Univ Of Arkansas For Med Scis

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY Exposure to environmental genotoxins poses a considerable risk, contributing to the formation of pro-mutagenic DNA lesions. These DNA lesions, in turn, can give rise to mutations and ultimately contribute to the development of cancer. Unfortunately, our knowledge of the precise origins of subsequent mutations has been hampered by the inability to comprehensively characterize the DNA lesion landscape, comprised of both the type (DNA adductome) and genomic positions of the DNA lesions. This lack of knowledge about the DNA lesion landscape has resulted in an inability to precisely link DNA lesions to subsequent mutational outcomes. Indeed, many common mutations found in human cancers are known to be derived from error-prone endogenous processes. This may explain the low level of agent-specific mutations reported in tumors, despite strong epidemiological evidence that environmental agents play key roles in carcinogenesis. Consequently, it is currently unknown whether mutations are the result of exposure-induced DNA lesions or arise indirectly from endogenous processes. We hypothesize that the error-prone endogenous processes significantly contribute to mutagenesis and are enhanced upon exposure to environmental mutagens. The overall objective of our proposed project is to elucidate the origins of mutational landscapes by adopting a highly synergistic approach that integrates cellular DNA adductomics, Nanopore long-read sequencing, and single-molecule duplex sequencing. Each platform will generate a specific dataset that relates to, respectively, DNA lesion types/amounts, DNA lesion positions/types, and mutation types/positions, along with a probability of the mechanisms involved. These complementary datasets will be analyzed for causal relationships among key DNA lesions and mutational outcomes, whether derived directly from exogenous DNA lesions or via endogenous processes. Here, we focus on 1,2,3- Trichloropropane (TCP), bromochloroacetic acid (BCA), and furan as representative environmental mutagens known for their characteristic pro-mutagen DNA lesions and mutational signatures. First, we will generate DNA suitable for studying endogenously and exogenously derived DNA lesions and mutational landscapes and generate DNA adductomes, using stable isotope labeling and high-resolution mass spectrometry (Aim 1). Second, we will map the genomic positions of DNA lesions using Nanopore sequencing (Aim 2). Lastly, we will determine the mutational landscape and build a model for predicting the probabilities of acquiring somatic mutations from DNA lesions (Aim 3). This synergistic analysis of the DNA adductome and mutational landscape will provide unprecedented insights about the positions and frequencies of exogenous and endogenous DNA lesions and subsequent mutational outcomes. This translational ViCTER project will elucidate the origins of novel and established mutational signatures and will contribute significantly to our understanding of the dynamics of the endogenous and exogenous DNA adductomes and their role in environmentally induced mutagenesis, thereby addressing key questions in cancer biology.

NIH Research Projects · FY 2026 · 2025-01

Project Summary The MIRA will support the productive, long running Research Program in the Raney lab. The mechanism and regulation of DNA helicase activities are being addressed in Project 1 whereas signaling mechanisms for G- quadruplexes follows in Project 2. Helicases are molecular motor proteins that transduce chemical energy from ATP hydrolysis into mechanical energy capable of unwinding dsDNA, translocating on ssDNA, unfolding quadruplex DNA and remodeling protein-DNA complexes by moving protein along DNA. Two percent of the yeast genome encodes helicases, and the human genome encodes over 100 helicases. Each metabolic pathway involving nucleic acids such as replication, transcription, repair, translation, and other processes requires the activity of one or more helicases. Many cancers are correlated with helicase mutations. Many viruses such as SARS2, ZIKA, West Nile, Ebola, and many others encode one or more helicases that is essential for viral replication, therefore helicases can be targets for-cancer and anti-viral development. The over-arching question for Project 1 is “what is the mechanism utilized by a helicase to perform multiple functions?” We are utilizing the yeast Pif1 helicase to address this question and others. Pif1 is in the largest superfamily of helicases. The biochemical and biological studies needed to determine the underlying mechanisms are facilitated in the yeast system. Pif unwinds duplex DNA, unfolds G-quadruplex DNA (G4DNA), translocates on single-stranded DNA, and remodels DNA bound to proteins by moving the proteins. Experiments here will address the hypothesis that these activities can be understood within a unified mechanism. A major gap is the lack of a consensus for how energy from ATP hydrolysis is transduced into molecular motion that can be used to unwind dsDNA or unfold quadruplex DNA. Another major gap includes the lack of knowledge of how helicases fit into macro-molecular machines such as the mitochondrial DNA replication holoenzyme. We have identified key amino acids that strongly control energy transduction through novel helicase motifs and we will determine the mechanism of these amino acids. Project 2 will address the over-arching question of “what is the function of the guanine-rich DNA sequences that can fold into G-quadruplex structures (G4DNA)?” These sequences clearly play important roles in replication, transcription, translation, and repair because they appear in highly disproportionate levels in the genome including promoters, telomeres, and mitochondrial DNA. In Project 2, we will determine whether G4DNA is excised from the genome through an excision repair mechanism. DNA repair mechanisms often remove damaged DNA from the genome. Our hypothesis is that G4DNA is excised, resulting in a signaling molecule that triggers a cellular response affecting many pathways including stress granule formation. We will test this hypothesis through a variety of structural, molecular, and cellular approaches. Initially, we will perform screens for nucleases that excise G4DNA. Projects 1 and 2 will continue to have a strong and lasting impact through the work in this Research Program.

NIH Research Projects · FY 2025 · 2024-12

PROJECT SUMMARY Residents in Arkansas (AR) face high risks in generational exposure to pesticides and fertilizers from agricultural production; heavy metals such as arsenic found in the soil, water, air; and aromatic hydrocarbons (benzene, benzo[a]pyrene) from frequent burning of trash, crop and timber residues, and high-temperature cooking. Arkansas Rural Community Health Study (ARCH) is the first and the largest epidemiologic cohort of adult women in AR to examine the effects of both genetic and environmental exposures (EE) on an individual’s risk of developing breast cancer (BC) and predicted response to treatment. In total, the institutional-supported ARCH cohort has 26,375 women from all 75 AR counties. In contrast to most cohorts conducted among populations well below average risk, ARCH is enriched with a high rate of early-onset breast cancer (EOBC) cases among all BC prevalent cases at baseline and incident cases when linked with Arkansas Cancer Registry. Given increasing incidence of EOBC nationwide, it is crucial to invest in an understudied rural population with generations of exposure to identify factors responsible for increasing risk and the mechanisms underlying EOBC etiology. Our goal is to maintain, enrich, and enable a broader use of data and sample resources for the ARCH cohort by facilitating longitudinal follow-up since the baseline recruitment 17 years ago. By partnering with the University of Arkansas for Medical Sciences (UAMS) Translational Research Institute and Rural Research Network, we will have the unprecedented opportunity to leverage the existing 8 UAMS Regional Campuses to target recruitment efforts among existing mother-daughter pairs especially in the rural and underrepresented minority (URM) communities for additional biospecimen and exposure surveys, especially during key windows of susceptibility. The project will promote widespread data sharing and scientific collaborations, while strengthening scientific and workforce diversity in environmental health with the goal to 1) expand our collaboration and hiring of URM faculty and staff, 2) enrich the cohort with environmental constructs and social determinants of health, 3) follow up existing ARCH participants, focusing on the mother–daughter pairs to understand generational exposures in the rural state, and 4) develop an interactive dashboard to facilitate data sharing and sample request. The proposed project will enrich the established ARCH cohort in AR with insurance- cancer registry databases, EE and biospecimens (saliva, urine, blood - including viable immune cells) since the baseline recruitment. The collaboration with RRN will ensure enrollment of rural and URM populations and the target follow-up of mother–daughter pairs will allow future research on generational exposure, modifiable lifestyle factors, and genetics contributing to EOBC etiology. The implementation of an interactive dashboard will further facilitate broader use of data and sample resources for future projects to identify interventions on cancer health disparities, prevention strategies, and to support development and treatment of cancer immunotherapy.

