Univ Of Arkansas For Med Scis

NIH Research Projects · FY 2026 · 2023-03

Abstract Excess reactive oxygen and nitrogen species (RONS) from radiation, polluted air, as well as chemicals in food and water induce oxidative stress and cause direct damage to nucleotide bases. A prominent form of oxidized damage in the genome and free nucleotide pools is 8-oxoG or 8-oxo-dGTP, respectively. 8-oxoG can hydrogen bond with adenine, resulting in mutations upon DNA replication. 8-oxoG also produces double strand breaks (DSBs) that undergo error-prone repair through non-homologous end-joining (NHEJ). This results in mutagenesis and genomic instability. DNA polymerases mediate repair of oxidative DNA damage. A major obstacle to understanding the etiology and progression of diseases caused by oxidative stress is that the DNA polymerase mechanism employed in the repair of oxidative lesions and effects of accessory factors in the DNA repair complex remain poorly understood. Solving this problem will enable a more complete understanding of the role of DNA polymerases in cancer, aging and disease. The knowledge gained will enable development of therapies to target cancer, neurodegenerative disorders and aging. I will uncover the impact of oxidative stress-induced DNA repair on genome integrity by determining how active site contacts and dynamics in polymerases influence repair outcomes. I will also relate my observations to accessory repair factors and larger repair complexes. To accomplish this task, I will use pH jump crystallography to determine snapshots that will reveal the active site contacts and dynamics employed by NHEJ polymerases λ and μ to insert and extend from an 8-oxoG lesion (Aim 1, K99 phase). The functional significance of these contacts will be verified using kinetic assays and mutant enzymes. I hypothesize that these contacts regulate the unique behavior of these polymerases in promoting productive and accurate synthesis and provide insight into the role of 8-oxoG in mutagenesis. I will then employ a combination of transient kinetics and time- lapse crystallography to determine the atomic level contacts and dynamics employed by polymerases λ and μ to perform translesion synthesis past and proofreading of the 8-oxoG lesion (Aim 2, R00 phase). The structural intermediates determined in this aim will allow understanding of the structural requirements for mutation prone bypass of 8-oxoG. Building on the results of the latter two aims and training during the K99 period, I will determine the role of substrate channeling among accessory factors during oxidative DNA damage induced NHEJ (Aim 3, R00 phase). Cryo-EM studies will enable determination of how the dynamic and heterogenous populations of NHEJ repair complexes impact oxidative DNA damage repair. I will also determine the structural basis for 8- oxoG processing by Artemis during oxidative NHEJ repair. Completion of this aim will require training in Cryo- EM that will be provided by Dr. Mario Borgnia. The knowledge gained as a result of the work on how polymerases impact repair of oxidative damage and how this mediates productive repair will provide a significant advance in the understanding of how environmental agent induced DNA damage repair. I will gain expertise in state-of-the-art methods such as crystallography, transient kinetics, cryo-EM, DNA replication and DNA repair that will help me achieve my career goals and establish an independent laboratory.

NIH Research Projects · FY 2026 · 2023-03

This R01 application focuses on the underlying mechanisms of neurovascular coupling dysfunction. The brain consumes a large amount of energy which must be supplied as oxygen and glucose by blood flow. Neurovascular coupling, a mechanism that matches local neuronal activity to blood flow, is critical to maintain local microenvironment and normal brain function. However, normal neurovascular coupling is disrupted in seizure, traumatic brain injury, and other neurological disorders. Despite continued high neuronal metabolism, small cerebral arteries and arterioles begin to inappropriately constrict to limit CBF to the challenged neurons. This pathogenic vasoconstriction, termed the “inverse hemodynamic response” (IHR), is thought to contribute to brain damage and functional impairment in these neurological diseases. The mechanism of IHR is unknown. This proposal seeks to test a novel hypothesis that seizure-induced IHR is mediated by an endothelial signaling pathway consisted of Neuropeptide Y Receptor 1 (NPYR1), Transient Receptor Potential (Canonical) 3 (TRPC3) channels, and endothelin 1 (ET1). We generated inducible and brain-specific endothelial TRPC3 knockout line and NPYR1 knockout line. These novel mouse lines will be used in combination with NPYR1, TRPC3 and ET1 receptor selective inhibitors to test our hypothesis. Aim 1 will demonstrate the existence of an endothelial NPYR1-TRPC3-ET1 signaling pathway that mediates cerebral vasoconstriction using acutely isolated brain parenchymal arterioles and cranial window preparations in vivo. Aim 2 will show that the same signaling pathway mediates seizure-induced IHR. Aim 3 will determine whether disruption of this signaling pathway will reduce susceptibility to seizures and their deleterious consequences. The studies rely on complementary areas of expertise pooled by a research team with expertise in cerebrovascular reactivity, epilepsy and neuroinflammation and neurodegeneration. Collectively, these experiments will reveal new mechanistic insights regarding IHR and may lead to new treatments for epilepsy and other neurological diseases.

