University Of South Carolina At Columbia

NIH Research Projects · FY 2025 · 2023-12

Project Summary/Abstract Due to advances in antiretroviral therapy (ART), the vast majority of youth living with HIV (YLH) in the US now survive to adulthood, and, thus, must transition from pediatric to adult HIV care. Achieving a successful transition to adult HIV care is a pressing public health issue with implications for ongoing efforts to end the HIV epidemic in the US. During the pediatric-to-adult HIV care transition (“HCT”), youth must navigate forming new relationships with providers and taking on greater independence in their care. Challenges to a successful HCT also vary by geographic location and sociocultural context. As one of the rural states targeted by the Ending the HIV Epidemic (EHE) initiative, South Carolina (SC) is characterized by profound HIV disparities among racial, ethnic, sexual, and gender minority communities, as well as high rates of poverty, structural barriers to healthcare, and healthcare provider shortages. While there have been some attempts to characterize such transition in other southern states with high HIV burden, data regarding the status of HCT of YLH and barriers and facilitators of a successful HCT are still limited, largely because of some gaps in the existing research (e.g., with data predominately from YLH with perinatal acquisition, qualitative or quantitative studies with small sample sizes and short follow up time). To address the gaps in HCT research among YLH, we will build a longitudinal cohort (estimated ~6,000) of youth (13 to 24 years of age) who were diagnosed with HIV during 2005-2023, extract and link their electronic health records (EHR) data from six SC state agencies, and link these data to aggregated county-level community and social structural level data from multiple publicly available data sources to develop a robust, multi-faceted dataset with biological, clinical, behavioral, and contextual variables. With the integration of multilevel data from multiple sources and advanced data analytics (e.g., machine learning algorithms), the current study will assess the HCT status (e.g., successful, delayed, or loss/failure in transition) and post-transition care continuums (e.g., retention in adult care, viral suppression in adult care) among YLH over time, and identify the barriers and facilitators of success HCT for YLH. This study will provide an in-depth assessment of the HCT status of a large longitudinal cohort of YLH in SC using real world data. Identification of the barriers and facilitators for successful HCT of YLH could help policymakers and HIV care providers improve systems and services to better support YLH as they move from pediatric to adult-oriented HIV care and inform state health department to devise more precise, targeted intervention strategies for YLH to maintain continuous engagement in care during the transition, to support the ability of YLH to effectively manage their disease, and ultimately to decrease HIV-related morbidity and mortality rates among these youth, especially those who are minoritized.

NIH Research Projects · FY 2025 · 2023-12

PROJECT SUMMARY Nucleus Accumbens (NAc) activity is critically important for response to motivated stimuli, including aversive stimuli. However, it is not known how the NAc processes and responds to these stimuli across the 24hrs cycle. We and others have found NAc shows daily changes in neuronal activity which appears to be in phase with circadian-dependent dopamine release from the primary dopamine input to the NAc, the ventral tegmental area (VTA). Therefore, response to motivated stimuli may vary depending on time-of-day. We recently discovered the circadian gene CRYPTOCHROME (CRY) modulates Gs-protein coupled with dopamine 1 (D1) receptor which may alter neuronal activity and excitability of NAc projection neurons. These data suggest circadian regulation of dopamine receptor activity in the NAc has the ability to strongly alter response to dopamine driven by aversive stimuli via the dopamine 1 receptor. We hypothesize that CRY controls circadian NAc activity through modulation of dopamine 1 receptor function. In year 1 of this proposal, we will assess the role of CRY in regulating circadian dopamine 1 receptor function ex vivo and in vivo. We will selective knockdown CRYs in the NAc and assess D1 receptor function by whole-cell patch clamp physiology by monitoring voltage-gated K+ currents ex vivo and by fiber photometry to monitor D1 receptor signal transduction dynamics in vivo. In year 2, we will use ex vivo approaches with selective knockdown of CRYs to assess DA-dependent NAc excitability. We will further determine circadian-dependent VTA dopamine release and NAc neuronal activity changes in response to aversive stimuli in vivo by monitoring calcium signaling with fiber photometry. This study will allow us to dissect mechanistic, circadian regulation of NAc neurophysiological response and dopamine receptor function. The overall aim of this project is to determine the role of CRY in regulating excitability and function of the NAc and how this regulation controls NAc response to aversive stimuli. This proposal will provide translationally relevant information about circadian regulation of basic mechanistic underpinnings of NAc dopamine function and behaviorally relevant, neurobiological response to aversive stimuli. This work will further provide a foundation for understanding how circadian-driven NAc changes underlie susceptibility to mood disorders such as depression.

NIH Research Projects · FY 2026 · 2023-12

Assessing children’s 24-hour movement behaviors (i.e., time spent active, sedentary, and asleep) can reveal the complex and interdependent ways energy expenditure and sleep are related to health outcomes. However, assessing energy expenditure and sleep among children in free-living conditions is inherently difficult, and no single method is without limitation. A combination of heart rate and accelerometry data provides a more precise estimate of energy expenditure and sleep than either heart rate or accelerometry alone, when compared to a criterion measure of indirect calorimetry or polysomnography, respectively. Yet, devices that measure both heart rate and acceleration (such as ActiHeart or Fitbit) were not designed for children and may be distracting or uncomfortable. Moreover, nearly all devices use proprietary algorithms and do not allow access to raw signal data, and thus, are fundamentally unverifiable. Our study team has developed the PATCH, a small, open-source wearable device which integrates multiple sensors to measure heart rate and acceleration among children. The proposed project leverages the initial PATCH calibration progress and extends this work to conduct a series of studies to establish the validity of the PATCH to measure children’s energy expenditure and sleep in both laboratory and free-living conditions. The objectives of the proposed project are (1) develop estimates of energy expenditure for children aged 3-8 years, (2) measure sleep, compared to criterion polysomnography and (3) validate PATCH estimates of energy expenditure and sleep in 24-hour free-living contexts. Our long-term goal is to advance the measurement field for epidemiologic- and intervention-based studies that measure energy expenditure and sleep in the context of free-living 24-hour movement behavior. This project is innovative because it leverages off-the-shelf hardware and open-source processing. This means that results from this project will enable other researchers to build their own PATCH device and independently process the data, thereby overcoming issues related to proprietary hardware and algorithms that currently limit the field of wearable devices. This project is significant because this technology has the potential to substantively improve measurement of 24-hour movement across development in epidemiological studies and improve wear- time compliance, given the PATCH’s small, unobtrusive design. Thus, this technology has promise to serve as a powerful assessment tool for evaluating children’s free-living energy expenditure and sleep in observational and intervention studies.