NIH Research Projects · FY 2026 · 2024-12

Residents in Arkansas (AR) face high risks in generational exposure to pesticides and fertilizers from agricultural production; heavy metals such as arsenic found in the soil, water, air; and aromatic hydrocarbons (benzene, benzo[a]pyrene) from frequent burning of trash, crop and timber residues, and high-temperature cooking. Arkansas Rural Community Health Study (ARCH) is the first and the largest epidemiologic cohort of adult women in AR to examine the effects of both genetic and environmental exposures (EE) on an individual’s risk of developing breast cancer (BC) and predicted response to treatment. In total, the institutional-supported ARCH cohort has 26,375 women from all 75 AR counties. In contrast to most cohorts conducted among populations well below average risk, ARCH is enriched with a high rate of early-onset breast cancer (EOBC) cases among all BC prevalent cases at baseline and incident cases when linked with Arkansas Cancer Registry. Given increasing incidence of EOBC nationwide, it is crucial to invest in an understudied rural population with generations of exposure to identify factors responsible for increasing risk and the mechanisms underlying EOBC etiology. Our goal is to maintain, enrich, and enable a broader use of data and sample resources for the ARCH cohort by facilitating longitudinal follow-up since the baseline recruitment 17 years ago. By partnering with the University of Arkansas for Medical Sciences (UAMS) Translational Research Institute and Rural Research Network, we will have the unprecedented opportunity to leverage the existing 9 UAMS Regional Campuses to target recruitment efforts among existing ARCH participants especially those residing in communities with high environmental exposures in the rural communities for additional biospecimen and exposure surveys, especially during key windows of susceptibility. The project will promote widespread data sharing and scientific collaborations in environmental health with the goal to 1) enrich ARCH cohort maintenance and resource infrastructure, 2) collect longitudinal sample and exposure data, 3) develop and implement an interactive dashboard to promote cohort data management and sharing. The proposed project will enrich the established ARCH cohort in AR with insurance-cancer registry databases, EE and biospecimens (saliva, urine, blood -including viable immune cells) since the baseline recruitment. The collaboration with Regional Campuses will ensure enrollment of target communities, and the follow-up of mother–daughter pairs will allow future research on generational exposure, modifiable lifestyle factors, and genetics contributing to EOBC etiology. The implementation of an interactive dashboard will further facilitate broader use of data and sample resources for future projects to identify interventions on rural cancer health, early onset cancers, environmental research, and to support development and treatment of cancer immunotherapy.

NIH Research Projects · FY 2026 · 2024-11

Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s Sarcoma (KS) and Primary Effusion Lymphoma (PEL), which preferentially arise in immunocompromised patients (e.g., HIV+ personnel or organ transplant recipients) and lack of effective therapeutic options. Despite the reduced incidence of KS in the era of combined Antiretroviral Therapy (cART) for HIV infection, KS still remains one of the most common AIDS-associated tumors and a leading cause of morbidity and mortality in this setting. PEL is a rapidly progressing malignancy with a median survival time of approximately 6 months, even under the combinational chemotherapy. Therefore, KSHV-induced malignancies still represent a serious threat to immunosuppressed patients due to the lack of effective therapies. This project aims to design and develop O’PROTAC-based degraders which specifically targeting LANA expression, a KSHV-encoded major oncoprotein, to interfere with the survival of KSHV+ tumor cells in vitro and in vivo. We hope we can develop new interventional strategies through targeting oncogenic virus itself for improving the outcome of these virus-associated malignancies in high-risk immunocompromised patients.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Methamphetamine use is increasing rapidly across the country, paralleled closely by severe addiction- and health-related outcomes. Behavioral treatment interventions for methamphetamine use disorder (MUD) are available, but treatment utilization is low and dropout is high. While medication treatment for opioid use disorder has made substantial progress, there is currently no approved medication treatment for MUD. A high-affinity methamphetamine antibody medication (IXT-m200) is in development for treatment of MUD, with a Phase III clinical trial planned for the near future. Given that abstinence is extremely difficult for these patients, patient-reported outcomes (PRO) must be considered alongside conventional clinical metrics such as reported drug use and urine drug screens. Defining endpoints for use in future treatment studies that assess improvement in functioning beyond abstinence, as has been done with opioids, would create opportunities for new medicines to be evaluated and approved that might not be otherwise. Both NIDA and the FDA have expressed support for a broad range of practicable endpoints for treatment medication drug trials. Evaluating new medications using PRO may also spur development of new products that address a fuller range of the symptoms of addiction. No validated instrument exists to assess PRO outcomes for new methamphetamine-specific therapies. Better understanding such endpoints may inform the development of more tailored treatment interventions for a population historically hard to reach and unlikely to initiate or complete treatment. The proposed study will develop and validate a PRO survey intended for use in evaluations of medications to treat MUD (PROMT, Patient-Reported Outcomes for Methamphetamine Treatment). We will develop a conceptual framework to inform a first PROMT draft, review the content of PROMT with key stakeholders and people who use methamphetamine through qualitative interviews, and evaluate the psychometric properties of the survey items through statistical analysis. Importantly, as our study population is difficult to reach and often stigmatized, we will collaborate with community partners to assist with interview and pilot survey recruitment, including the Central Arkansas Harm Reduction Project (Little Rock, Arkansas), KC CARE Health Center (Kansas City, Missouri), and CAPTUS Clinical (Dallas, Texas). A multi-partner, multi-state study design will be critical in meeting recruitment goals and will maximize the generalizability of PROMT to the US treatment population.