NIH Research Projects · FY 2025 · 2022-09

Non-Hispanic Black infants have twice the rates of low birthweight births as non-Hispanic White infants. As adverse birth outcomes increase risk of infant mortality and adverse outcomes across the life course, improving birth outcomes is a national priority. Despite this important public health issue, many public and private payers are unable to adequately reduce adverse infant outcomes because of a lack of race/ethnicity data. This K01 fills a critical need for evidence-based recommendations for collection and use of racial/ethnic data among payers to enable population health management programs to develop predictive algorithms that could be used to reduce adverse birth outcomes. Failure to include race/ethnicity in predictive models used for resource allocation may ultimately lead to biased algorithms that preclude adequate resource allocation. Aim 1 of this study will use an algorithmic fairness framework to test multiple algorithms for developing predictive models for low birthweight birth. In addition to testing model accuracy, predictive models will be tested for seven measures of algorithmic fairness to assess whether having race/ethnicity improves algorithmic fairness (e.g., equal [or better] predictive accuracy for non-White relative to White women) after applying four fairness-enhancing approaches. This project will utilize medical claims, birth certificates, and beneficiary information from the Arkansas All Payer Claims Database. Linkage to the birth certificates uniquely allows this study to have race/ethnicity, which are absent in the commercial claims given lack of collection by most payers. The seminal Institute of Medicine Report Unequal Treatment recommended collection of race/ethnicity to improve health and healthcare delivery; however, it is well known that payers fear accusations of redlining and rarely collect race/ethnicity in most states. Research on payer and provider views regarding collection of race/ethnicity has been conducted, but similar research on the views of minority beneficiaries are severely lacking. Aim 2 of this study will conduct raciallyhomogenous focus groups among Black, Hispanic, and Marshallese women in Arkansas regarding attitudes on acceptability of collecting and using race/ethnicity data as well as administrative aspects (e.g., when to collect the data), with an emphasis on perinatal programs. These aims will provide an evidence-base and serve as a national model for collecting and using racial/ethnic data with community input. Large third-party payers have the infrastructure to improve health outcomes, but lack a community-engaged approach to inform collection and use of these data to guide development of algorithms. The K01 will allow the investigator to build on her expertise in insurance claims analysis to acquire skillsets in predictive modeling, community engagement, and qualitative methodologies. These important skillsets will allow the researcher to achieve her long-term goals of becoming a productive and independent researcher with a focus on identifying and mitigating factors that serve as drivers of r adverse infant and maternal outcomes.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY The Little Rock Green Schoolyard Initiative, with training and technical assistance from the National League of Cities and the Children and Nature Network, aims to transform the grounds of two elementary schools into nature-filled greenspaces. Using a community-schools model, several critical needs were identified. These include: (1) opportunities for outdoor learning; (2) improved outdoor play experiences; and (3) safe, welcoming spaces to connect with nature outside of school hours. Both schools serve low-income, predominately African American communities. Each school is centrally located in a walkable neighborhood, but residents in these neighborhoods have limited access to city parks within walking distance. The communities surrounding these schools are disproportionately affected by cardiometabolic conditions linked to inadequate physical activity and obesity. For the children, more opportunity for active learning and play may increase physical activity which has been shown to be beneficial for cardiometabolic profiles of children and may help address obesity-related health disparities. These health disparities are already evident in children in the two neighborhoods being impacted by this city-led program with higher proportions of severe obesity by 4th grade (body mass index exceeding 120% of the 95th percentile) than other schools in the city and state. The goal of this study is to explore the pathways through which green schoolyard improvements can reduce the development of obesity- related health disparities, as well as improve academic outcomes and community well-being. A growing literature on the health benefits of greener environments suggests that physical activity, air quality, sleep, and social behaviors are intertwined pathways that may protect against excess weight gain. Data will be collected on outcomes related to these pathways before, during, and after the green schoolyard transformations from children in the two program schools and in comparable non-program schools within the Little Rock School District. The study is designed to understand how these pathways work in combination and whether greener schoolyards influence patterns of play in ways that improve opportunities for physical activity among children who are at greater risk for developing severe obesity. Community and school-level barriers to implementation of the green schoolyard intervention will also be identified to inform future initiatives. Another strength of this study lies in the fact that there will be different dimensions to the greenspace improvements across the two schools. This allows for a richer understanding of how characteristics of the greenspace and differences in implementation affect these pathways. The lessons learned from Little Rock’s green schoolyards program will inform pragmatic and cost-effective interventions that slow the growth of severe childhood obesity in communities across the United States and reduce obesity-related health disparities.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT Background. Tobacco control policies have been used to address the ongoing epidemic of adolescent ecigarette use in the US and are believed to have contributed to the decline in youth e-cigarette use from 2019 to 2020. During 2019-2020, two federal tobacco control laws were enacted: (1) Tobacco 21, which increased the minimum legal sales age for tobacco to 21 years, and (2) a partial flavor restriction that prohibited pod/cartridge-based e-cigarette products containing flavors other than mint/menthol. While traditional methods (e.g., compliance checks, surveys, and document analyses) have been employed to evaluate policy impact, complementary and innovative social media-based methodologies can be used to systematically examine organic public discussion about policy-relevant issues. Such data are particularly valuable to uncover critical policy-relevant information and provide more prompt feedback than traditional methodologies. Building on my experience and learning from my research mentors’ expertise, I will conduct the first comprehensive social media assessment aimed at uncovering highly valuable yet often difficult-to-ascertain information regarding tobacco control laws in three areas: policy efficacy, enforcement challenges, and potential interferences with implementation. Such research is not intended to influence future legislation, but rather it would provide peerreviewed research regarding enforcement of current tobacco control laws. Research. The overarching goal of the proposed investigation is to reduce youth/young adult tobacco use. Therefore, the proposed research will (1) identify loopholes that may circumvent existing tobacco control laws; (2) identify key enforcement challenges of existing tobacco control laws; and (3) investigate interferences with existing tobacco control laws. To achieve these aims, we will use specialized software and a comprehensive list of social media-optimized search terms to collect data from several social media platforms (e.g., Twitter, Instagram, Reddit, Facebook). Using a two-step process, we will ensure search strings are comprehensive, feasible, specific, and informal. After developing a codebook via a deductive and inductive process, two trained independent coders will annotate collected data, stratifying by month, day, and time. Finally, content analyses and social network analyses will be used to explore loopholes, enforcement challenges, and interference with tobacco control laws. Training. Pedagogically, the training plan for this proposed K01 is comprised of didactic training (certificate program, workshop, coursework, seminars), mentoring (directed research, conference calls, inperson contact hours, readings), and dissemination deliverables (peer-reviewed publications, presentations at academic conferences, and future research proposals) required to complete the project on the projected timeline. Outcomes from these research aims will complement my career-development aims (i.e., developing expertise in tobacco control policies, social media analysis, and social network analysis) that focus on the intersection between health, policy, communication, and technology.