NIH Research Projects · FY 2026 · 2023-09

Summer (i.e., May-August) is a period of accelerated BMI gain that leads to increases in childhood obesity. Two theories may explain accelerated summer BMI gain. The Circadian and Circannual Rhythm Model (CCRM) posits that BMI gain during summer is biologically driven by the shifting light dark cycle with BMI gain accelerating during the summer when days are longer and weight gain outpaces height gain and decelerating during the winter when days are shorter and height gain outpaces weight gain. The Structured Days Hypothesis (SDH) proposes accelerations in BMI gain during the summer are due to the removal of the structured school day (i.e., school vs no school during summer) which influences children’s engagement in key obesogenic behaviors (physical activity, sedentary/screen time, dietary intake, and sleep). Breaks throughout the school year (1-week fall break, 2-week winter break, 1-week spring break) may also cause accelerated BMI gain. Current accelerated BMI gain research is focused exclusively on summer vs. school year comparisons. These studies measure children in the spring (May prior to summer) and fall (August following summer) exclusively allowing only for comparisons of BMI gain between the 3 months of summer and the other 9 months of the year. It does not allow for the measure of decelerations in BMI gain predicted by the CCRM during the winter, nor does it allow for the measure of accelerations in BMI gain during the fall, winter, and spring breaks predicted by the SDH. This is a critical limitation in our understanding of WHEN childhood obesity occurs and HOW to treat it. This study will overcome these limitations by identifying monthly patterns in the accelerations and decelerations of children’s height, weight, and BMI gain and the associated behavioral, social (i.e., social support and parenting practices for healthy physical activity, diet, sleep, screen use, family eating practices), environmental (i.e., community resources, school resources, home resources, neighborhood safety, neighborhood food outlets, home food inventory), and biological (i.e., genome-wide polygenic obesity risk score) determinates. We will recruit 3 cohorts (3K, Kindergarten, and Second grade) of 200 children (600 children in total) to participate in a cohort-sequential design. We will collect BMI monthly, obesogenic behaviors (physical activity, sedentary/screen time, dietary intake, and sleep) in the spring, summer, fall, and winter, and social, environmental, and biological information over three years for each cohort. The cohort-sequential design will allow us to map BMI development and seasonal shifts in behaviors 3K to 5th grade. We will accomplish the following specific aims: Aim 1: Identify monthly variations in height, weight, and BMI change in a large and diverse cohort of children (3K to 5th grade, N=600). Aim 2: Examine the relationship between monthly patterns of height, weight, and BMI change with seasonal (fall, winter, spring, summer) patterns in obesogenic behaviors. Aim 3 Exploratory: Examine the relationship of social, environmental, and biological factors with patterns in behaviors and variations in height, weight, and BMI z-score change. This project is significant because it fills a major gap (monthly patterns of BMI z-score gain) in the knowledge about the development of childhood obesity, a widespread public health crisis. This project is innovative because it will be among the first studies to measure BMI gain monthly along with the associated behavioral, social, environmental, and biological determinates that predict accelerated/decelerated BMI gain.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract Vector-borne disease surveillance requires monitoring the geographic distribution of infected vectors and is a costly process that typically involves collecting vectors in the field and subsequently testing them for the presence of various pathogens. These costs are often prohibitive to financially strained public health labs and local municipalities, thus leaving the geographic distribution of many vector-borne diseases poorly understood. This is especially true for emerging diseases and those with expanding geographical ranges. Firmly understanding the spatial distribution of vectors infected with various pathogens is critical for healthcare providers who are using potential exposure to guide diagnostic and treatment decisions. To provide these assessments, this project will develop multiple cost-efficient vector-borne disease surveillance strategies, including both active and passive strategies. The active strategy reduces cost by leveraging pool testing techniques; i.e., rather than testing vectors one-by-one, multiple vectors are physically amalgamated to form a pooled specimen which is tested for the pathogen of interest. These techniques have the potential to drastically reduce testing cost, especially for surveillance efforts, but do so at the expense of a far more complicated data structure. To overcome this complication, we will develop a novel suite of spatial and spatio-temporal regression models which can be used to analyze pool testing data with an end goal of being able to better understand the geographic distribution and expansion of various vector-borne diseases. The passive strategies will leverage existing information, as well as data collected through this proposal, to develop ‘nowcasts’ of vector activity levels. These nowcasts will assimilate climate and habitat suitability, weather patterns and other key environmental factors to forecast activity, and therefore can be updated in real time without any associated cost. These nowcasts are intended to supplement active surveillance efforts and field collection, especially in areas where large scale collection is not feasible. To validate our surveillance strategies, we plan to undertake an ambitious study aimed at collecting and testing ticks for spotted fever group Rickettsia along the expanding geographic range of A. maculatum (South Carolina) and A. americanum (the Midwest). The data from this study will be used to validate and inform the design of both our active and passive surveillance strategies. In summary, our proposal seeks to transform the paradigm of vector-borne disease surveillance by reducing costs, improving accuracy, and quantifying risk in real time, while elucidating the spatio-temporal patterns vector infection by spotted fever group Rickettsia species.

NIH Research Projects · FY 2026 · 2023-09

This application requests R13 funding support to the National Big Data Health Science Conferences at University of South Carolina (USC) for five years (2024-2028). This conference is a signature event of the USC Big Data Health Science Center (BDHSC). BDHSC is an intramurally funded interdisciplinary enterprise established in April 2019 that promotes and supports Big Data health science research at USC and across the state through capacity development, academic training, professional development, community engagement, and methodological advancement. Building on our successful experience with 4 intramurally-supported conferences (2020-2023), the overall goal of this R13 is to stimulate further advancements in Big Data health science research through rich interdisciplinary and multidisciplinary collaboration. Consistent with its overarching goal, the conference will: (1) create a multidisciplinary scientific venue for the exchange of new concepts, methods, and results to encourage the sharing of theoretical, methodological, and substantive knowledge from Big Data health science research; (2) identify new issues that are, to date, understudied in this area, and then generate, promote, and support innovation in BDHS; (3) expand impact and scholarly excellence by producing new and interdisciplinary publications; and (4) promote excellence in training and mentoring opportunities by engaging and supporting junior investigators and students in the conference.