NIH Research Projects · FY 2026 · 2024-09

Project Summary Addiction and trauma exposure are ubiquitous among the 5.5 million people (1 in 47 adults) who are either incarcerated or under correctional supervision in the US. Approximately 85% of people in prison have an active substance use disorder or are incarcerated for a drug-related crime, and pre-incarceration exposure to chronic and severe trauma is the norm rather than the exception. Posttraumatic stress symptoms (PTSS), a common outcome of trauma exposure, are linked to greater drug use severity and increased rates of relapse and crime among people who use drugs. PTSS and substance use disorder (SUD) each increased risk for new arrests and new felony arrests among people who are justice-involved, indicating that reducing trauma sequelae such as drug use and PTSS may also reduce recidivism and the community burden associated with incarceration. Yet, evidence-based interventions for PTSS have poor reach in prisons and, to our knowledge, there have been no tests of whether providing therapy for PTSS in prisons reduces post-release drug use, PTSS, or crime. This 5-year R01 proposal will test group-delivered Cognitive Processing Therapy that has been adapted for implementation in criminal justice settings (CPT-CJ) as an intervention for reducing post-incarceration drug use, mental health symptoms, and drug-related crime. We will use a patient-randomized Hybrid type II implementation-effectiveness design in which CPT-CJ is compared to individual self-help via workbook (i.e., bibliotherapy, an enhanced treatment-as-usual comparison condition) and concurrently evaluate implementation facilitation as a strategy to support CPT-CJ uptake in prisons. We will also collect data on the costs and cost offsets of both the CPT-CJ and facilitation. Participants in the effectiveness portion of the trial (N = 640; 50% female) will be enrolled from 10 prisons in 5 states, ensuring variability in population and setting characteristics. The study builds on a NIDA K23 to the PI, which found strong preliminary evidence that CPT was acceptable, feasible, and effective when delivered in prison by bachelor’s-level addiction counselors who were supported by an external facilitator. Importantly, our study vision aligns with NIDA’s Strategic Plan, as we aim to both “develop and test novel strategies for preventing drug use, SUDS, and their consequences” (Goal 2.1) and “support research to scale up the application of evidence-based interventions for SUDs, including in justice settings” (Goal 4.3). Indeed, this study will be the first fully powered randomized trial of treatment for PTSS in prisons as a method for reducing drug addiction. Together, our work will provide foundational information on PTSS as a novel intervention target for reducing post-incarceration drug use and will gather the implementation and cost data needed to inform rapid scale-up if effective.

NIH Research Projects · FY 2025 · 2024-09

Project summary/abstract: Our research focuses on identifying cellular mechanisms and therapeutic targets for retinopathies caused by ischemia or trauma including diabetic retinopathy, retinal artery or vein occlusion and traumatic optic neuropathy. A shared pathogenic event of these diseases is the myeloid cell response to retinal injury. In this project, we will study ‘efferocytosis’, which refers to the process by which myeloid cells (macrophages/microglia) clear dead cells by ‘eating’ them. In pathological conditions including stroke, atherosclerosis, and cancer, efferocytosis is thought to promote resolution of inflammation by clearance of dying cells; however, its role in retinopathy is poorly understood. We hypothesize that impaired timely clearance of dead cells in the injured retina contributes to progressive neurovascular damage. Our preliminary data show strong upregulation of the enzyme histone deacetylase 3 (HDAC3) in retinal myeloid cells after injury. Deleting HDAC3 from macrophages boosts their efferocytic capacity. Unbiased RNA-seq screening showed upregulation of the pro-efferocytic secreted protein, CD5 Molecule Like (CD5L) in stimulated macrophages that lack HDAC3. We also observed that the ‘don’t eat me’ signal cluster of differentiation 47 (CD47), which impairs efferocytosis of dead cells, is upregulated in the injured retina and this was ameliorated with myeloid HDAC3 deletion. CD47 impairs efferocytosis by binding to signal regulatory protein α (SIRPα) on myeloid cells. We plan to induce retinal injury by ischemia or trauma, and then evaluate the impact on retinal outcome of two potential therapeutic strategies that enhance efferocytosis: deleting HDAC3 in myeloid cells, and neutralizing CD47 or its ligand SIRPα with antibodies. Our central hypothesis is that: Upregulation of HDAC3 in myeloid cells after retinal injury increases expression of the “don’t eat me” signal CD47 on apoptotic cells and concurrently downregulates the pro- efferocytotic molecule CD5L, contributing to defective efferocytosis and worsened retinal outcomes. This hypothesis will be tested by three related yet independent specific aims: Aim 1 will determine whether myeloid HDAC3 signals through tumor necrosis factor α (TNF-α) to upregulate CD47 on apoptotic cells and inhibit efferocytosis in the injured retina. Aim 2 will determine whether myeloid HDAC3 deletion enhances efferocytosis and retinal injury resolution by upregulating CD5L. Aim 3 will assess whether enhancing efferocytosis by disrupting the ‘don’t eat me’ CD47-SIRPα axis promotes resolution of retinal injury. We will employ novel methods to test our hypothesis including high-resolution microscopy, flow cytometry, monitoring of diverse in vivo retinal neurovascular endpoints, imaging using optical coherence tomography, and assessment of retina function by electroretinography. Our proposal is designed to provide new insights leading to the development of new treatments for ischemic and traumatic retinal injury and it aligns with the NEI mission to support research studying visual disorders and their mechanisms.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Maternal mortality rates are increasing in the United States and hypertensive disorders of pregnancy are a leading cause of maternal death. Women with hypertensive disorders of pregnancy have increased risk of adverse fetal and maternal outcomes, developing chronic hypertension, and developing earlier onset of cardiometabolic risk factors and cardiovascular events after pregnancy. Arkansas’ rurality and health disparities underscore the need for innovative strategies to address growing adverse health outcomes in the population. The overall mission of the Arkansas Center for Women’s Health (ACWH) at the University of Arkansas for Medical Sciences is to develop research and educational programs to enhance public health practice to reduce risk for hypertension, hypertensive disorders of pregnancy and maternal mortality, among the state’s highest risk women who have limited resources and health care access, with a long-term goal of eliminating chronic disease health disparities. Through its networks and partnerships, the ACWH will conduct a scalability assessment to rigorously assess the implementation outcomes (e.g., adoption, reach, acceptability, and facilitators), cost, and scalability. With Arkansas’ current context of leadership in healthcare reform and healthcare delivery, implementation of a statewide initiative (Healthy Active Arkansas), and a multidisciplinary team of investigators with more than 30 years of experience in community-engaged, applied public health research and expertise in women’s health, the ACWH is well-positioned to tackle this critically important public health issue among women in rural areas of the state.