NIH Research Projects · FY 2025 · 2022-09

Abstract/Project Summary Falls among adults ≥ 65 years are a leading cause of morbidity, mortality, and high healthcare costs. Clinical guidelines indicate that all healthcare providers should conduct annual falls prevention (FP) by screening all older adults and assessing and intervening for those at risk. FP efforts using CDC’s STEADI (Stopping Elderly Accidents, Deaths, and Injuries) are used in primary care, but barriers limit uptake and sustainability. Physical therapists (PTs) are trained and qualified healthcare providers who can provide FP within their scope of practice and have more one-on-one time and frequent follow-up compared to primary care, positioning them to incorporate STEADI in outpatient rehab (rehab). Yet, studies indicate PTs are not providing FP to at-risk older adults in rehab. We will examine how to best support uptake of STEADI and address this gap through the following aims: (1) Identify clinic-, provider-, and patient-level barriers to and facilitators of implementing STEADI in rehab; (2) Develop implementation strategies to support the adoption of STEADI in rehab; (3) Pilot test the impact of implementation strategies for STEADI in rehab on implementation outcomes (clinic- and provider-level) and explore clinical outcomes. We will use innovative methods, including implementation science (IS) and mixed-methods approaches (Aims 1 and 3) and a stakeholder-driven evidence-based quality improvement (EBQI) process (Aim 2). Dr. Vincenzo’s background, career development plan, and mentor support make her an excellent Beeson award candidate. She is an Associate Professor of Physical Therapy and Geriatrics, and a board-certified clinical specialist in geriatric physical therapy with an MPH and PhD in exercise science. She has been a leader in aging and FP research for the past 8 years. Her career development objectives complement the proposed research aims. She will obtain training, mentorship, and skills in IS, mixed methods research (used in IS), leadership, and geriatric research. The University of Arkansas for Medical Sciences (UAMS) is an ideal environment for her career development and research. UAMS and its Translational Research Institute (TRI) supported Dr. Vincenzo’s career through a KL2 award and will continue to provide training, equipment, consultation, and mentoring. The UAMS Center for Implementation Research, led by Geoffrey Curran, PhD (primary mentor), will support her career development and mentored research in IS. Jeanne Wei, MD, PhD (advisor), UAMS Institute on Aging executive director, will support development in geriatric research. Co-mentors Jonathan Bean, MD, MPH, and Jennifer Brach, PhD, PT, are experts in geriatric rehab and existing collaborators with Dr. Vincenzo. Dr. Vincenzo will also benefit from the expertise of STRIDE (Strategies to Reduce Injuries and Develop Confidence in Elders) study director Nancy Latham, PhD, PT (advisor). The research strategy, career development objectives, and mentoring plan support Dr. Vincenzo’s goals of becoming a leader in aging research and independent investigator in IS and FP.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY/ABSTRACT The vector-borne spirochetes that cause relapsing fever are transmitted to humans by either ticks or human body lice. Despite identification of the etiological agents of relapsing fever over 100 years ago, very little information exists regarding their pathogenesis. Although relapsing fever is more common in developing countries, tickborne relapsing fever (TBRF) occurs in areas of the U.S. where Ixodes and Ornithodoros species of ticks, the vectors for TBRF spirochetes, are endemic. During their natural enzootic cycle, vector-borne spirochetes exist in two distinct niches found within the arthropod vector and the vertebrate. It is well established that Lyme disease spirochetes must undergo significant changes in global gene expression to allow them to adapt to these two diverse environments. Cyclic dinucleotide second messengers (e.g., c-di-GMP and c-di-AMP) play key roles during the enzootic cycle of Borrelia burgdorferi, but their regulatory contributions in TBRF spirochetes have not been investigated. We will test the role of the c-di-AMP signaling pathway in promoting adaptation of TBRF spirochetes to the different host environments encountered during the bacterial natural lifecycle. Because the c-di-AMP signaling pathway is found in all pathogenic Borrelia, findings from this work also has the potential to provide insight into the function of this system in Lyme disease Borrelia. In Specific Aim 1, we will inactivate individual components c-di-AMP signaling system in the TBRF spirochete, Borrelia turicatae, and define their roles in messenger molecule production and general spirochetal physiology. We will also study the regulation of individual pathway components and c-di-AMP synthesis. Specific Aims 2 and 3 will elucidate the impact of the c-di-AMP signaling system on global regulation, pathogenesis, and vector colonization/transmission. These aims will provide critical knowledge regarding the regulatory networks that control B. turicatae adaptation during transmission and infection and identify virulence determinants required by the bacteria for host-pathogen and vector-pathogen interaction(s). Regulators and virulence factors identified in this project represent potential targets against which future therapeutic interventions and/or diagnostics for TBRF could be developed. Molecular characterization of the c-di-AMP-dependent signaling system and c-di-AMP-regulated virulence determinants will be the focus of future R01 grant proposals.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY/ABSTRACT Altered mitochondria quality control in osteoblasts and osteoclasts has been implicated in the loss of bone mass associated with aging and estrogen deficiency – the two most important causes of osteoporosis in humans, however the underlying mechanisms remain unclear. Sirtuin-3 (Sirt3) is the primary mitochondrial protein deacetylase and plays a critical role in mitochondrial quality control, including mitochondrial biogenesis, mitochondrial dynamics, and mitophagy—all of which are affected in age-related metabolic diseases. Earlier work aiming to elucidate the role of Sirt3 in bone has produced conflicting results with some studies suggesting that Sirt3 is critical for skeletal homeostasis while others found no physiological role of Sirt3 in bone. We have shown that deletion of Sirt3 or pharmacologic inhibition of Sirt3 in mice prevents the loss of bone mass caused by aging and estrogen deficiency and this is associated with decreased bone resorption. Osteoclasts lacking Sirt3 exhibit impaired mitophagy and increased acetylation of the mitophagy protein PTEN-induced kinase 1 (PINK1). Moreover, the mitophagy inhibitor mdivi-1 mimics the effects of Sirt3 deletion or Sirt3 inhibition on osteoclast generation and bone resorption. We have also obtained proteomic evidence to suggest that the protective effects of Sirt3 deletion on bone mass are mediated by its posttranslational regulation of ATPase inhibitory factor 1 (ATPIF1), an essential protein for mitophagy. Notably, ATPIF1 silencing osteoclast progenitors exhibit impaired polykaryon formation and resorptive activity as well as decreased mitophagy. We hypothesize that Sirt3-mediated deacetylation of ATPIF1 promotes osteoclast function via PINK1-dependent or independent mitophagy and that this process contributes to the excessive bone resorption that occurs with aging and estrogen deficiency. In Aim 1 we will determine the contribution of Sirt3/PINK1-mediated mitophagy to the development of osteoporosis in aged or ovariectomized mice with PINK1 loss-of-function. We will also quantify mitophagy and mitochondrial architecture in vivo using a mitochondria reporter mouse. In Aim 2 we will determine the role of ATPIF1 in the actions of Sirt3 on osteoclast function. Successful completion of this work should establish novel molecular and cellular mechanisms that contribute to osteoclast function and osteoporosis. These studies also should elucidate a previously unappreciated deleterious role of Sirt3 in age- related metabolic diseases.

NIH Research Projects · FY 2025 · 2022-07

RESEARCH SUMMARY In a large-scale nuclear event, many people could be exposed to high doses of ionizing radiation (IR). This can have long-term adverse effects on immune function, putting victims at risk for immune disorders and contributing to the dysfunction of organs that depend on a functional immune system. Currently no FDA-approved drugs are available to mitigate immune dysregulation in radiation victims. The overall objectives of this project are to understand how platelets contribute to immune dysregulation after exposure to IR and to test platelet-centric countermeasures to mitigate IR-induced immune dysregulation and organ damage (specifically in the intestine and heart). Platelets can regulate immune function by binding directly to immune cells or by delivering submicron platelet-derived microparticles (PMPs) to the cells. In every healthy individual, platelets form platelet–leukocyte aggregates and generate PMPs in the circulation under normal conditions, but these activities increase under pathological conditions. Various platelet receptors interact with their specific counter receptors on leukocytes, specifically polymorphonuclear neutrophils (PMNs) and monocytes—2 crucial members of the innate immune system that can modify the adaptive immune response—to form platelet–leukocyte aggregates. Central to this interaction is platelet glycoprotein Ibα (GPIbα) binding to leukocyte Mac-1, resulting in activation of both platelets and leukocytes. PMPs can activate PMNs and monocytes by delivering cytokines, growth factors, and RNA. Notably, proteolytic cleavage of platelet GPVI is an essential step for PMP generation. Our preliminary data show that mice with dysfunctional GPIbα (cannot bind Mac-1) exhibit increased inflammation, intestinal injury, PMP generation, and lethality following a single dose of 8.5 Gy total-body irradiation (TBI) compared to wild-type mice. Moreover, we showed that mice with dysfunctional GPIbα are more prone to inflammation following polymicrobial sepsis, which can occur after IR exposure. Finally, GPVI-KO mice generate fewer PMPs and exhibit reduced plasma pro-inflammatory cytokine levels compared to mice with dysfunctional GPIbα after 8.5 Gy TBI. We hypothesize that lack of GPIbα–Mac-1 interaction and enhanced PMP generation contribute to IR-induced immune dysregulation and predict that administering exogenous GPIbα or limiting PMP generation will mitigate IR-induced immune dysregulation and organ damage. The studies outlined in this proposal will: 1) Determine whether selective blocking of GPIbα binding to Mac-1 exacerbates, while exogenous GPIbα administration mitigates, TBI-induced immune dysregulation and 2) Evaluate whether limiting PMP generation by inhibiting GPVI mitigates TBI-induced immune dysregulation. Our studies will provide insight into the previously unexplored role of platelet–leukocyte interaction and PMP generation in modulating IR-induced immune dysregulation. Most importantly, the findings will help to develop novel radiation mitigators.