NIH Research Projects · FY 2025 · 2023-09

This Pathway to Independence Award (K99/R00) will facilitate my transition to an independent scientist who conducts innovative research on mechanisms and pathways of developmental and cognitive risk outcomes in Down syndrome (DS). Down syndrome is the most common childhood genetic disorder and characterized by substantial phenotypic impairments across several areas of development, including motor, attention, communication, and cognition. There has been virtually no investigation, however, into the developmental pathways of early phenotypic impairments in motor or attention, or their role as determinants for impaired cognitive or communication outcomes in DS. Motor and attention are key developmental domains effortlessly coordinated to support communication and cognitive learning in typical development. Delayed achievement of key motor milestones in DS – postural control in particular – has serious implications for the development of infant attention, as well as for outcomes related to communicative and cognitive functioning through compromised learning opportunities. Therefore, I propose to investigate the dynamic influence between postural control and attention in infants with DS and determine their mutual or distinct role in impaired communication and cognitive outcomes at 24-months in DS. I will characterize the behavioral and physiological features of postural control and attention by quantifying the kinematics of postural variability and defining heart-rate phases of attention. I will examine the dynamics of how these features influence one another during discrete learning opportunities, and also across development to inform their role as determinants on communication and cognitive risk outcomes in DS. Examining the biobehavioral concordance between these constructs is an innovative, precise, and multi-method approach that can yield better insight into the developmental complexity in DS. This will be accomplished across three complementary studies that will provide advanced training and employ cutting-edge methodology. Training initiatives will be accomplished across two studies implemented during the mentored K99 phase, and then systematically applied to a longitudinal study during the independent R00 phase. The specific aims across these studies are: 1) Identify differences in physiological and behavioral facets of attention at 12-months and their role in communication and cognitive skill outcomes at 24-months as a function of postural control in infants with DS (K99 phase); 2) Determine the concordance across biobehavioral facets of attention and the reciprocal association between biobehavioral attention and postural control at 9, 12, and 18-months in infants with DS (K99/R00 phase); and 3) Characterize the biobehavioral pathways and developmental dynamics of attention and postural control across 9, 12, and 18-months and test whether these domains have a shared or unique influence on communication or cognitive skill outcomes at 24-months in DS (R00 phase). This novel and multi-method biobehavioral approach will shed light on the pathogenesis of impaired motor and attention in DS. Further, findings will contribute to advanced phenotyping approaches of infant development in DS and serve as an initial step in the development of targeted interventions. My team of incredibly strong mentors and one collaborator is uniquely poised to assist and promote my training and research goals, and to ensure my successful transition to an independent scientist.

NIH Research Projects · FY 2024 · 2023-08

Accurate assessment of children’s (5-12yrs) free-living physical activity energy expenditure (PAEE) is critical to understanding the complex and interdependent relationship between children’s PAEE and health outcomes. The combination of movement (e.g., steps, counts, raw signal) and heart rate data provides reasonably accurate estimates of children’s PAEE during lab conditions. However, the combination of movement and heart rate (MOVE+HR) may be inadequate for predicting children’s free-living PAEE. Studies in adults demonstrate including the type of activity (e.g., the participant is walking, running, cycling, etc.) improves estimates of free- living PAEE, relative to using movement or MOVE+HR. Yet, this evidence is based on studies conducted in adults. No studies of children have investigated the impact of adding activity type to PAEE prediction equations that use MOVE+HR. Existing consumer wearables (e.g., Fitbit, Garmin) are promising for the assessment of children’s free-living PAEE. These devices incorporate built-in pattern-recognition features that automatically detect activity type, and these metrics are provided in a user-friendly format for the end-user; however, no known studies have evaluated the ability of consumer wearables to autodetect activities in children. Consumer wearables also use photoplethysmography to capture HR and accelerometry to capture movement. Their unique ability to capture activity type, HR, and movement metrics could significantly improve estimates of free-living PAEE in children. Aim 1 will evaluate the impact of including activity type, captured via direct observation, to regression equations that use movement and HR data from consumer wearables (i.e., Garmin Vivoactive 4S and Fitbit Sense). Aim 2 will evaluate the ability of consumer wearables (i.e., Garmin Vivoactive 4S and Fitbit Sense) to automatically detect activities (i.e., walking, running, biking). To accomplish these aims, this study will capitalize on the validation design (i.e., semi-structured physical activity protocol and data management/extraction procedures) and draw on data collected from 120 children (5-12yrs) from an existing R01 project. This project will use analytical techniques, including cross-sectional time series (CSTS), multivariate adaptive regression spline (MARS), machine learning, and equivalence testing to address the following aims. The project’s long-term goal is to advance the assessment of children’s PAEE in epidemiologic- and intervention- based studies for children, which is critical to understanding the complex relationship between children’s PAEE and health outcomes. Through the execution of this project, the following will be gained: an in-depth knowledge of the literature related to assessment of PAEE in children, expertise designing and implementing validation studies assessing PAEE in children, hands-on training using gold standard measures to assess children’s PAEE and activity type, proficiency performing advanced analytical techniques, and scientific communication and grantsmanship skills, including peer-reviewed publication, scientific presentation, mentored manuscript review, and a drafted post-doctoral grant application.

NIH Research Projects · FY 2024 · 2023-08

PROJECT SUMMARY Exposure to psychosocial stress has widespread deleterious effects on the body and brain that lead to the development of many physiological and neuropsychiatric disorders. Importantly, conditions such as anxiety and opioid use disorder (OUD) are two of the most common stress comorbidities that not only cause drastic effects on the patient but also represent an extreme public health crisis. Notably, females often suffer from these conditions at twice the rate of men, but research into the potential sex differences that allow for this susceptibility has traditionally been under studied. Further, the underlying neural mechanisms by which stress confers susceptibility to future psychiatric illness has not been fully explored. The overall goal of this project is to determine the neural alterations induced by psychosocial stress in discrete stress-sensitive brain regions in animal models utilizing both male and female rats. Specifically, these experiments aim to investigate neuroimmune signaling within the locus coeruleus (LC) to determine how stress-induced alteration of microglial activation influences noradrenergic output and subsequent anxiety-like and drug seeking behaviors. Increased neuroimmune signaling in this brain region has been associated with increased norepinephrine (NE) output, but the downstream impact of stress-induced microglial alterations of LC-NE activity on projection regions involved in the control of anxiety and drug seeking behaviors has not been assessed. Therefore, these experiments have been designed to test the hypothesis that stress exposure augments microglial signaling within the LC which, in turn, affects noradrenergic tone in downstream regions including the basolateral amygdala (BLA), a region known for its control of anxiety- and drug-related behaviors. This hypothesis will be tested using a variety of techniques including behavioral pharmacology, chemogenetics, and microdialysis to modulate and measure the impact of stress-induced LC microglial activation on anxiety-like and opioid seeking behaviors. Male and female rats will be exposed to our model of vicarious social stress, witness stress, where a rat experiences the sensory and psychological aspects of a social defeat encounter. Aim 1 is designed to determine the effects of LC microglia modulation, through intra-LC DREADD mediated inactivation of microglia, on anxiety-like and opioid reinstatement behaviors using marble burying and opioid conditioned place preference testing. These animals will also be implanted with microdialysis probes within the BLA for Aim 2 which is designed to determine the downstream effects of LC microglial modulation on NE activity in the BLA. These studies have the potential to identify novel mediators of maladaptive stress responses that escalate to opioid use disorder with the ultimate goal of determining preventative treatments for stress-induced comorbidities. These data support the mission of the NIH in the search for a cure for the opioid epidemic and allows for the training necessary to create an independent scientist that will continue to pursue this goal throughout their career.