NIH Research Projects · FY 2025 · 2024-09

Kidney-resident memory CD8+ T cells promote hypertension and memorize salt sensitivity. Abstract: An estimated 116 million adult Americans suffer from hypertension, a leading contributor to cardiovascular mortality in the United States. Despite the development of many classes of antihypertensive drugs, only 23.9 million patients obtain effective blood pressure control, implying gaps in our understanding of the complex pathogenesis of hypertension. In recent years, immune cells, specifically CD8+ T cells (CD8Ts), have been implicated in the onset of hypertension. Studies from our group tied CD8Ts directly to aberrant sodium retention within the kidney, beginning with the activation of CD8Ts via purinergic receptor P2X7-mediated calcium influx, resulting in increased production of IFNγ, which enhances the direct interaction between CD8Ts and distal renal tubules, leading to sodium chloride cotransporter (NCC)-mediated excessive salt retention, thereby promoting hypertension. An intriguing discovery in our study is that although antihypertensive treatment temporarily lowered BP in hypertensive animals, it failed to disrupt T cell residency in the kidneys, and salt-sensitive hypertension resurges after ceasing treatment. These findings raise the possibility that a continued adaptive immune response to an initial BP elevation may contribute to the ‘memory of salt sensitivity’ within the kidneys. We hypothesize that the P2X7-TGFβ axis establishes long-term residency of kidney CD8Trms, which exacerbates salt retention and instills “salt memory” of hypertension. First, we aim to determine the critical role of TGFβ signaling in forming kidney-CD8Trms and their impact on the progression of salt- sensitive hypertension. Next, we will define the impact of kidney-CD8Trms on ‘salt memory’ in the kidney and the subsequent recurrence of salt-sensitive hypertension. By establishing long-term CD8T residence through kidney Trms, this study will provide a mechanism behind the longevity of hypertension and identify a resident immune cell population in the kidney that confers the ‘salt memory’ contributing to the progression and recurrence of hypertension.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Breast cancer is the most diagnosed cancer in the world with the largest survivorship group. The rise of breast cancer survivors (BCS) living longer, healthier lives merits attention to important areas of cancer survivorship such as employment and physical activity. Employment is associated with quality of life, health insurance, treatment adherence and recovery, and financial security. Cancer-related fatigue and cognitive impairment are two frequent obstacles to working, but current literature shows they are alleviated by physical activity (PA). Limited studies have shown disproportionate adverse health outcomes among Black BCS living in the rural South and much is still unknown. Common drivers behind these adverse outcomes experienced by Black BCS include accessibility to exercise opportunities and lived experiences. Therefore, we will: (1) identify differences in employment status, (2) determine the relationships between PA and work outcomes, and the role of fatigue, cognition, accessibility to exercise opportunities, and lived experiences, using structural equation modeling and mediation analysis, and (3) use semi-structured interviews to better understand the PA-work life relationship and identify obstacles and facilitators of desired program elements to apply to multilevel tailored intervention design. The proposed research strategy will build the foundation for tailored, comprehensive intervention design to reduce cancer health and employment differences and help ALL cancer survivors live longer, healthier lives. The proposed training period will allow applied learning and formal training in (1) cancer research, (2) mediation analysis with structural equation modeling, and (3) qualitative research for intervention design. These training opportunities will enhance my research capability to establish independence, leading to significant contributions in the fight towards eliminating health differences for cancer survivors. I have assembled an exceptional mentoring team, in an outstanding training environment to achieve my training goals and career transition. This K01 will equip me with the skills to become a leader in cancer differences and behavioral health.

NIH Research Projects · FY 2025 · 2024-09

The anterior pituitary functions as the endocrine core of the organism, regulating hormonal synthesis and secretion to effect adaption to changing metabolic and reproductive needs. The distinct pituitary hormone- producing cell populations are known to possess remarkable plasticity of fate. However, the underlying mechanisms that mediate pituitary cell plasticity in response to changing hormonal demands have not been established, which is a major gap in knowledge. While it is recognized that stem cell differentiation and cellular homeostasis are directed and regulated at multiple levels including gene transcription, signaling, epigenetic and chromatin remodeling, these processes appear to be particularly sensitive to mechanisms that impinge upon the control of mRNA translation. Identification of the molecular mediators that regulate cellular plasticity within pituitary hormone-producing cell lineages would present a valuable resource for therapeutic intervention to promote tissue regeneration or to oppose cancer progression. The mRNA translation control protein, Musashi, plays a critical role in mediating physiological and pathological stem cell function in many tissue types and has been shown to be broadly expressed in the adult anterior pituitary in non-stem/progenitor cell populations to modulate hormone expression. This study will focus on mechanisms by which Musashi differentially regulates distinct target mRNAs, its mode of action and contribution to cell fate plasticity and its relevance to adult human pituitary function. The long-term goal of this project is to determine the physiological mechanisms that control pituitary cell fate determination. Specifically, the overall objective of this application is to assess the role of regulated mRNA translation in general, and the Musashi protein specifically, in mediating adaptive changes of cell fate in the pituitary. We will also perform an unbiased assessment on the role of transcriptional and post- transcriptional control during hypothyroidism and lactation, known drivers of pituitary cell lineage plasticity. The central hypothesis is that post transcriptional mechanisms are critical for the plasticity of hormone producing cell lineages in the adult pituitary during adaptive responses to organismal stress. We expect to fully inform the field about the molecular mechanisms underpinning Musashi target mRNA-specific translational control. We will determine the relevance of Musashi-dependent control of human pituitary mRNAs under physiological and pathological conditions and will elucidate in an unbiased manner the molecular mechanisms controlling pituitary cell plasticity in response to changing hormonal demands. Wherever possible, sex will be considered a variable. Findings from this study will positively impact development of gender-specific therapeutic treatments for combined pituitary hormone deficiency and pituitary tissue repair.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The purpose of this K01 Mentored Research Scientist Career Development award is to support Dr. Margaret Gorvine's current trajectory toward independent investigator status—via achieving the study aims and training goals to extend innovative research in the arenas of implementation science, integrative health, and criminal justice. Dr. Gorvine is an Instructor/ Postdoctoral Fellow in the Department of Health Behavior and Health Education in the College of Public Health, University of Arkansas for Medical Sciences (UAMS). Jail incarceration rates in the United States have tripled since the 1980s. More than 3,100 jails nationwide serviced 10.8 million jail admissions in 2018. Jail correctional officers (COs) are responsible for maintaining security and supervising detainees in facilities that are often low-resourced (e.g. funding, staffing shortages), are overcrowded, and replete with health risk exposures (e.g. Covid-19). Therefore, COs experience high levels of stress due to violence and low autonomy. The high risk of adverse mental health outcomes and health disparities among COs necessitates addressing CO stress management in jail settings. The study will use an evidence-based quality improvement (EBQI) method to achieve the first 2 aims including: 1) identifying barriers and facilitators to implementing a stress management intervention for correctional officers in a jail setting through formative evaluation (e.g. in-depth qualitative interviews with key jail stakeholders); 2) developing an implementation strategy package and intervention modifications. Thirdly, conduct a pilot hybrid type II effectiveness-implementation trial of the stress management intervention for correctional officers at the jail, measuring implementation outcomes of acceptability, appropriateness, feasibility, and fidelity of the intervention and the implementation strategy package. The training goals of the K01 Mentored Research Scientist Career Development award include: 1) developing expertise in implementation research methods related to intervention delivery in jails; 2) enhance skills in community-engaged research with partners within criminal justice settings; 3) learning how to build community-engaged partnerships in the jail; 4) developing expertise in evidence-based mind-body intervention delivery and research; and 5) Increase biostatistics expertise to be fully informed for in-depth collaboration with biostatisticians.