NIH Research Projects · FY 2024 · 2022-07

PROJECT SUMMARY While many questions remain regarding specific rates for HIV PEP preventable transmissions related to the real world challenges of HIV seroconversion and measuring risk, we do know that: 1) among people who experience a known exposure, HIV PEP is effective and potentially cost saving if initiated in a timely manner and completed fully; 2) patients who have been offered, accepted, and even completed HIV PEP continue to report confusion and inaccurate information regarding its use; and 3) in many contexts decision aids have been demonstrated to improve patient reported knowledge regarding decision making, decrease decisional conflict, and improve patient-provider communication. Given these gaps, the long-term goal of this work is to develop, refine, and validate a technology-delivered decision aid to assist providers in better understanding and effectively implementing HIV PEP in practice, and assist patients to better understand the decision they are making when provided with HIV PEP as an option so that they may more successfully 1) make the decision, and 2) complete the entire 28-day course of medication when they decide to initiate HIV PEP. The proposed decision aid leverages a known clinical opportunity to engage patients who are at risk for seroconversion in initiation of HIV PEP. By creating an internet-delivered multimedia tool that: 1) removes provider biases regarding what qualifies as an HIV risk from the discussion process; 2) slows the process of information sharing and decision making down and presents information in short, repeatable pieces; and 3) incorporates an opportunity for patients to reflect on key aspects that have been shown to impact decision making and adherence (e.g. social support/stigma, HIV risk perception, cost/access, side effects) prior to making the decision we anticipate that patients will have less decisional conflict, feel more confident about their decision, and for patients who initiate HIV PEP, be more able to complete the entire regimen. Lastly, the proposal includes relationship building via a community advisory board to support all steps of decision aid development and subsequent testing. Principles of design justice (e.g. adopting co-design methods, developing specific mechanisms for accountability, centering the needs of marginalized users) will be used to partner with this group of patient and health care providers to design specific aspects of intervention content, and plan details of the future efficacy testing study.

NIH Research Projects · FY 2025 · 2022-05

Health disparities in rural America begin early in life, arising from social determinants of health that start in childhood. School health programs often provide the only access to preventive services for rural children. However, school screening is variably implemented, plagued by loss to follow-up, and limited specialists in rural areas compound barriers to care. We propose to prospectively implement a novel model of care in Appalachian schools of rural Kentucky to address social determinants at the school, health system, and policy levels that hinder identification and treatment of preventable health disparities for two NIH-designated disparity populations: underserved rural and socioeconomically disadvantaged children. Our goal is to establish a novel, generalizable model of school-based, telehealth-driven preventive care that can be disseminated in underserved populations across rural America. We will adapt and evaluate our evidence-based approach, “STAR” (Specialty Telemedicine Access for Referrals), that we have found effective in a Tribal setting in rural Alaska. Appalachia has some of the poorest counties in the US, making this region ideal for adapting across rural America. The innovative “Appalachian STAR trial” will be the first study to apply school-based telehealth for preventive services, with direct access to specialists. Hearing screening will be the prototype for STAR due to the high burden of preventable, infection-related hearing loss in underserved children and the profound lifelong implications of childhood hearing loss. Our interdisciplinary team has relationships with underserved communities in Kentucky and partnership with a Community Advisory Board and Stakeholder Advisory Board providing support from the highest levels of state government (See KY Governor Letter). We will begin by adapting the STAR model of care to meet the needs of rural communities and schools through a community-and stakeholder-driven approach. We will evaluate the STAR care model in 66 schools in rural Kentucky through a stepped wedge cluster-randomized hybrid type 1 effectiveness-implementation trial with kindergarten children in 14 counties (n=~3600/year). The STAR intervention includes county-level school screening policy change with enhanced mHealth school hearing screening, followed by virtual specialty care referral. The stepped-wedge design allows evaluation of the policy/screening and referral components as well as comparison of usual care vs. full intervention (years 2 vs.5), while meeting community input that the intervention be available to all. Primary outcomes are the percentage of 1) children screened and 2) referrals resulting in specialty care within two months of screening. We conservatively hypothesize the percentage screened will improve by 20% and follow-up will improve by 40%. During the trial, we will assess multi-level implementation factors and outcomes to inform scale-up into other rural areas. Our STAR model could be both scaled across rural America and applied to other preventable health disparities, combining policy change on school health with digital innovations to radically expand access to care for underserved rural and socioeconomically disadvantaged children nationwide.

NIH Research Projects · FY 2025 · 2022-05

ABSTRACT Hearing loss is the second leading impairment worldwide. Childhood hearing loss has lifelong implications and disproportionately affects individuals in low- and middle-income countries (LMICs). Up to 75% of childhood hearing loss in LMICs is preventable due to the high prevalence of infection-related hearing loss. School hearing screening is critical for identification of childhood hearing loss in low resource settings, where newborn screening is unavailable. However, most screening programs only use pure-tone screening that does not identify middle ear disease widespread in populations with a high prevalence of infection-related hearing loss. This is because tympanometry, used to clinically identify middle ear disease, is expensive and designed for trained professionals. Our goal is to develop and validate an mHealth tympanometer with machine learning diagnostic support to transform this technology into a low-cost tool that could be broadly disseminated in LMICs, where the burden of hearing loss is greatest and is not addressed by current hearing screening methodology. Our study team is comprised of international leaders in hearing loss, audiology, data science, engineering, user- centered design, and device development in LMICs. We have also partnered with hearX, a University of Pretoria spinout company that developed the only validated mHealth pure-tone screening device. To test this new device in an appropriate LMIC setting, we have partnered with the South African site from the Global HEAR Collaborative, our consortium of collaborators from 28 countries that is the only international research network dedicated to hearing loss. We documented the need for this device in a large cluster randomized trial recently completed in rural Alaska, where tympanometry significantly improved the accuracy of school hearing screening in a population with a high prevalence of infection-related hearing loss. Using data from this trial and pilot funding, we are developing a machine learning tympanometry algorithm for lay screeners, and early hardware prototype fabrication is underway. In Aim 1, we will refine the hardware prototype using a user-centered design approach, cyclically incorporating feedback from South African team members during testing in a lab environment. In Aim 2, we will develop software through user-centered design that integrates the machine learning algorithm and refined hardware prototype. The resulting mHealth tympanometer will advance to the R33 phase. Technology development will be completed in Aims 3 and 4 through integration of the mHealth tympanometer with existing health information technology and an early feasibility study in 15 preschool children in South Africa to optimize device design for lay users. In Aim 5, we will validate the mHealth tympanometer with lay screeners through a clinical performance study in 500 preschool children in South Africa. This technology, developed through partnership and testing in an LMIC setting, will empower teachers and community health workers to identify children at risk for preventable hearing loss. The Global HEAR Collaborative will provide infrastructure for future studies with the proposed device across LMICs, directly addressing disparities in childhood hearing loss globally.