NIH Research Projects · FY 2024 · 2023-08

Project Summary Vascular malformations (VMs) are resulted from developmental abnormalities in vasculatures including veins, arteries, capillaries, and lymphatic vessels. Treatment of VMs is a big challenge due to the large variety of lesion types, complexity of symptoms, and limited interventional options, which results in unsatisfied therapeutic outcomes. Port Wine Birthmarks (PWB) is one of the most common types of VMs. It mainly appears on the face and can be highly associated with Sturge Weber Syndrome (SWS) with brain blood vessels’ involvement and seizure disorders. One long-term obstacle to our understanding of the disease causes of PWB and the therapeutic development for it has been a lack of clinically relevant cell and animal models. In this proposal, we will take advantages of utilizing our current advancements in the generation of PWB-derived induced pluripotent stem cells (IPSCs) and their differentiated lineages such as endothelial cells (ECs) and vascular spheroids/organoids (VSs). VSs derived from PWB show larger diameters, longer lengths, and more tortuous branches as compared to the VSs derived from normal IPSCs. In addition, such vascular phenotypes can be reproduced in vivo after an implantation of spheroids/organoids into the mouse skin. These proof-of-principle and feasibility studies let us propose to develop in vitro and in vivo clinically relevant cell and organoid models derived from PWB patient’s IPSCs and validate them subsequently. For evaluation of in vitro cell and organoid models, we will perform a series of molecular and phenotypic characterizations of ECs and VSs derived from PWB IPSCs as compared to normal IPSCs. Furthermore, next generation sequencing approaches will be used to explore and integrate the molecular, epigenetic, and signaling pathway profiles that underlie the abnormal cell-fate and lineage-specification in PWB. These molecular pathological features will be further validated with PWB skin lesions. For evaluation of the in vivo model, we will implant VSs into skins in mice, monitor and characterize the dynamics of the vasculature formation and remodeling. We will determine the recapitulated PWB pathologies in this in vivo model as compared to the existing data from PWB skin lesions. The project is highly innovative as it aims to develop clinically relevant and paradigm-shift cell and organoid models for mechanistic and therapeutic studies of PWB. The use of patient-derived IPSCs, ECs, and VSs are unprecedented; the data is translational. These models are not only a significant evolution in disease model development for understanding of pathological characteristics of PWB, but also a substantial advancement in development of a novel platform for clinical therapeutic studies.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY Developmental language disorder (DLD) is a highly prevalent neurodevelopmental disorder with significant impacts on many aspects of life functioning including literacy, educational attainment, and employment opportunities. Unfortunately, most children with DLD are not identified and do not receive services to improve their outcomes. The long-term goal of this project is to improve the identification of DLD and to contribute to improved systems of support for language and literacy development for all children. We will characterize the developmental trajectory of language comprehension in the primary grades using novel, group-administered measures focusing on skills which (a) undergo significant development in the primary grades, (b) appear frequently in academic settings, (c) are important for reading comprehension, and (d) are appropriate for use with students from diverse cultural and linguistic backgrounds. The use of group-administered measures promotes feasibility and allows for practical implementation in real-world classrooms. Items measuring syntax, vocabulary, and derivation of novel word meanings will be developed and calibrated to create an across-grade vertical scale of measurement for language performance. Developmental change in language comprehension will be evaluated with three administrations of language comprehension measures per year in grades K and 1 (e.g., Fall, Winter, Spring) and one administration in grade 2. We will evaluate the clinical and educational validity of the novel language comprehension measures by conducting an accelerated cohort design study spanning grades K through 3 and relating them to standardized measures of language and reading abilities that will be administered once in each grade. Clinical utility will be examined using (a) traditional binary classification analyses of sensitivity, specificity, and likelihood ratios, and (b) with cutting-edge continuous measurement models. The latter models will estimate individual change along a continuum, allowing us to evaluate student trends over time rather than simplistic pass-fail criteria, which may be arbitrary and inconsistent. This information will help clinicians identify when children may appear to be achieving adequately but at risk of approaching a clinical threshold, as well as when children receiving language supports are rising back up toward a level of performance more typical of their peers or level of instruction.

NIH Research Projects · FY 2024 · 2023-07

Colorectal cancer is the third most commonly diagnosed cancer in the world. Sarcopenia, defined as a loss of skeletal muscle mass and function, is highly prevalent in colorectal cancer, with rates of up to 60% reported. Sarcopenia etiology in cancer is multifactorial, with aging and inactivity compounded by treatment toxicities, malnutrition, tumor burden, and high-grade inflammation. Consequently, it’s unlikely that unimodal interventions will be sufficient to overcome the burden of sarcopenia in this population. Creatine monohydrate is a naturally occurring compound in the body that plays a critical role in energy provision during exercise.4 Creatine is the most widely studied nutritional supplement to date, with well over 1,000 studies establishing its safety and effectiveness in men, women and older adults, in addition to other clinical populations. There is strong and consistent evidence that creatine supplementation can enhance the positive adaptations to resistance training in older adults and clinical populations. Therefore, there is strong potential for the application of creatine and resistance training to offset the decline in muscle mass and function after cancer treatment. The purpose of the proposed study is to examine the feasibility and acceptability of creatine supplementation combined with resistance exercise, compared to resistance exercise alone in individuals treated for colorectal cancer who are sarcopenic. We propose a randomized controlled pilot trial, examining the effects of 10-week multimodal resistance exercise and creatine supplementation (EXSUPP) (n=20) relative to resistance exercise alone (EXPLA) (n=20) in individuals treated for colorectal cancer who have sarcopenia. The specific aims of this project are to 1) determine the feasibility and acceptability of the intervention in colorectal cancer patients? diagnosed with sarcopenia after cancer treatment, 2) compare the effects of an exercise and creatine supplementation intervention (EXSUPP) to exercise alone (EXPLA) on body composition, muscle strength, physical function, and quality of life and 3) explore muscle molecular-level adaptations, i.e., mitochondrial health and protein turnover, in response to the interventions. This project will be one of the first to combine exercise with creatine, specifically targeting sarcopenia in individuals previously treated for colorectal cancer. This project is directly in line with the priority research initiative from the NCI Cancer MoonshotSM to “minimize Cancer Treatment’s Debilitating Side Effects.” Our trial is innovative in addressing one of the most important health problems for individuals treated for colorectal cancer in that it will be the first to 1) examine the feasibility and acceptability of a multimodal exercise and nutritional intervention relative to exercise alone in individuals treated for colorectal cancer who are sarcopenic and 2) explore the molecular mechanisms underpinning the response to exercise and nutritional interventions.

NIH Research Projects · FY 2025 · 2023-07

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. This predoctoral research training program focuses on transdisciplinary training of future behavioral scientists organized around research concepts and methods at the interface of behavioral and biomedical domains. The program’s cross-cutting theme emphasizes translational sciences, accentuates facets of prevention science, and engages both human and animal-model approaches to research. The predoctoral Behavioral-Biomedical Interface Program (BBIP) stems from NIGMS's “Interface of the Behavioral and Biomedical Sciences” initiative. BBIP engages trainees from three disciplinary units that are heavily involved in the behavioral sciences: epidemiology, exercise science, and psychology. The behavioral and biomedical sciences faculty mentors and BBIP trainees are working on health-related research problems linked for example to cancer, cardiovascular health, children’s behavioral and mental health, diabetes, obesity and physical activity in childhood and adulthood, stroke and brain injury, and substance abuse. Providing the cross-disciplinary training are faculty mentors, laboratory hosts, program leaders, and course instructors who bring to bear a broad array of disciplines and research areas such as epidemiology and related public health areas, exercise science, genetics, neuroscience, prevention science, psychology, and quantitative methods/biostatistics. BBIP training includes coursework, integrated with doctoral degree curricula, in neuroscience, genetics, translational science, prevention science, responsible conduct of research, methods to enhance rigor and reproducibility, and advanced statistical and design methods. Trainees participate in two laboratory rotations and in a behavioral-biomedical-interface seminar course; and they engage in mentored research throughout training. A Topic Sessions Series addresses scientific, methodological, career and professional development, and scientific integrity topics. The program aims to foster a positive multi-disciplinary climate, encourage advanced quantitative/statistical skill development, and inspire dissertational research informed by behavioral-biomedical interface issues. This training program runs parallel to each trainee's discipline-specific doctoral degree program and builds capacity with respect to behavioral scientists who are sufficiently exposed to the biomedical sciences to effectively contribute to multi-disciplinary teams engaged in research aimed at understanding and preventing significant health disorders and conditions to promote positive health outcomes.