NIH Research Projects · FY 2026 · 2024-09

PROJECT SUMMARY Diabetes Self-Management Education and Support (DSMES) addresses the clinical, psychological, and behavioral aspects of care needed to successfully self-manage diabetes. Despite the proven value of the DSMES on patient outcomes, it remains underutilized. Only a small fraction of patients receive DSMES within a year of being diagnosed with diabetes: 5% of those with Medicare and 6.8% of those with private insurance. While the causes of low enrollment in DSMES are systemic and patient- and provider-based, the role of the system-level factors, especially collaboration among providers, in DSMES utilization is not fully understood. Since providers have a significant impact on whether patients attend DSMES, it is essential to understand the practice patterns of providers regarding DSMES utilization. This K25 fills this gap in knowledge by using 2 theoretical concepts—diffusion of innovations and social network analysis—to determine whether patient-sharing relationships among the providers who care for patients with T2D is associated with DSMES utilization. Aim 1 leverages health insurance claims for Medicare, Medicare Advantage and privately insured patients to examine DSMES participation in Arkansas at the patient level. Aim 2 will construct a multilevel network model comprising patients, providers, and a patient-sharing network of T2D providers. The network, created using health insurance claims data, connects pairs of providers if they both deliver care to the same patient. A multilevel statistical method, auto-logistics actor attribute models will examine whether the social network structure of providers caring for T2D patients is associated with DSMES utilization. This project will utilize membership, medical claims, and provider data for Medicare and Medicare Advantage enrollees (65 years old and above) and privately insured enrollees (aged 18 and above) from 2013–2020 from the Arkansas All-Payer Claims Database. The principles of innovation diffusion suggest that the rate of diffusion of the adoption depends on influential members of the social system (i.e., opinion leaders) adopting an innovation and their decision being communicated to other members, who then follow their lead. Aim 3 examines the feasibility of identifying opinion leaders through the use of self-designating survey instruments, providing a foundation that can potentially be utilized to enhance DSMES uptake among providers. These aims will serve as a system-science methodological approach to understand DSMES utilization given patient and provider characteristics and patient-sharing relationship among providers. Understanding the network structure of T2D providers will facilitate the identification of network intervention strategies to promote DSMES referral behavior among providers. This K25 will provide the investigator with foundational training in network science and diffusion of innovations and is aligned with her long-term career goal of becoming a productive independent researcher in designing network interventions to improve diabetes care.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Access to healthcare is a persistent public policy concern, particularly for Marshallese Compact of Free Association (COFA) migrants in the United States. This research addresses the impact of Medicaid policy changes, prompted by the COVID-19 pandemic, on healthcare access for Marshallese COFA migrants residing in Northwest Arkansas, where the largest settlement of this population (~15,000) exists. Despite their eligibility for Medicaid under the 1986 RMI-US COFA agreement, subsequent legislative changes, notably the 1996 Personal Responsibility and Work Opportunity Reconciliation Act (PRWORA), resulted in a significant portion (approximately 50%) of the Marshallese population being devoid of healthcare coverage. Even after the enactment of the Affordable Care Act and Medicaid expansion in 2014, which did not reinstate Medicaid coverage for COFA migrants, these disparities persisted. The Consolidated Appropriations Act of December 2020 reinstated Medicaid access after a 25-year gap. However, the effectiveness of this policy change in ensuring enrollment and optimizing healthcare service utilization remains unknown. The overall objective of this study is to determine the effect of Medicaid policy changes enacted in response to the COVID-19 pandemic for Marshallese COFA migrants. We will leverage our long-standing community-engaged relationship with the Marshallese community in Arkansas to collect primary data to generate important data on the barriers and facilitators to Medicaid enrollment for Marshallese COFA migrants, and to inform effective community-based interventions. Our Specific Aims are: Aim 1: Examine the Medicaid enrollment process and identify barriers and facilitators to healthcare for Marshallese newly eligible under Medicaid policy changes. We will conduct four focus groups with 50 Marshallese to qualitatively explore barriers and facilitators to Medicaid enrollment and accessing healthcare services. Aim 2: Conduct a needs assessment to assess barriers and facilitators to inform community-based interventions to improve Medicaid enrollment and use of primary and preventative healthcare services. We will develop and administer a survey to 750 Marshallese to assess the need for community-based interventions to increase enrollment and the use of healthcare services. The survey will focus on barriers and facilitators to Medicaid enrollment and primary/preventative healthcare utilization, and use the themes that emerge in Aim 1 to direct the selection of additional existing validated survey measures. The study's findings will contribute essential information for the development of community-based interventions tailored to enhance Medicaid enrollment and healthcare service utilization among COFA migrants and other underserved populations. The established rapport with the Marshallese community uniquely positions us to implement and evaluate these interventions, fostering equitable healthcare delivery.

NIH Research Projects · FY 2025 · 2024-08

Cardiovascular disease (CVD) is a rapidly growing public health concern for breast cancer (BC) survivors. This is due, in part, to cardiovascular (CV) toxicities from common cancer therapies that are associated with CVD. CV toxicities are more common in certain patient populations, including those from communities with economic challenges, those with limited insurance coverage, and those residing in rural areas or neighborhoods with limited resources. Yet, the complex role of demographic, economic, and geographic factors in influencing CV toxicity risk among BC survivors remains unknown. Few studies have examined how such factors interact to affect CV toxicity outcomes. Given the known relationship between demographic, economic, and geographic factors and cardiometabolic conditions, variation in these contexts may contribute to CV toxicities among BC survivors through comorbid cardiometabolic dysfunction. Therefore, to improve the CV health of BC survivors, it is critical to examine CV toxicity risk in the context of cardiometabolic dysfunction. To address this issue, the following specific aims will be completed: Identify the extent of differences in incident CV toxicity among BC survivors in Arkansas across key demographic, economic, and geographic factors. Develop a predictive algorithm for risk stratification in BC survivors at high risk for CV toxicity using machine learning approaches that incorporate demographic, economic, and geographic factors with traditional clinical characteristics. Data collected from 2013–2019 in the Arkansas All-Payer Claims Database (APCD) linked to the Cancer Registry, as well as clinical and refined demographic, economic, and geographic information from the electronic health records system at the University of Arkansas for Medical Sciences, will be utilized in this study. A longitudinal analysis for the development of CV toxicities in a cohort of BC survivors (stage I–III at diagnosis), with passive follow-up in the claims data through 2023, will be conducted. Machine-learning methods will be used to develop an algorithm that predicts CV toxicities among BC survivors based on demographic, economic, geographic, and other clinical factors. This K01 will: 1) provide training in contextual influences on health and health outcomes research; 2) promote research skills using large-scale, longitudinal administrative healthcare data; 3) develop competence in advanced analytic methods; and 4) increase understanding of BC survivorship and provide content expertise in cardio-oncology research. This study responds to the NHLBI’s compelling question (5.CQ.10) to reduce cardiac morbidity and mortality in cancer survivors. By identifying factors that contribute to differences in CVD outcomes among BC survivors and using them to predict CV toxicity, this research can inform targeted interventions (e.g., multidimensional intervention programs tailored to patients’ clinical profiles and community and environmental factors) to improve the CV health of this population. Modified