NIH Research Projects · FY 2025 · 2022-05

Project Summary Meiosis couples one round of DNA replication, high-frequency recombination between homologs, and two rounds of chromosome segregation to produce haploid meiotic products. Meiotic recombination is required for the proper segregation of homologs in meiosis, and it generates genetic diversity required for the process of natural selection. Interestingly, meiotic recombination is clustered at “hotspots” that regulate its frequency distribution throughout the genome. Our model system, fission yeast, led to the discovery that discrete DNA sequence motifs and their binding proteins position the initiation of recombination at hotspots. They do so by inducing histone PTMs and nucleosome displacement, which promote locally the catalysis of recombination- initiating dsDNA breaks by the basal recombination machinery (Spo11/Rec12 complex). The general, DNA site- dependent mechanisms are conserved between species that diverged about 400 million years ago and are implicated by association to be even more broadly conserved. Remarkably, a screen of short, randomized DNA sequences generated by base-pair substitutions in the fission yeast genome—which directly analyzed rates of meiotic recombination in about 46,000 independent clones—identified 202 distinct, short DNA sequence elements that activate recombination hotspots. These striking findings suggest the most meiotic recombination, like most transcription, is positioned and regulated by discrete DNA sites and their binding proteins. However, only five of the 202 hotspot-activating DNA sequences have been defined functionally at single-nucleotide resolution, and the binding/activator proteins have only been identified for three of the DNA sites. Our long-term goal is to define systematically the discrete DNA sites and binding/activator protein codes of meiotic recombination. First, we will use a newly developed tool called “targeted forward genetics” (TFG), which can generate more than 100,000 independent allele replacements in a single experiment, to define at single- nucleotide resolution the discrete DNA sequence motifs required for hotspot activity in vivo. Second, we will use an approach called “DNA affinity capture with mass spectrometry” (DAC-MS), coupled with a tandem mass tagging (TMT), triple-stage mass spectrometry (MS3) strategy that can analyze many samples simultaneously, to identify the candidate binding/activator proteins. Candidates will be validated for DNA site-specific binding and hotspot activation in vivo. Third, we shall test the hypothesis that the different cis-acting regulatory modules each promote recombination via a common downstream mechanism that involves chromatin remodeling. This systematic, multifaceted approach will provide new insight into the mechanisms (and discrete codes) that position meiotic recombination, which has implications for the etiology of meiotic aneuploidies (e.g., Down's syndrome), for linkage mapping, and for the evolutionary dynamics of genomes.

NIH Research Projects · FY 2026 · 2022-05

PROJECT SUMMARY/ABSTRACT The Center for Microbial Pathogenesis and Host Inflammatory Responses (CMPHIR: P20-GM103625) was established at the University of Arkansas for Medical Sciences (UAMS) in 2012. The underlying scientific theme is that addressing existing and emerging problems in infectious disease in a clinically relevant fashion will require an understanding of both the pathogens themselves and how they impact the host immunological and inflammatory response. This theme is based on the premise that understanding the complex interplay between diverse pathogens and their common human host is a prerequisite to maximizing opportunities to manipulate one or both sides of this equation in favor of the desired prophylactic and/or therapeutic outcome. In Phases I and II, we assembled a critical mass of investigators around this scientific theme and provided them with the administrative and technical resources they needed to establish successful scientific careers. In Phase III, we will refine and expand on these efforts with the overall goal of building on our success in Phases I and II to establish a self-sustaining Center of Biomedical Research Excellence that focuses on infectious diseases in a comprehensive and clinically relevant fashion. To this end, the specific aims of this Phase III application are to: 1) provide an infrastructure that maximizes the competitiveness of CMPHIR investigators through the support of essential core facilities; 2) promote continued growth of the CMPHIR and career development of its investigators; and 3) transition the CMPHIR to a nationally recognized, self-sustaining Center of Biomedical Research Excellence with the expertise and resources to address existing and emerging problems in infectious disease.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY Inorganic arsenic (iAs) produces significant reproductive toxicity in adult males leading to decreased sperm quality. Aside from workplace exposure, individuals are exposed to high levels of iAs near hazardous waste sites and in geographic areas enriched with iAs. A recent study revealed that transient prenatal exposure to a high dose of iAs impaired sperm quality in multiple generations. However, it is not known whether paternal exposures to environmentally relevant dose of iAs during adolescence or early-life (gestation to weaning) produce adverse inheritable reproductive outcomes. We posit that adolescence and early-life are windows of susceptibility during which exposure to iAs negatively impacts not only the individuals being exposed but also their offspring. However, the molecular mechanisms mediating paternal intergenerational transmission of exposure-induced traits remain unclear. Recently, sperm-borne small-RNAs and their specific 5'-methylcytosine (m5C) modifications were shown to mediate the paternal transmission of diet-induced disorders. Yet, similar studies on environmental toxicants such as iAs are absent. In our pilot study, we discovered iAs-induced changes in pseudouridine (Ψ) and m5C abundance in sperm small-RNAs. Ψ and m5C were found to be the most abundant RNA modifications in sperm small-RNAs, and we hypothesize that these modifications mediate the paternal inheritance of poor sperm quality associated with iAs exposure, particularly during the developmental windows of adolescence (Aim 1) and early life (gestation to weaning) (Aim 2). We will determine if adolescent (Aim 1A) and early-life (Aim 2A) iAs exposure are windows of susceptibility conferring the intergenerational inheritance of impaired sperm quality. We will identify the mediating role of sperm small-RNAs and their modifications, Ψ and m5C, in adolescent (Aim 1B) and early-life (Aim 2B) exposure-induced paternal inheritance of impaired sperm quality by performing zygotic microinjection (ZI) of sperm small-RNA isolated from exposed or control mice to generate offspring from naïve zygotes. We expect the offspring of the adolescent exposure group to have poorer sperm quality, as in exposed fathers and sons produced by natural mating. To validate the functional role of specific modifications in our sperm phenotype inheritance model, we will isolate Ψ- and m5C-enriched sperm small-RNA fractions by RNA immunoprecipitation for zygotic microinjection. We will determine if microinjection of specific modification-enriched sperm small-RNAs during adolescent (Aim 1C) and early-life (Aim 2C) can reproduce the paternal sperm phenotype. We expect the ZI-produced offspring exposed to Ψ- or m5C-enriched sperm small-RNAs from adolescent and/or early-life exposure groups can recapitulate the poor sperm quality phenotypes. We will use Nanopore native RNAseq to map sperm Ψ and m5C modifications and identify small-RNA populations associated with the exposure window- specific intergenerational inheritance. Finally, we will correlate RNA epitranscriptomic and transcriptomic changes with the intergenerational effects of adolescent/early-life iAs exposure on sperm quality.