NIH Research Projects · FY 2024 · 2023-07

PROJECT SUMMARY Obesity increases the risk of cancer; thus, individuals that are obese are more likely to undergo chemotherapy in their lifetime. However, there is a dearth of literature on the impact of weight status on cancer patient life quality and functional capacity throughout treatment. For instance, our knowledge of the impact of obesity on cancer and chemotherapy-induced cachexia - the unintentional loss of lean mass, which directly contributes to functional dependency, poor treatment outcomes, and decreased survival – is incomplete. An “obesity paradox” has been postulated; however, the epidemiology remains equivocal on the benefits/detriments of a high pre-treatment body weight and body mass index. While obesity and cachexia are diseases at opposite ends of the weight spectrum, these pathologies share some underlying perturbations (e.g. mitochondrial dysfunction) that may exacerbate functional decrements when these morbidities co-occur. Our lab made the novel and significant discovery that obese mice, dosed for lean mass, were unable to survive 2-3 cycles of the chemotherapeutic, 5 fluorouracil (5FU). Indeed, contrary to what has been suggested, we discovered that obese mice are not protected against chemotherapy-induced cachexia and show exacerbated skeletal muscle toxicities. Disruptions to mitochondria are 1) central to chemotherapy-induced skeletal muscle mass loss, and 2) are known to be existent with obesity and metabolic dysfunction; however, mitochondrial dysfunction and resultant functional deficits have not been assessed when these morbidities co-occur. Antioxidants have been shown to improve mitochondrial function. Indeed, we have shown that the antioxidant dietary compound, quercetin, can reduce cancer, cancer cachexia, and chemotherapy-induced fatigue, and can increase mitochondrial function in healthy mice. Thus, quercetin may hold promise as a dietary strategy to treat cachexia associated with cancer and its therapies in the obese condition. The primary goal of my proposed F31 is to 1) understand the impact of obesity on 5FU-induced skeletal muscle dysfunction and 2) provide mechanistic and therapeutic insights aimed at better improving 5FU tolerance with obesity. My central hypothesis is that 5FU-induced mitochondrial loss and dysfunction is exacerbated with an obese phenotype and intervening with quercetin will mitigate the deleterious effects of 5FU on skeletal muscle. To test this hypothesis, I propose three related but independent specific aims: 1) Examine the impact of obesity on cancer and 5FU-induced cachexia and function loss; 2) Determine the role of mitochondria in obesity-exacerbated 5FU toxicities; and 3) Explore the utility of dietary quercetin on improving 5FU treatment tolerance and off- target toxicities with obesity. The proposed studies align with my training aims and will provide me with the opportunity to gain expertise in obesity phenotyping and natural compounds as therapeutics, mitochondrial health and dynamics, cachexia and functional testing. Further, the professional development training will promote advancement to the next step in my path to research independence.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY Disrupted attention is among the earliest-emerging, lifelong features of autism spectrum disorder (ASD) and research suggests a critical point in the neonatal and early infant period at which disrupted attention may be detectable. The timing of this disruption aligns with key maturational shifts in neurodevelopment, but the neurobiological mechanisms associated with disrupted attention in ASD remain elusive. One neurobiological system that regulates attention from early infancy is the autonomic nervous system (ANS). Broad ANS dysfunction is observed in older children already diagnosed with ASD, but whether and when ANS dysfunction contributes to attention abnormalities in ASD remains unknown. The overall goal of this study is to examine how atypical autonomic regulation of attention may be associated with the emergence of ASD symptoms. A key marker of autonomic regulation of attention is heart defined attention. Accordingly, maturation of heart defined attention in the early infant period and the developmental consequences therein for the emergence of interactive behaviors and ASD symptoms will be examined. A critical innovation of this study is leveraging a three-group design in which infants who experience elevated ASD symptoms (infant siblings of children with ASD; ASIBs) will be compared to typically developing (TD) and preterm (PT) control groups. Infants born preterm experience broad ANS dysfunction from birth and comparing ASIBs to PTs will help delineate how attention-specific ANS dysfunction predicts the emergence of ASD-specific symptoms. Aim 1 will compare the emergence of autonomic regulation of attention during a very critical period of neurodevelopment (1-3 months) across ASIBs, PT infants, and TD infants. Aim 2 will quantify the association between heart defined attention and interactive behavior on a moment-to-moment basis at 6, 9, and 12 months, and compare across the three groups. Aim 3 will utilize machine learning techniques to predict ASD symptoms at age 3 years from early autonomic and attentional features (from Aims 1-2). Determining the specificity of autonomic regulation of attention as a key, early emerging feature associated with ASD, has significant translational potential for a cost-effective biomarker. This work will inform developmental models of ASD wherein disrupted autonomic regulation of attention has proximal effects on real-world interactions that may interfere with learning and have cascading effects on long-term outcomes.

NIH Research Projects · FY 2026 · 2023-07

PROJECT SUMMARY Disrupted attention is among the earliest-emerging, lifelong features of autism spectrum disorder (ASD) and research suggests a critical point in the neonatal and early infant period at which disrupted attention may be detectable. The timing of this disruption aligns with key maturational shifts in neurodevelopment, but the neurobiological mechanisms associated with disrupted attention in ASD remain elusive. One neurobiological system that regulates attention from early infancy is the autonomic nervous system (ANS). Broad ANS dysfunction is observed in older children already diagnosed with ASD, but whether and when ANS dysfunction contributes to attention abnormalities in ASD remains unknown. The overall goal of this study is to examine how atypical autonomic regulation of attention may be associated with the emergence of ASD symptoms. A key marker of autonomic regulation of attention is heart defined attention. Accordingly, maturation of heart defined attention in the early infant period and the developmental consequences therein for the emergence of interactive behaviors and ASD symptoms will be examined. A critical innovation of this study is leveraging a three-group design in which infants who experience elevated ASD symptoms (infant siblings of children with ASD; ASIBs) will be compared to typically developing (TD) and preterm (PT) control groups. Infants born preterm experience broad ANS dysfunction from birth and comparing ASIBs to PTs will help delineate how attention-specific ANS dysfunction predicts the emergence of ASD-specific symptoms. Aim 1 will compare the emergence of autonomic regulation of attention during a very critical period of neurodevelopment (1-3 months) across ASIBs, PT infants, and TD infants. Aim 2 will quantify the association between heart defined attention and interactive behavior on a moment-to-moment basis at 6, 9, and 12 months, and compare across the three groups. Aim 3 will utilize machine learning techniques to predict ASD symptoms at age 3 years from early autonomic and attentional features (from Aims 1-2). Determining the specificity of autonomic regulation of attention as a key, early emerging feature associated with ASD, has significant translational potential for a cost-effective biomarker. This work will inform developmental models of ASD wherein disrupted autonomic regulation of attention has proximal effects on real-world interactions that may interfere with learning and have cascading effects on long-term outcomes.