NIH Research Projects · FY 2025 · 2024-08

Project Summary/Abstract Our current vaccine development strategies against tuberculosis (TB) focus on the induction of adaptive immune responses, but that may not be sufficient to mount effective immunity. Mycobacterium tuberculosis (Mtb) resides in heterogenous lung macrophages with various levels of permissiveness in the presence of the same immune pressure. Among them, lung alveolar macrophages (AMs) are highly permissive cells, which facilitate rapid growth of Mtb and promote disease dissemination at the early stage of infection. However, the underlying mechanism that determines this permissive nature of AMs during Mtb infection remains elusive. Identifying determinants regulating the response of AMs to Mtb is thus essential for the development of new therapeutics and novel vaccine platforms. While AMs are derived from embryonic precursors in naïve mice, they can be replaced by bone marrow-derived monocytes during infection. It is unknown whether the origin of AMs change and how the altered ontogeny impacts the permissiveness and functions of AMs during Mtb infection. In addition to ontogeny, our previous work has demonstrated that lung macrophage metabolism plays a critical role in promoting or controlling the progression of TB. AMs consume fatty acids and engage in fatty acid oxidation (FAO), a pathway that has been associated with the optimal growth of Mtb. Given that both ontogeny and metabolism play pivotal roles in modulating how macrophages respond to Mtb infection, we hypothesize that ontogeny and metabolism are intrinsic features that regulate the permissiveness of AMs during Mtb infection. We further propose that harnessing these two features will allow the reprogramming of AMs for better control of Mtb at the early stage of infection. We will test this hypothesis with three aims: Aim 1. Determine how ontogeny contributes to the response of AMs during Mtb infection. Aim 2. Delineate how glycolysis and FAO differentially regulate the permissiveness of AMs during Mtb infection. Aim 3. Reprogramming AMs by leveraging their ontogeny and metabolism against Mtb infection. To address these aims, we will exploit multi-disciplinary approaches, including immunology, metabolism, genomics, microbiology, novel mouse models and human primary AMs to directly probe how ontogeny and major metabolic pathways regulate the permissiveness of AMs during Mtb infection. Knowledge gained from these studies is expected to provide a better understanding of the mechanism regulating AM response to Mtb, which opens the gate for reprogramming AMs for enhanced control of Mtb at the early stage of infection as well as aiding in development of host-directed therapies against TB.

NIH Research Projects · FY 2026 · 2024-07

Substance use disorders (SUDs) such as addiction to opioids, methamphetamines and alcohol are a significant burden in the US, affecting almost 50 million individuals annually. Community specialty SUD treatment programs (“SUD programs”) are a key type of SUD providers and while effective treatments for SUD exist, significant issues in the organization and delivery of SUD programs (e.g., burnout, turnover) undermine the delivery of high-quality services. Clinical supervisors are centrally positioned to support SUD counselors (frontline clinical providers) and ensure high service quality. For clinical supervisors to effectively support counselors, they need evidence-based supervision strategies. Currently, supervisors in community SUD programs receive very little training, support, and direction for supervision, and thus their supervision practices are highly variable, raising concern about the effectiveness of clinical supervision as currently provided in these programs. Evidence-based supervision strategies can help fill the gap, and evidence from child welfare settings shows they improve leadership, climate, and client outcomes. Based on our preliminary formative work with SUD providers in Arkansas, a reinforcement-based supervision strategy developed for counselors was deemed acceptable and feasible in SUD programs, and had high perceived potential to improve supervision quality, counselor well-being and performance, and client outcomes. Participants thought the structure and content of the strategy were a good fit for SUD settings. However, for a supervision strategy to be supportive of the work they do, it needs to be developed to reflect the language, case examples, and organizational factors relevant to the SUD settings. The goals of our study are to iteratively develop and refine a supervision strategy for SUD settings, and to pilot it in residential treatment programs using quality improvement and implementation science tools and approaches. Aim 1 involves leveraging previous experience developing supervision strategies and partnering with SUD providers to develop and refine the supervision strategy for SUD. Using the Evidence-Based Quality Improvement (EBQI) process, we will engage SUD partners in a series of collaborative meetings to review and discuss the supervision strategy and related study materials, and to make key decisions. The output of this work will be a refined and optimized SUD supervision strategy. Aim 2 involves conducting two pilot cycles with supervisors and counselors in a sample of SUD residential treatment programs to assess the feasibility and acceptability of the supervision strategy, examine its impact on key organizational, counselor, and client outcomes, and to document barriers and facilitators for its implementation and sustained use in routine practice. This study will provide key information to inform planning and design of a future fully powered study to assess the effectiveness of the new supervision strategy in a large sample of SUD programs.

NIH Research Projects · FY 2026 · 2024-07

SUMMARY The human genome preserves a strict regulation of gene expression to maintain physiological integrity. RNA processing plays a key central role in this regulation and has drawn significant attention in recent times due to its implications for a wide breadth of diseases. Alternative splicing (AS) can encode different protein isoforms from the same gene to support rapidly changing biological processes. AS often generates erroneous mRNAs with a premature translation termination codon, which are selectively degraded by nonsense-mediated mRNA decay (NMD) to safeguard the generation of defective proteins. This coordinated action is termed as AS-NMD. In humans, ~95% of genes undergo AS, among which ~33% are targets of AS-NMD, suggesting that it is not merely noise. Substantial evidence demonstrated that AS-NMD evolved as a powerful mechanism to regulate gene expression in normal physiology and is often fine-tuned in a developmental stage-specific or tissue-specific manner. Growing evidence suggests that AS-NMD is frequently dysregulated (induced or suppressed) and is the root of many human maladies. Why certain genes in certain tissues or diseases are susceptible to differential or aberrant AS-NMD regulation remains an unresolved mystery. Therefore, elucidating the regulation of AS- NMD is crucial to understanding this vital mechanism in normal physiology and diseases, which will redefine therapeutic strategy and significantly impact clinical outcomes. We recently showed that AS-NMD is induced in splicing factor mutated hematopoietic defects. In contrast, AS-NMD is suppressed in splicing factor overexpressed diseases (such as cardiac and liver dysfunction, brain and developmental abnormalities, diabetes, lupus, and neoplasia). These provide excellent model systems to systematically identify positive and negative effectors and underlying mechanisms of differential AS-NMD regulation. We will characterize the AS- NMD regulation in normal cells and its misregulation (induction and suppression) in disease-specific model cells. We will define cis-acting RNA codes that regulate AS-NMD, characterize trans-acting protein networks and their dynamic interactions with RNA in the AS-NMD pathway, and delineate tissue-specific or disease-specific mechanisms. Finally, we will develop tools to manipulate AS-NMD errors using oligonucleotide-based pharmacology as a therapeutic approach. Completion of these studies will connect the missing puzzles in the AS-NMD regulation, answer how an evolutionarily conserved surveillance mechanism can be exploited to turn on pathological maladies, and develop a commonly approached innovative molecular technology to correct AS- NMD errors applicable to a range of human diseases.