NIH Research Projects · FY 2025 · 2022-03

Abstract Currently, we can record non-invasive fetal magnetocardiographic (FMCG) signals with a magnetic sensor- based system called SARA (SQUID Array for Reproductive Assessment) installed at University of Arkansas for Medical Sciences. The study of the fetal heart, and in particular, the developing cardiac conduction system, has been significantly aided in the last two decades by the introduction of FMCG. The American Heart Association recently acknowledged the academic and clinic usefulness of this new modality. Several studies have shown that FMCG can provide new relevant clinical parameters for assessment of fetal cardiac activity and also supplement the parameters that are currently available. Despite all these benefits, the major hurdles facing SQUID technology include system and maintenance cost, cryogenic helium cooling, a rigid one-size-fits-all array, and a single position option for the mother. We have shown the feasibility of using uncooled biomagnetometer for potential prenatal assessments based on microfabricated optically-pumped magnetometers (OPM). The OPMs have many features similar to cryogenic SQUID-based systems as they measure the same field components, and are compatible with standard magnetically-shielded rooms. This proposal is in response to NIBIB’s PAR-19-158 Bioengineering Research Grants, where we apply a multidisciplinary integrative team approach to we plan to design, test and validate a 24-channel OPM sensor system that fits over the maternal abdomen. Performance of the OPM in a three-layered shielded room will be evaluated with respect to the data quality of FMCG signals which will be compared to those obtained from a gold standard SQUID based system. The overall goal is to demonstrate that with OPM systems (a) we can design a stand-alone flexible array for maternal-fetal application (b) record the desired biomagnetic signals equivalent to SQUID sensors; (c) be able to separate the signal into their constituents to extract FMCG and (d) quantify fetal heart signals and the relevant metrics. We believe that with potential lower costs and maintenance requirements, the benefits of using fetal biomagnetometery could be translated from the research to possible widespread clinical applications. The specific aims are as follows: Aim 1: Design and configure a bed-based stand-alone array of OPMs that conforms to the shape of the maternal abdomen in order to obtain signals with sufficient signal-to-noise ratio for fetal applications. Aim 2: Extract and quantify the FMCG waveform components to compute a) PQRS and T wave detection rates and cardiac time intervals (CTI). Aim 3: Record and characterize FMCG of fetuses that have been referred with abnormal heart conditions detected through routine ultrasound examination.

NIH Research Projects · FY 2026 · 2022-02

ABSTRACT Health disparities in the Republic of the Marshall Islands (RMI) are striking with extremely high rates of diabetes and other cardiometabolic diseases. Documented rates of type 2 diabetes mellitus (T2DM) in the RMI range from 20%-50%. This is significantly higher than global (8.5%) and US (11%) rates. The extreme disparities in the RMI are exacerbated by a lack of research, lack of funding, a lack of services, and a lack of culturally-appropriate interventions. Residents of the RMI experience unique barriers to self-management of T2DM, as well as possess unique cultural assets that can be leveraged to help mitigate these barriers. The research team worked with the Marshallese community in Arkansas to develop and evaluate a culturally- adapted family model of DSMES (Ājjmuurur Baamḷe DSMES). Ājjmuurur Baamḷe DSMES is based on a collectivist approach, incorporates Marshallese cultural practices, and uses “talk story” as a conversational, rhythmic, and culturally preferred way of sharing knowledge. Ājjmuurur Baamḷe DSMES includes family members as participants and focuses on family motivational interviewing, family goal setting, and family behavioral change with specific focus on education about supportive and nonsupportive family behaviors. The curriculum is assets based and it works to overcome barriers facing Marshallese patients by leveraging culturally specific facilitators of healthy behavior change. Our central hypothesis is that persons who receive the Family Model DSMES "Ājjmuurur Baamḷe" will have improved HbA1c (primary outcome), blood pressure, lipids, BMI, increased knowledge, self-efficacy, empowerment, and quality of life, along with decreased diabetes-related complications and diabetes-related distress. This study's objective is to conduct a cluster RCT using a wait-list control to evaluate the effectiveness of Ājjmuurur Baamḷe DSMES when delivered in faith- based organizations (FBOs) by Community Health Workers (CHWs). Our specific aims are: 1. Test the effectiveness of Ājjmuurur Baamḷe DSMES to improve diabetes-related outcomes among Marshallese patients; 2. Evaluate the effect of Ājjmuurur Baamḷe DSMES on family members; and 3. Conduct an indigenous evaluation to understand the extent to which the intervention adheres to Pacific Islander cultural values and evaluate the cultural appropriateness of the research. Data will be collected from patients (Aim 1) and their family members (Aim 2) at baseline, immediately post-intervention (12 weeks), at four months and twelve months post-intervention. An indigenous evaluation (Aim 3) will be conducted at six months and each year thereafter to document and inform process improvement efforts in study implementation. While the Marshallese are a small population, this population is underrepresented in research, and they are experiencing a health crisis that must be addressed. The proposed study offers a promising intervention that has the potential to affect substantially health disparities experienced by Marshallese and other Pacific Islanders in the USAPI.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY - OVERALL Arkansas, located in the Southern region of the United States, ranks among the lowest in the nation in overall health outcomes and in cancer and cardiovascular disease. Within Arkansas, the place-based burden of chronic diseases is quite profound, with rural and low resource communities faring the worst. Forty-one percent of Arkansans live in rural areas where chronic disease risk factors and underlying determinants of health have not changed in decades. Poverty and food insecurity are higher, and wages, employment opportunities and health care access are lower in rural than in urban Arkansas, and particularly in the Delta region of the state. To address the place-based health burden in Arkansas, the Center for Research, Health, and Society (CRHS) will use a community engagement framework to inform the development and implementation of a robust process for advancing novel multilevel and transdisciplinary research. The Center will engage communities in partnerships to address the causes of chronic diseases and build and train a competent workforce among academics and community members who are prepared to reduce cancer and cardiovascular diseases. Our community change theme will help the CRHS identify factors in the community and the academy that inform how the cores, research projects, advisory boards, and our broad-based coalition of partners can work synergistically to accomplish CRHS goals. Our coalition of stakeholders includes partners in the Northwest, Highlands and Delta regions of Arkansas and multiple organizational partners integrated into the cores and research projects who will employ common measures, tools, methods, and approaches to accomplish the CRHS goals. The CRHS will work with the Research Coordinating Center to leverage and share resources, engage in cutting-edge cross center research, and increase networking and research opportunities for new investigators. The CRHS will leverage multiple federally funded resources including the Clinical Translational Science Award program, the National Research Mentoring Network, federally funded center grants, and federal surveys to help facilitate research, training, mentoring, dissemination, and translation of research to inform public practice and interventions. CRHS builds on our prior successes and will create a robust broad-based research ecosystem that serves as a national model for reducing chronic diseases.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY/ABSTRACT The University of Arkansas for Medical Sciences (UAMS) will be a clinical site for the HEAL Initiative: Neonatal Opioid Withdrawal Syndrome Pharmacological Treatments Comparative Effectiveness Trial-Clinical Sites (UG1), RFA-HD-21-031. Arkansas (AR) is a rural state with the second highest opioid prescription rate in the nation and is in the top 3 states nationwide for opioid prescriptions to pregnant mothers. Additionally, AR has the second highest number of Adverse Childhood Experiences in the nation, thus making this an ideal site to study the effects of opioid use in a state with other environmental stressors. Recruitment will be from a robust Women's Mental Health Program, which saw 899 pregnant women with opioid use disorder last year, the general obstetrical clinic, and the 64 bed academic Neonatal Intensive Care Unit (NICU) at UAMS. Innovative strategies for recruitment will include investigator attendance at prenatal classes and a Community Advisory Board, while retention will be bolstered by frequent electronic communication, updated contact information, financial and scheduling incentives. Follow-up will be performed at the Arkansas Children's Hospital Research Institute in a state of the art Pediatric Clinical Research Unit. Compliance for follow-up is anticipated to be challenging for this trial, so innovative strategies to encourage compliance will include monetary incentives, ease of scheduling, and case managers to arrange free travel, meals, and other needs for participants. Parents will also be given results of their psychological exams to encourage compliance. This project is well supported by the Translational Research Institute (TRI), home of a Clinical and Translational Science Award. This site has extensive experience conducting multicenter trials and is currently involved in two similar trials, which will be completed by the time this site will begin enrolling patients assuring this site will be ready to begin enrollment after funding. This site also has extensive experience in opioid research and will actively contribute to protocol development. Major strengths of this site include experience in pk/pd modeling, a robust telemedicine program to bolster awareness of the study statewide, and a Center for Implementation Science to implement evidence based weaning medication. This site has a large diverse clinical population with an average of 3450 annual deliveries, approximately 10% of the state's annual deliveries, with 273 opiate exposed neonates and 49 pharmacologically treated newborns annually. There are 53% white, 33% African American and 11% Hispanic mothers who deliver annually at UAMS. Public insurance accounts for 81% and private insurance accounts for 16% of all newborn admissions. This site has an excellent track record of participation in multicenter trials (12 trials are open currently) and a robust scholarly publication record. The assembled group of researchers at this site will contribute to the analysis, interpretation, and publication of results. The environment at this site is supportive of this initiative, and leadership will provide the support, protected time, and the infrastructure to successfully complete the study.