NIH Research Projects · FY 2026 · 2023-06

Abstract Anxiety and fear related disorders comprise some of most common mental illnesses. For anxiety disorders alone, approximately 1 in 3 U.S adults will be affected at some point in their life. Currently available treatments leave approximately 40% of patients without symptom resolution underscoring the need for new therapies to be developed. A key to the rational development of new treatments is improved understanding of the neurobiological mechanisms that regulate the neurons and circuits involved in fear and anxiety behaviors. Areas of the brain involved in emotion, such as the basolateral amygdala (BLa) and medial prefrontal cortex (mPFC) rely on synchronized neuronal oscillations in the theta band (4-12 Hz) to entrain local pyramidal neurons (PNs) and synchronize activity across brain regions for proper long-range communication, and information processing. Aberrant synchronization in these circuits contributes to deficits in emotion that underlie fear disorders. However, despite the established role for theta oscillations in mPFC and BLa during fear states, the mechanisms through which oscillations are generated in the BLa and synchronize with mPFC are poorly understood. Critical to the function of these regions is the neurotransmitter acetylcholine (ACh), which promotes emotional learning and theta oscillations in BLa and mPFC. Supporting the vital role of ACh in emotional circuits is the finding that perturbations of cholinergic signaling produce a range of behavioral effects, including anxiogenic, or anxiolytic states, depressive symptoms, and disrupted fear and extinction learning. Moreover, in all mammals, including humans, the BLa receives by far the most robust cholinergic innervation of any target of the cholinergic basal forebrain. Despite its remarkably dense cholinergic innervation, and critical importance in emotional memory, surprisingly little is known about the mechanisms through which ACh modulates BLa circuits. Therefore, the objective of these studies is to determine at a cellular and circuit level how endogenously released ACh modulates amygdalar microcircuits to regulate fear behaviors. Our central hypothesis is that ACh acts on distinct inhibitory microcircuits in the BLa to promote local oscillations and synchrony between BLa and mPFC and enhance emotional memory. Our hypothesis is based on preliminary data showing that basal forebrain-derived ACh alters BLa circuitry and facilitates oscillatory synchrony with mPFC by differentially modulating distinct types of inhibitory interneurons in BLa. Here, we propose to use electrophysiology, intracranial EEG recording, cell type specific targeting, optogenetics, and behavior to determine the circuit mechanism by which synaptic acetylcholine modulates local BLa oscillations (Aim 1), facilitates BLa-mPFC oscillatory synchrony and gates fear learning (Aim 2) and regulates discrimination between safe and threatening cues (Aim 3). These studies will shed new light on mechanisms underlying anxiety and fear disorders and the role of ACh in emotional processing.

NIH Research Projects · FY 2026 · 2023-06

Project Summary: Despite the success of combination antiretroviral therapy (cART), a significant proportion of infected individuals exhibiting neurocognitive decline, and a prior history of substance use disorder (SUD) may result in an exacerbated rate of decline. Thus, prior drug history may be clinically significant in the treatment of neurological HIV-1 infection. The specific aims of the project are: 1) To define the dendritic “spine- targeted” - microglial interactions which produce HIV-1/psychostimulant-induced synaptodendritic loss and spine dysmorphology. Dendritic spine loss is a key pathology of HAND; however, the underlying mechanisms remain largely uncharacterized. We will investigate whether HIV-infected microglia play a key role in spine loss/dysmorphology using an in vitro HIV infection model and psychostimulant drug exposures in sex- specified brain cell cultures. 2) To establish whether a history of psychostimulant abuse drives an accelerated progression of microglial dysfunction and dendritic spine alterations following HIV infection. Dopamine will be assessed both prior to and after EcoHIV-infection in animals with or without a history of cocaine self-administration. The mechanisms by which HIV-infected microglia produce dopaminergic circuit dysfunction will be critically tested using proviral gene excision techniques; cART, and SABV are integral factors of the design. 3) To establish executive function “choice” deficits in EcoHIV-infected animals, and the role of microglial HIV infection, following psychostimulant self-administration. We will establish prior drug history and HIV-1 infection as variables that influence the effect of fronto-striatal circuit dysregulation on choice behavior, thereby identifying factors that may exacerbate resistance to treatment. We will examine synaptodendritic integrity in pyramidal neurons of the medial prefrontal cortex (mPFC) and medium spiny neurons (MSN) of the nucleus accumbens given their sensitivity to drug history and/or HIV-1 infection. Targeted proviral gene excision of HIV from microglial cells will be used to determine the role of infected microglial cells in executive function deficits. Thus, this proposal addresses two key questions regarding neuroHIV – 1) does a history of drug dependence alter the progression and clinical outcomes of HIV-1- associated neurocognitive disorders? and 2) how do substances of abuse and HIV interact to produce dendritic spine alterations, one of the key neuropathologies of neuroHIV in the current cART era? The program goal is to identify how microglial HIV infections produce synaptodendritic loss; knowledge that will lead to novel therapeutic strategies for restoring fronto-striatal circuitry.

NIH Research Projects · FY 2024 · 2023-06

SUMMARY Prostate cancer (PCa) is the second most common cancer in men in the United States. The absolute number of men with PCa is projected to increase as a result of the ageing baby boomer population. However, the lack of reliable biomarkers for PCa screening has led to decreased early detection, particularly for African American (AA) men who have the highest PCa morbidity, metastatic risk and mortality rates than any other racial or ethnic group in the US. When cancer is suspected, patients must undergo multiple needle core biopsies because of the multifocal nature of PCa. Nonetheless, up to 34% of biopsied men are told they are cancer-free when they are not, because the biopsies missed the cancer foci. Hence, it is critical to better define the cellular and molecular features indicative of PCa development and risk for aggressive disease in benign biopsies of PCa patients to improve diagnosis and screening. In this grant, we are proposing to explore a variation on the concept of field effect in PCa, postulating that histopathologically benign looking prostate core biopsies may in fact feature alterations indicative of PCa and of PCa aggressiveness present in the same patient at another prostatic site, using age- and race-matched (AA and Caucasian Americans (CA)) sets of samples (benign and cancer-bearing biopsies for each patient). Prostate-resident mast cells (MC) aggregate in stromal, peritumoral and/or intratumoral areas but their clinical relevance remains controversial. Our preliminary data suggests the usefulness of establishing MC profiles in benign prostatic tissues of PCa patients. The objectives of this application are: to investigate MC functional profiles in benign human prostate tissues as predictors of PCa aggressiveness and candidate functional biomarkers of PCa race disparity; to define and validate a molecular signature indicative of PCa and PCa aggressiveness present in benign human prostate biopsies and test its predictive value for PCa disparity and association to MC; and apply our new screening modalities in clinics, contingent upon successful validation studies. We anticipate that our approach may improve diagnosis and screening for high-risk PCa and position MC as potential drivers of PCa disparity.