NIH Research Projects · FY 2025 · 2024-07

Clinical prediction models have increasingly been developed due to advances in big data, computational speed, and statistical techniques. Such models are also growing for pregnancy-relevant outcomes such as maternal mortality, severe maternal morbidity, diabetes/hypertension, and delivery types of stillbirths or ectopic pregnancies. However, these models largely lack external validation and also suffer from heterogeneous performance and poor reporting. More importantly, evidence is lacking on these prediction models’ performance across groups such as younger/older pregnant women, privately/publicly insured, and those residing in rural/urban areas. Research on documentation of differential model performance, their plausible reasons, and the methods to correct them is lacking, particularly in pregnancy, where there is high variability in health outcomes. This administrative supplement to 1UM1TR004909 proposes to investigate performance of two types of risk scores across two maternal age groups (younger/older), two insured categories (public/private), and two rural/urban categories (rural/urban residence). The following two aims will be pursued: 1) estimate model performance (true positive/false positive rates) of the in-built Epic risk scores for diabetes-related hospitalization or emergency department visit across maternal age, insurance status, and rural/urban groups of pregnant women; and 2) estimate algorithm performance measures of a published prediction model for obstetric comorbidity risk score across maternal age, insurance status, and rural/urban groups of pregnant women. These studies will be conducted using a national database of electronic medical records from Epic, known as the Epic Cosmos database, from 2019 through 2024. The database is a result of community collaboration between health systems using Epic EMR system and encompasses more than 289 million individuals from 1,626 hospitals and 37,700 clinics. In addition to utilizing previously developed model performance measures that assess true/false positive rates and model calibration, this project will also introduce novel approaches to probe for differential performance of risk scores, such as covariate-adjusted true/false positive rates, adjustment for treatment drop-in, and the application of gap-closing estimand framework. The project will also adapt two in-processing methods (a regularization technique and constrained learning for misclassification) to post-processing setting, contributing to methodological advances in algorithm performance. As these risk scores could drive preventive and treatment decisions, poorly calibrated risk scores could perpetuate variability in health outcomes. Examining these risk scores for poor performance, inspecting the likely causes, and correcting them would optimize aligning clinical decisions with the true risk, thereby improving health outcomes among all pregnant women.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY/ABSTRACT Training the next generation of translational scientists to transform discoveries into benefits for clinical care will require a strong research foundation adjoined to pioneering training in innovation and entrepreneurship. Here, we propose a new T32 Postdoctoral Training Program, the Health Sciences Innovation and Entrepreneurship (HSIE) Training Program, which is designed as an innovative learning solution to speed the process of turning observations in the laboratory into clinical interventions to improve the health of individuals and the public. The two-year, multi-disciplinary HSIE Training Program will offer traditional department-based research training and deep disciplinary knowledge to trainees in the Colleges of Medicine, Nursing, Pharmacy and Public Health at the University of Arkansas for Medical Sciences. Basic skills of entrepreneurship also will be taught to postdoctoral trainees, who exhibit a passion for transforming health science discoveries into new diagnostics, medications, medical devices, and telemedicine products. Seventy- nine of the most innovative clinical and translational scientists across our campus will serve on coaching teams with primary research mentors and entrepreneurship advisors from the Arkansas business community to formulate individual development plans with trainees that will harmonize with their career goals. Trainees will earn a 15-credit Graduate Certificate in Health Science Innovation and Entrepreneurship that will provide individualized experiences tailored to their career interests including industry internships, shadowing of entrepreneurs, and other opportunities to cross boundaries. The HSIE Training Program will sponsor a 2-credit cross-CTSA seminar series, “Health Science Entrepreneurs: Innovators of Health Care”, which will offer postdocs the opportunity to interact with national entrepreneurs, learn about varied career paths within the translational science spectrum, and increase entrepreneurial activity across CTSA hubs by heightening awareness of the steps required to translate new technologies and concepts through commercialization into improved health care. Three 3-credit courses will be offered to trainees by the nationally ranked Graduate Entrepreneurship Program in the Walton College of Business at the University of Arkansas flagship campus in Fayetteville. After learning business principles, a Capstone Project is a gateway for teams of interdisciplinary trainees to gain skills in communication, systems thinking, and process innovation while they develop a business plan for translating a research discovery into a health care product or service. The HSIE Training Program is an exciting opportunity that directly addresses the NRSA program objective of the National Center for Advancing Translational Scientists (NCATS) to equip trainees with the knowledge, skills and abilities to advance diagnostics, therapeutics, clinical interventions and behavioral modifications that improve health.

NIH Research Projects · FY 2025 · 2024-07

The goal of the UAMS K12 program is to build a cohort of successful translational scientists that enable the mission of the UAMS Translational Research Institute (TRI) to “develop and test translational science innovations that will drive real-world solutions to enhance the health of all populations. This proposed program emphasizes gaining experience and expertise in translational science through interdisciplinary training opportunities, mentored research projects, individualized training, and education of mentors. The program aims to develop scholars who will be productive, funded and generate meaningful and impactful results to improve the health of all Arkansans. Mentored research projects will be able to leverage our hub’s unique resources in implementation science, stakeholder engagement, data science and telehealth. The program plan includes training in the seven foundational knowledge, skills, and abilities of a translational scientist: domain expert, boundary crosser, team player, process innovator, skilled communicator, systems thinker and rigorous researcher. The K12 program includes a robust plan for evaluation to assess and improve its effectiveness in producing translational scientists with careers that will improve the health of all Arkansans. Our evaluation will be enhanced by participating in ongoing cross-CTSA efforts to develop competency-based assessment tools. The K12 program includes a robust and open plan for scholar recruitment and retention. The proposed K12 builds on the success of our current KL2 program which has produced scholars who are creating solutions for multiple health needs in Arkansas. Beyond UAMS, strong collaboration with the Central Arkansas Veterans Healthcare System and Arkansas Children's Hospital/Arkansas Children’s Research Institute (ACH/ACRI) allows us to train numerous, qualified applicants. In summary, our proposed K12 program will leverage the unique resources available through TRI to produce a successful cohort of investigators that will improve the health of all Arkansans.