NIH Research Projects · FY 2025 · 2021-09

ABSTRACT Rural Alaska Native children experience a high prevalence of preventable childhood hearing loss. School-based programs provide the only access to preventive services for many underserved rural and minority children, yet loss to follow-up from school hearing screening is common and scarcity of specialists in rural areas compound barriers to care. The Alaska Tribal Health System addresses geographic barriers to care with a telehealth network, but the network is not used for school hearing screening and is only available in Tribal regions. This proposal brings a novel telehealth model directly into schools to reach underserved rural and minority children across the state of Alaska, including non-Tribal regions. The overall objective is to prospectively implement and evaluate a new virtual specialty care model in Alaska schools to reduce loss to follow-up from school hearing screening and improve access to specialty care in rural environments. This work builds on the team’s recent PCORI-funded cluster-randomized trial that translated Alaska’s existing Tribal telehealth network in village clinics to a prevention model for school hearing screening referrals. Children randomized to clinic- based telemedicine specialty referral were 2.3 (95% CI 1.4, 3.8) times more likely to receive an ear/hearing diagnosis than those receiving the standard referral of a letter home. Success of the clinic-based intervention varied substantially between communities; stakeholder interviews revealed implementation challenges that could be addressed by delivering telehealth directly in schools. The current proposal will establish a unique model of care in Tribal and non-Tribal regions across the state, bringing virtual specialty care directly into schools. Three accomplished and complementary multi-PIs, who collaborated on PCORI- and NIDCD-funded studies in rural Alaska, will lead an interdisciplinary team, and an Alaska Stakeholder Team that includes Alaska Commissioners for Education and Health and Social Services will guide study development. In Aim 1, the team will develop and pilot an implementation protocol for school-based virtual specialty care for hearing loss through focus groups and interviews with community stakeholders. In Aim 2, they will conduct a stepped wedge, cluster-randomized implementation trial of virtual specialty care in three representative regions (n=31 schools; 2,008 children). The primary outcome is proportion of hearing referrals resulting in specialty follow-up within two months of screening date. The conservative hypothesis, based on PCORI trial data, is that virtual specialty care will improve follow- up by 100%. In Aim 3, the team will evaluate sustainability of virtual specialty care in Alaska schools through a policy analysis to assess alignment between health and education sectors, identify policy and practice barriers and accelerators, and ascertain payment models for future programmatic financing. This school-based telehealth model to address preventable childhood hearing loss could be translated to other underserved rural and minority groups, bringing high-value services into rural schools to alter the paradigm of prevention nationwide.

NIH Research Projects · FY 2025 · 2021-09

PROJECT ABSTRACT The prevalence of obesity is on the rise and a better understanding of the drivers of this epidemic is crucial. As novel insights implicate bone in regulating energy metabolism, it is crucial to understand how diseases of positive energy balance, like obesity, affect the different functions of bone. While obesity is known to impact the structural function of bone causing increased fragility, it is unclear how the metabolic function of bone is compromised in obesity. Filling this gap in our knowledge is critical for developing therapeutics that can reestablish energy metabolism while maintaining musculoskeletal health in obesity. In this proposal, we explore the effects of obesity on bone regulated energy metabolism and focus particularly on osteocytes, that constitute 95% of cells in bone. Our compelling preliminary data puts forth the premise that TGFβ signaling is a key modulator of osteocyte-intrinsic energy metabolism (cellular). Thus, we test the hypothesis that obesity impacts osteocytic TGFβ signaling that in turn contributes to deregulated systemic energy metabolism. Furthermore, our data suggest that osteocytic TGFβ signaling also coordinates the activities of epigenetic factors to shape the transcriptome of osteocytes. These epigenetic factors have previously been implicated in obesity; however, their relation to TGFβ signaling and cellular energy metabolism of osteocytes remains unexplored. Together, these findings motivate my central hypothesis, that osteocytic TGFβ signaling drives metabolic dysfunction in obesity through an epigenetic mechanism. My aims to test this hypothesis are to: 1) determine if obesity induces metabolic reprogramming in osteocytes in a TGFβ- dependent manner, 2) determine if ablation of osteocytic TGFβ rescues metabolic dysfunction in obesity, and 3) identify the function of TGFβ responsive epigenetic factors in regulating osteocyte driven energy metabolism during obesity. Using hyperglycemia and hyperlipidemia (in vitro) and DIO (diet-induced obesity, in vivo) to model obesity, we will monitor the link between osteocytic TGFβ signaling, cellular- and systemic- energy metabolism, and study its role in regulating the obesity-induced metabolic dysfunction. For combining ChIP- Seq, ATAC-Seq, and RNA-Seq approaches, we will generate a network landscape connecting epigenetic marks, modifiers, chromatin accessibility patterns, and corresponding molecular pathways that are impacted by obesity in osteocytes. In the future, this landscape of molecular and epigenetic networks will serve as a blueprint that can be used to interpret osteocyte function in metabolism in response to distinct nutrient cues. Such a blueprint will be particularly informative in devising or predicting outcomes of pharmacologic interventions and will lay the foundation for my independent research that dissects the intricacies behind the crosstalk between bone function and energy metabolism. Project Abstract