NIH Research Projects · FY 2026 · 2023-06

Summer is a period of accelerated BMI gain for children (5-12yrs). Studies show that virtually all increases in BMI occur during the summer, no matter children’s’ weight status (i.e., normal weight, overweight, or obese) at summer entry. Our research team recently developed the Structured Days Hypothesis (SDH), which may explain accelerated summer BMI gain. The SDH posits that structure, defined as pre-planned, segmented, and adult-supervised compulsory environments, protect children against obesogenic behaviors and prevent excessive BMI gain. The SDH draws upon the ‘filled-time perspective’, which posits that time filled with favorable activities cannot be filled with unfavorable activities. In the context of the SDH, this means that children engage in more obesogenic behaviors that lead to increased weight gain during times that are less-structured (e.g., summer days) compared to times that are more structured (e.g., school days). Based on the SDH, pre-existing community-operated summer day camps (e.g., B&G Club, YMCA), may exert a positive influence on summer BMI gain by limiting children’s engagement in obesogenic behaviors. Recent preliminary studies show that children engage in healthier behaviors on days that they attend summer day camps, and that BMI gain does not accelerate for these children. A major weakness in the rigor of these preliminary studies is that they cannot identify the dose-response relationship between structured summer programming and summer BMI gain. Dose-response studies can definitively identify the smallest dose at which a useful effect is observed while simultaneously revealing the maximum dose beyond which there is no further beneficial effect. In the same way determining the effective dose of structure to mitigate negative health outcomes is necessary to inform feasible, scalable interventions and health policy. The proposed randomized dose-response study will identify the dose-response relationship between amount of summer programming and summer BMI gain. The impact of 4 weeks (n=90, 20 days), 6 weeks (n=90, 30 days), and 8 weeks (n=90, 40 days) of summer programming compared to no program (n=90) will be evaluated. We will also conduct comprehensive implementation monitoring to evaluate implementation, and to identify factors associated with children’s summer BMI gain and obesogenic behaviors. The aims of the study are to: Aim 1. Evaluate structured summer programming’s impact on children’s BMI gain and obesogenic behaviors. Aim 2. Evaluate implementation and contextual factors and their relationship with children’s summer BMI gain and obesogenic behaviors. Aim 3. Determine the cost effectiveness of 4, 6, 8 weeks of summer programming for mitigating accelerated summer BMI gain. This work is significant as it addresses a critical public health goal – reducing obesity – through programing during a timeframe – summer vacation – when substantial, long-lasting negative effects occur. This application is innovative because of the focus on identifying the dose-response relationship between structured summer programming and summer BMI gain. This innovation addresses a weakness in the rigor of previous studies and is critical for identifying the ideal dose of summer programming for mitigating accelerated summer BMI gain.

NIH Research Projects · FY 2026 · 2023-05

Disparities in overweight and obesity (OWOB) prevalence between children (ages 5-11) from low- and middle-to- high-income families persist. The structured days hypothesis posits that structure within a day, defined as a pre- planned, segmented, and adult-supervised compulsory environment (like a school day), plays a protective role for children against obesogenic behaviors and, ultimately, prevents the occurrence of negative health outcomes, such as excessive weight gain. Essentially, the structured days hypothesis draws upon concepts in the ‘filled-time perspective’ literature which posits that time filled with favorable activities cannot be filled with unfavorable activities. There are at least two “windows of vulnerability” for children outside of the school day. These critically important windows include the hours immediately following school (i.e., 3-6pm school days) and the 10 weeks of summer vacation. Programs that can provide a healthy structured environment and prevent unhealthy weight gains exist for both of these time periods (i.e., afterschool programs and summer day camps). Unfortunately, these programs are too expensive for children from low-income families to attend. Thus, based on demand-side financing, which has a long history addressing large scale public health problems in the United States through federal, state, and local programs like the Supplemental Nutrition Assistance Program and the 21st Century Learning Centers Program, we will rigorously test the impact of providing access to pre-existing, community- operated afterschool and summer programs on weight status (i.e., BMI z-score) and obesogenic behaviors (i.e., physical activity, screen use, diet, and sleep) of elementary children from low-income households. This approach will potentially be less costly than current obesity treatment programs which cost up to $4,600 per child. This study will employ a 2x2 full factorial design. The four groups will be a no-treatment control, afterschool program voucher only, summer day camp voucher only, and vouchers for afterschool and summer day camp combined. We will accomplish the following specific aims: AIM 1: Compare differences in primary and secondary outcomes among children provided no voucher, a voucher for after-school only, a voucher for summer camp only, and a voucher for both after-school and summer camp. AIM 2: Evaluate the cost-effectiveness of providing a voucher for after-school only, a voucher for summer camp only, and a voucher for both after-school and summer camp. Aim 3: Evaluate facilitators and barriers to the implementation, effectiveness, and sustainability of the voucher program by conducting qualitative interviews with key stakeholders (i.e., children, parents, staff, administrators). This study is significant because nearly one in five children are obese, and disparities in OWOB exist between children from low- and middle-to-high-income households persist despite past school-based interventions. This study is innovative because it represents one of the first attempts to provide access to healthy structured programming during two “windows of vulnerability” for children outside of the school day. Should the proposed intervention strategy prove effective, it has the potential to mitigate disparities in OWOB prevalence.