NIH Research Projects · FY 2026 · 2024-07

PROJECT SUMMARY Gammaherpesviruses (GHVs) are DNA tumor viruses that establish lifelong, chronic infections of host lymphocytes. The expression of viral gene products that manipulate host cell physiology and thwart antiviral immune responses places the infected host at risk for numerous cancers. For individuals with AIDS, infection by Kaposi sarcoma-associated herpesvirus (KSHV) is a major cause of morbidity and mortality. However, KSHV does not infect mice, which complicates attempts to define mechanisms by which KSHV establishes long-term infections and disease. To overcome this barrier, we have used a chimeric virus approach in which KSHV genes are transferred into the closely related virus, murine gammaherpesvirus 68 (MHV68), which is a natural rodent pathogen that readily infects laboratory mice. The KSHV latency-associated nuclear antigen (kLANA) is an oncogene that modulates viral and host-cell transcription and is required for maintaining latent viral episomes as infected cells divide. We used this MHV68-KSHV chimeric virus approach to evaluate kLANA functions during productive viral replication, latency establishment, and maintenance. Our published work demonstrated that kLANA was sufficient to replace MHV68 LANA (mLANA) for viral latency in mice. Remarkably, kLANA, but not mLANA, suppressed MHV68 lytic replication by inhibiting the activity of the promoter for lytic transactivator RTA, suggesting that KSHV-specific LANA functions are also active in the chimeric MHV68. In new preliminary data we demonstrate that suppressed lytic replication by kLANA correlates with a drastic reduction in adaptive immunity to chimeric virus infection, which supports the guiding hypothesis for this proposal that kLANA- mediated inhibition of viral replication and reactivation is immune evasive. Experiments in Aim 1 will define the scope of immune avoidance by MHV68-KSHV chimeric virus and determine the impact of reduced immunity on outcomes of infection. We will simultaneously identify kLANA’s role as a transcription regulator in the process. Experiments in Aim 2 will leverage reduced replication and immune evasion to define how kLANA functions impact viral pathogenesis during immune impairment, especially when CD4 T cells are depleted as in non-drug- controlled HIV infection. We have also developed a combinatorial MHV68-KSHV chimeric virus that encodes multiple KSHV oncogenic latency genes for future development of chimeric virus models. Through the use of innovative and rigorously established small-animal models of infection and disease, we will better define mechanisms through which KSHV LANA contributes to latency and pathogenesis. This work will increase the experimental tractability and relevance of a preclinical model and may foster the development of therapies that target LANA and other viral proteins to treat or prevent KSHV-related cancers as a result.

NIH Research Projects · FY 2024 · 2024-06

ABSTRACT Replacing the Illumina NovaSeq 6000 Next Generation Sequencing (NGS) system with the new Illumina NovaSeq X Plus NGS system will improve services provided by the UAMS Genomics Core Facility to all users by: i) reducing the cost of sequencing by up to ~80% compared to the current system (NovaSeq 6000), ii) accommodating advanced chemistries allowing for NGS read lengths up to 7KB and thus improving the specificity of NGS findings, and iii) allowing for the storage of NGS reagents at room temperature versus refrigeration. The NovaSeq X Plus system will reside in the University of Arkansas for Medical Sciences (UAMS) Genomics Core Facility, which is an important resource for faculty and students in Arkansas who are engaged in research that impacts human health. The mission of the UAMS Genomics Core Facility is to provide investigators with convenient access, at affordable prices, to the latest technologies for advanced molecular profiling of biological samples. Importantly, this includes NGS-based studies, experiments, and assays. Services are provided to investigators at UAMS, other universities in Arkansas including faculty and students from undergraduate institutions in the Arkansas INBRE network, and importantly NIH Institutional Development Award (IDeA) centers in Arkansas. Three funded IDeA center grants on the UAMS campus that will be a part of the major users group, which will occupy the bulk of time on this new instrument are: i) the Center for Translational Pediatric Research (P20GM121293), ii) the Center for Musculoskeletal Disease Research (P20GM125503) and, iii) the Center for Studies of Host Response to Cancer Therapy (P20GM109005). Additional members of the major user group will predominately be involved with research activities related to obtaining NCI Cancer Center designation for UAMS. Services provided by the UAMS Genomics Core may be “all inclusive” and consist of consultation and in-person meeting(s) concerning an investigator’s question (hypothesis) along with assistance and guidance for an experimental design. Initial meetings are essential in order to manage new users’ expectations and foster their success. Additional NGS service components include: i) sample preparation with QA/QC validation, ii) running the sample on the NGS instrument and, iii) bioinformatics pipeline processing (data analysis). The UAMS Genomics Core Facility is fully supported and supplemented by the UAMS Rockefeller Cancer Institute and the College of Medicine. State-of-the-art genomic scientific instrumentation is essential to facilitate novel research (eg, advanced liquid biopsy assays) for faculty and students in Arkansas. The goal of obtaining NCI Cancer Center Designation by UAMS will be strengthened by the addition of the NovaSeq X Plus NGS system.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY Bacteria are enveloped in sugary layers that maintain cell shape, protect against osmotic pressure, and resist environmental hazards. In Gram-negative bacteria, the cell envelope surrounds the cytoplasm and includes a cytoplasmic (inner) membrane, a thin peptidoglycan (PG) cell wall, and an outer membrane. The cell envelope is essential and is therefore a prominent target for antibacterials and vaccines. However, bacteria continue to develop new ways to evade these life-saving compounds. Thus, it is imperative that we understand the mechanisms of cell envelope assembly, ultimately to design new modes of interference. One poorly understood aspect of assembly revolves around the essential lipid carrier undecaprenyl phosphate (Und-P). Bacterial surface glycans, including PG and other clinically important polysaccharides, are assembled on and transported across the cytoplasmic membrane by Und-P. While decreasing the pool of Und-P induces cells to grow poorly and die, little to no effort has been applied to understand what effects occur when the pool of Und-P increases. Therefore, we will manipulate pathways that create Und-P to determine how maximizing the pool of Und-P affects Und-P-dependent processes. Similarly, pathways compete for a common pool of Und-P, but no one knows how this is done. Since such information is fundamental to disrupting the relationships among Und-P-utilizing pathways, we will manipulate pathways that use Und-P. Another poorly understood aspect of Und-P metabolism surrounds its utilization. Und-P inhibitors disrupt Und-P-dependent polymer formation, but how cells prioritize pathways when Und-P becomes limiting is not known. To that end, we will characterize Und-P pathways (including a potential new pathway) in Escherichia coli cells disrupted for Und-P metabolism. Finally, we will continue to pursue results from a genetic screen in a mutant defective for Und-P recycling, which has uncovered new and unexpected connections to Und-P metabolism that we propose to characterize in detail. In summary, results from this study will enable us to understand, in greater detail, the mysteries surrounding Und-P utilization and cell envelope assembly. At the same time, the tools and knowledge developed in the course of this work promise to provide signal benefits for those working on the design of antimicrobial therapies.