our previous efforts querying the Department of Veterans Affairs / Veterans Informatics Network Computing Infrastructure (VINCI) with specific hypotheses have successfully uncovered potential associations of unanticipated modifiers of HIV-associated pathologies. Collectively, these results led us to the central goal of this proposal to develop and apply an integrative AI-based approach to analyze biomedical datasets and Electronic Health Records to determine new mechanisms of HIV and substanses of abuse interactions, and to discover repurposed drug candidates to be tested for the treatment of HIV-infected SUD patients. This will be accomplished in three Aims. Aim 1 will develop a multidimensional AI-based text mining approach to explore new mechanistic connections between HAND and substanses of abuse. This will generate new knowledge of HAND and SUD interactions, and uncover small molecule and drug candidates that can be tested for activity against the neurotoxic insults caused by HIV and substanses of abuse. Aim 2 will develop and apply advanced machine learning and AI algorithms to explore health records of HIV and SUD patients. The outcome will be the development of the machine learning system to analyze VA data and generate of signals (hypotheses) for medications or medication targets that might have value to experimentally test for repurposing to manage HAND. Aim 3 will prioritize the selected candidates for experimental validation and further clinical development.

NIH Research Projects · FY 2025 · 2021-09

The environmental sensor, aryl hydrocarbon receptor (AhR) serves as a ligand for pollutants as well as for plant, microbial and endogenous compounds. Following AhR ligation, the activated AhR regulates gene expression through the binding of AhR/ARNT complex to specific DNA motifs known as Dioxin Response Elements (DREs). Studies from our lab and elsewhere have shown that some AhR ligands have potent immunosuppressive properties. Inflammatory bowel disease (IBD) results from chronic inflammation in the gastrointestinal tract that affects 1.5 million people in the US. The pathogenesis of IBD involves complex interactions between gut microbiota, immune response, environmental and dietary factors, and genetic/epigenetic regulation. Recently, we made an exciting observation that the AhR ligand and plant product, I3C ameliorates colitis in mice, which was associated with anti-inflammatory effects, regulation of gut dysbiosis, and enhanced expression of β-defensins (mBD1,2,3) by Colonic Epithelial Cells (CEC). β-defensins constitute antimicrobial peptides (AMPs) that resist microbial colonization of epithelial surfaces in the colonic tissue. β- defensins may also mediate anti-inflammatory effects. In fact, studies have shown defective expression of intestinal AMPs particularly defensins in IBD patients. We were excited to uncover DREs in the promoters of mouse β-defensins (mBD1, 2, and 3). In the current study, we will test the central hypothesis that dietary indoles (I3C) attenuate colitis through AhR activation leading to increased expression of mBDs by CECs via pathways involving DREs, and/or epigenetic regulation resulting in modulation of microbiota and prevention of epithelial barrier damage. Furthermore, we propose that mBDs induced by I3C play a critical role in restoring healthy gut microbiota, preventing intestinal barrier damage and suppressing colonic inflammation through induction of Tregs. Aim 1 will test the mechanisms of mBD induction by dietary indoles. We will use reporter assay, promoter bashing and electrophoretic mobility shift assay to determine whether I3C activated AhR directly binds to the DREs to induce mBDs. We will also determine the effect of I3C on the mBD expression by using AhR cKO mice with AhR deletion in IEC, ILC3 and Tregs. In Aim 2, we will study epigenetic regulation of β-defensins by dietary indoles. To that end, we will test whether I3C regulates mBD expression by altering histone modification and decreasing DNA methylation. We will specifically determine if I3C regulates the SATB1-mediated histone deacetylation and chromatin remodeling. In Aim 3, we will test whether administration of mBDs offers protection from colitis by regulating gut dysbiosis, preventing CEC barrier damage, enhancing Treg subsets and decreasing Th17 subpopulations to attenuate colonic inflammation. Finally, we will use mBD KO mice to test whether mBDs are required for I3C-mediated protection from colitis. The proposed studies are highly significant because they will identify novel mechanisms through which dietary indoles suppress colitis by altering the microbiota, through activation of AhR leading to increased expression of host-derived AMPs, specifically β-defensins.