NIH Research Projects · FY 2026 · 2023-05

Modified Project Summary/Abstract Section The global COVID-19 pandemic has imposed unprecedented pressure on health systems and has interrupted public health efforts for other major health conditions, including HIV. HIV service interruptions in the forms of redeployment of staff, reallocation of resources, lack of equipment and medicine (e.g., shortages of HIV/STI testing kits, strained drug supply chain), and reduced access to care (e.g., travel restrictions, lock downs) may have a profound and long-term impact on HIV treatment cascade outcomes, especially given the evolving nature of the pandemic. There are several gaps in the existing literature in addressing HIV service interruptions and their consequences. These gaps include a lack of using large-scale, real-world, multi-type data with theoretical guidance; the focus on single or limited HIV treatment cascade outcomes; and limited efforts to identify factors that can mitigate the negative impacts of such interruptions to inform potential interventions and capacity building at state or local levels. In response to NOT-AI-21-057, we propose to comprehensively investigate HIV service interruptions during the COVID-19 pandemic following a socioecological model, assess their impacts on various outcomes of the HIV prevention and treatment cascade, and identify resilience resources for buffering impacts of interruptions on HIV treatment cascade outcomes. Specifically, we will assess HIV service interruptions in South Carolina (SC) since 2020 using operational report data of Ryan White HIV clinics, in-depth interview data with clinic leaders and providers, and HIV service utilization data based on both electronic health records (EHR) and publicly available cellphone-based HIV clinics visitation data. We will further explore how HIV service interruptions affects HIV prevention and treatment cascade outcomes at appropriate geospatial units based on the integration of multi-type datasets (e.g., EHR, geospatial data) from multiple sources. Finally, we will identify institutional-, community-, and structural-level factors (e.g., resilience resources) that may mitigate the adverse impacts of HIV service interruptions based on the triangulation of quantitative (EHR data, online survey data) and qualitative (in-depth interviews, focus group discussion) data regarding health infrastructure, social capital, and organizational preparedness. Our proposed research can lead to a better understanding of complicated HIV service interruptions in SC and resilience factors that can mitigate the negative effects of such interruptions on various HIV treatment cascade outcomes. The multi-level resilience resources identified through data triangulation will assist SC health departments and communities in developing strategic plans in response to this evolving pandemic and other future public health emergencies (e.g., monkeypox, natural disasters). The research findings can also inform public health policymaking and the practices of other Deep South states with similar sociocultural contexts and experiences of HIV service interruptions during the pandemic.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY The precise establishment of neuronal connectivity during development is critical for normal nervous system function. This research examines how growth cones, which are the pathfinding structures of the developing neuron, connect with their appropriate targets. External cues regulate neuronal connectivity formation by resulting in the activation of intracellular signaling pathways and ultimately, reorganization of the cytoskeleton and adhesions. This proposal focuses on understanding the molecular mechanisms linking extracellular signaling with intra-axonal local translation in the developing nervous system. Local translation in axonal growth cones is necessary for axon growth and guidance, however our understanding of how local translation functionally directs axon guidance is limited. We recently demonstrated that point contacts, adhesion sites within growth cones, are a strategic location for targeted local translation. Point contact adhesions directly regulate axon guidance by linking the extracellular matrix to the intracellular actin cytoskeleton and providing the force for growth cone movement. Thus, this finding is important because it suggests that local translation of certain mRNAs at adhesions are situated to have a maximal impact on axon guidance. Point contacts are likely a fundamental puzzle piece that has been missing from our understanding of how local translation functionally directs axon guidance. Accordingly, our hypothesis is that local translation of β-actin mRNA is necessary for point contact dynamics, and point contacts are localized organizing nodes for translational regulation. We will test this hypothesis by determining if locally translated β-actin is integrated into point contacts to direct axon guidance (Aim 1) and elucidating the signaling pathway through which extracellular matrix-induced signaling stimulates intra-axonal mRNA translation (Aim 2). Furthermore, we will resolve the suite of mRNAs that are locally translated in response to extracellular matrix proteins, and their relationship to point contacts (Aim 3). Completion of the proposed aims will break new ground by discovering the interactions between the extracellular matrix, point contacts and local translation in the regulation of axon guidance. This research will enable a broad, mechanistic understanding as to how mRNA trafficking and local translation contributes to the establishment of neuronal connectivity, and increase our knowledge about the complex nature of brain development.

NIH Research Projects · FY 2026 · 2023-04

Abstract Heart failure (HF) continues to be a leading cause of death, disability and health care expenditures. Coronary artery disease culminating in a myocardial infarction (MI) remains a major cause for HF. HF secondary to MI is fundamentally due to changes in the structure and function of the left ventricle (LV) termed LV remodeling. In pathological remodeling such as cancer, the proliferation of an aggressive degradative cell type, the cancer associated fibroblast emerges. The cancer associated fibroblast alters normal tissue structure through degradation/remodeling of the extracellular matrix (ECM). In particular, a robust expression of a proteolytic enzyme, fibroblast activation protein (FAP). We have identified that the post-MI fibroblast contains a very similar proteolytic signature as the cancer associated fibroblast, in terms of ECM degradation and ultimately LV remodeling. Accordingly, we will test the guiding hypothesis that FAP induction/activation is essential for adverse post-MI remodeling and progression to HF and that specific localized targeting of FAP within the MI region is feasible and effective. The outcome from these translational studies will be to establish an entirely new therapeutic direction for myocardial recovery following MI and prevention of HF. We have established a transgenic line of FAP conditional knockout mice which will allow for FAP silencing following MI induction as well as following the development of HF. We have developed unique hydrogel formulations that allow for the release of small molecule therapeutics and protease inhibitors, which have been deployed in our pig model post-MI using a minimally invasive approach. The deliverables from this project will be to establish a novel therapeutic direction for the prevention as well as the treatment for HF secondary to MI through both temporal and localized control of FAP activation. These results will move the entire ECM field forward by establishing the role of the fibroblast in HF and open an entirely new direction through harnessing novel molecular tools and therapeutics to target specific cell phenotypes in this disease process.

NIH Research Projects · FY 2026 · 2023-03

Over 130 million individuals in the US have overweight and obesity, and rural communities experience significantly higher rates of obesity and related chronic diseases. Fortunately, weight losses of as little as 5-7% can ameliorate obesity-associated co-morbidities. Although lifestyle interventions successfully produce weight loss of this magnitude, the reach and availability of weight management programs is limited in rural areas. Digital interventions offer an attractive alternative for delivering lifestyle programs to rural populations. However, in-person behavioral obesity treatment programs achieve better weight losses than digital programs, likely because in-person programs typically include personnel-intensive “high touch” treatment components. Some studies indicate that having a human “behind the curtain” of a digital program through emailed feedback or with the addition of online group sessions can significantly increase weight loss. Thus, to reduce obesity-associated health disparities experienced by rural populations, it is time to move the field forward by identifying the specific constellation of human-delivered digital treatment components that produce the strongest weight loss outcomes. Therefore, the aims of this study are to increase the public health impact of digital obesity treatment for rural populations by simultaneously investigating 3 “high touch” intervention components. We will conduct a highly efficient 2 x 2 x 2 factorial experiment using the MOST framework with participants residing in non-urban areas recruited online from across the United States. Participants (N=616; 22% racial/ethnic minority; 40% male) will be randomized to: (1) weekly facilitated synchronous group video sessions (yes vs. no); (2) type of self-monitoring feedback received (counselor-crafted vs. pre-scripted); and (3) individual coaching calls (yes vs. no). Based on the results of the experiment, we will identify an optimized program in which each component (or combination of components) contributes meaningfully (≥1.5 kg at 6-months) to enhanced weight loss. We will investigate potential mediators (e.g., accountability, social support, self-regulation, motivation, and problem solving), as well as possible mediators (e.g., sex, race/ethnicity, age), to explore their impact on weight loss outcomes. We will also examine treatment delivery costs for each component and conduct exploratory analyses of weight trajectories 6-months post-treatment (i.e., at 12-months) to elucidate extended impact of the specific components on weight control. Ultimately, this research will set the stage for confirming the most promising digital behavioral weight loss intervention for dissemination without geographic borders to reduce obesity rates among rural residents and provide essential evidence to inform policy decisions on optimal dissemination.