NIH Research Projects · FY 2025 · 2021-09

Summary/Abstract The use of antibiotics has significantly increased in recent years. Antibiotics (ABX) severely alter the gut microbiome, destroying potentially pathogenic bacteria, as well as beneficial ones—producing a state of microbial imbalance called dysbiosis. Notably, a diminished gut microbiome has severe defects on the immune system, yet how these defects may affect cellular immunotherapy is largely unknown. To better understand how dysbiosis influences cellular immunotherapy, we focused on melanoma as an exemplary immunogenic solid tumor. The incidence of melanoma has increased drastically over the past decades, with its morbidity rate continuing to outpace that of most other cancers. Early stages of melanoma are often successfully controlled and treated; yet patients with advanced stages of melanoma are treated with cellular immunotherapy and only 50% respond. We hypothesize that ABX-induced dysbiosis dictates, at least in part, the reduction in treatment efficacy. Our overall goal is to define the systemic effects of antibiotic-induced dysbiosis on the distal tumor microenvironment and develop therapies to promote antitumor immunity. The major objective of this application is to overcome dysbiosis-induced ICAM-1 suppression and thereby enhance the effectiveness of cellular immunotherapy. Attaining this objective will be the next step in increasing the efficacy and response rate of immunotherapies. We formulated a robust and unbiased approach using various melanoma models to accomplish the following Aims: Aim 1. Identify ABX primarily responsible for stromal immune suppression resulting in tumor progression. Aim 2. Increase ICAM-1 on tumor-associated endothelial cells during dysbiosis. Aim 3. Increase cellular immunotherapy efficacy in melanoma during dysbiosis. Completing these aims will expand our understanding on how antibiotics-induced perturbation of the gut microbiome impacts the distal tumor microenvironment. This work has the potential to establish new paradigms aimed at enhancing the efficacy and response rate of immunotherapies by modulating the tumor vasculature, as all types of immunotherapy ultimately dependent on efficient trafficking of effector leukocytes into the tumor.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY Cellular therapies are a cornerstone in the field of cancer immunotherapy, and many consider them the next frontier in cancer treatment. Despite the success of adoptive cell therapies for the treatment of hematologic cancers, the question of its effective use against solid tumors remains unresolved. The extremely complex biology of solid tumors driven by tumor heterogeneity amongst and within patients is largely the source of failure. New approaches are needed to inform the engineering adoptive T cells and to monitor a patient’s T cell capacity to circumvent the multitude of barriers present in solid tumors. The ability of a cell to dynamically adjust proteome composition is essential during stress. For that reason, protein turnover rates are optimized to balance energy- saving stability and dynamic flexibility serving as a rapid mechanism for activation or inhibition of signaling pathways when cells respond to environmental changes. While it is common to ask the question “how do T cells respond to stress?” we intend to shift the paradigm to asking a fundamentally different question “how are T cells prepared for encountering stress?” The precise set of proteins T cells depend on to ensure adequate plasticity remains elusive. We have conceived and developed a novel integrative multi-omic technique for the analysis of proteome turnover dynamics. This technique integrates proteome, transcriptome, and protein dynamic profiling approaches for the identification of protein “operating points”, a measure of protein dynamic nature. We hypothesize that the ability of a T cell to adapt, through dynamic proteome control, determines persistence and function in solid tumors. Unveiling mechanisms that endow T cells with superior adaptability and the capacity to overcome solid tumors will be of great clinical interest in cellular therapy development. Further, identifying new ways to determine T cell fitness in immune monitoring will not only have implications in the treatment of cancer but, many other immune driven conditions as well. The aims of the study are 1) Define proteome turnover changes in response to co-stimulation and exhaustion, 2) Manipulate protein turnover rates to enhance T cell persistence, and 3) Utilize protein turnover rate measurements in patient immune monitoring.

NIH Research Projects · FY 2024 · 2021-09

Abstract The prevalence of Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D) is on the rise and represents a health concern for women of childbearing age. Over an 8 year period, a major increase in the prevalence of births complicated by pre-gestational diabetes increased by 50% .Pre-gestational diabetes is one of the most common maternal risk factors for maternal, fetal, and infant complications. Preliminary evidence by our group evaluated inflammatory biomarkers in pregnant subjects longitudinally during gestation. Several inflammatory cytokines including C-reactive protein (CRP) were significantly elevated in T2D relative to non-diabetic controls, and this effect was more evident in the third trimester. Thus, maternal inflammation later in pregnancy may represent an important mechanistic link associated with health risks for mother an infant in diabetic pregnancy. Infants and children from diabetic mothers are more likely to suffer neurological impairments compared to offspring of non- diabetic mothers. Thus, we hypothesized that the increase in third trimester inflammation found in diabetic pregnancy could adversely impact fetal brain development, a significant period of brain growth in humans. A majority of the studies to date have linked poor infant outcome with various maternal risk factors. However, these studies were limited in that the assessments did not occur in real time. The world’s first biomagnetic sensing system at UAMS was built specifically to track and understand the process of fetal brain development. The SARA (SQUID Array for Reproductive Assessment) system consists of 151 primary superconducting sensors which detect biomagnetic fields generated in the body including fetal heart, and fetal brain. SARA is based on the non- invasive magnetoencephalography (MEG) technique that permits the investigation of fetal parameters from early gestation until delivery. We developed an optimized combination of recording parameters using auditory and visual stimuli and spontaneous brain activity for a multimodal approach to understand fetal neurological development trajectory. The overall goal is to correlate fetal and infant brain development with inflammatory markers in mothers with pre-gestational T1D and T2D. We will obtain maternal blood samples for cytokine assessment at their regularly scheduled third trimester SARA visit. We will also collect maternal and cord blood samples at delivery. Aim 1: Implement an integrated multimodal approach to investigate fetal and neonatal brain activity along with assessment of blood inflammatory biomarkers in pre-gestational diabetic mothers. Aim 2: Track and quantify brain activity using MEG signals during fetal and neonatal stage of life. Aim 3: Correlate the inflammatory biomarkers to fetal and neonatal brain activity.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY Consuming a healthy diet and maintaining a healthy weight provide significant protection against cancer and cancer-related mortality. Early interventions are needed to decrease the risk of developing cancer later in life. Early care and education (ECE) is a promising setting for cancer prevention. “Together, We Inspire Smart Eating” (WISE) is an intervention that improves children's diets in ECE. WISE includes 4 key evidence-based practices (EBPs): (1) hands-on exposures to fruits and vegetables, (2) role modeling by educators, (3) positive feeding practices, and (4) a mascot associated with fruits and vegetables. Standard implementation approaches to WISE result in suboptimal implementation of WISE EBPs. Additional implementation strategies are needed to increase adoption and fidelity to EBPs. To date, most studies have employed an “all-or-nothing” approach, comparing multifaceted strategies to control groups without implementation support. Thus, there is an urgent need for optimized strategies that tailor implementation support intensity to the unique challenges and limited resources of the ECE context. The overall objectives of this application are to determine the effectiveness and cost-effectiveness of an adaptive implementation approach to improve adoption of the EBPs of WISE while also examining implementation mechanisms. Our central hypothesis is that the addition of high-intensity strategies at sites that do not respond to low-intensity strategies will improve implementation and health outcomes. Specific Aim 1. Determine the effectiveness of an adaptive implementation strategy that tailors the intensity of implementation support versus a low-intensity strategy. Using an enhanced non-responder trial, we will compare the effect of continuing low-intensity strategies vs. augmenting with high-intensity strategies. We hypothesize that sites receiving high-intensity strategies will outperform sites continuing the low- intensity strategies on the primary outcome of intervention fidelity and on secondary child health outcomes. Specific Aim 2. Examine moderators and mediators of implementation outcomes in a mixed- methods design. We will test organizational readiness and teacher experience as moderators of response to the implementation strategies. We will test educators' perceptions of barriers, local implementation climate, and implementation leadership as mediators of the effect of the strategies on implementation outcomes. Qualitative data will explore other potential moderators and mediators not measured quantitatively. Specific Aim 3. Assess the incremental cost-effectiveness of the adaptive implementation strategy. In this aim, we will estimate the cost per unit of fidelity associated with the adaptive implementation strategy. Results will also determine the incremental cost-effectiveness of applying the adaptive strategy compared to continuing low-intensity strategies for improving BMI and other child health outcomes.