Univ Of Arkansas For Med Scis

NIH Research Projects · FY 2026 · 2021-08

ABSTRACT The rising public health burden of opioid misuse, coupled with high relapse rates among individuals seeking treatment for opioid use disorder, necessitates novel interventions for improving opioid-related treatment response. Mobile technology such as smartphone-based applications (“apps”) represent one such intervention. Although smartphone apps are effective in reducing cigarette and alcohol use, their efficacy for reducing opioid use has not yet been established. The proposed clinical trial would evaluate the app OPTiMA (“OPiate Treatment Mobile App”) to prevent relapse among patients receiving medication-assisted treatment for opioid use disorder. OPTiMA implements two features shown to be effective for reducing substance use: daily self- monitoring of opiate use coupled with personalized feedback. Aim 1 would accrue 204 participants with 1:1 randomization into two arms (OPTiMA vs. Monitoring only) to evaluate differences in monthly opioid use at six months post-enrollment. Aim 2 would enroll a subset of participants (N=120) into a longitudinal functional neuroimaging (fMRI) study to model the neurocognitive mechanisms underlying individual differences in treatment response. Two putative mechanisms (attentional bias for drug cues and cue-induced craving) promoting abstinence would be studied. Aim 3 would explore the use of location-based geographic ecological momentary assessment (GEMA) for targeted intervention when participants enter self-identified areas of high risk for relapse. Collectively, the proposed aims would (1) evaluate mobile technology applications for reducing opiate use, (2) understand the neurocognitive mechanisms of action to improve upon this and other apps aiming to reduce drug use, and (3) evaluate the role of personalized, contextually-relevant intervention to promote successful treatment outcomes.

NIH Research Projects · FY 2024 · 2021-08

Project Summary Background: The cognitive deficits observed after treatment with chemotherapeutic drugs are a significant clinical problem, with a rapidly increasing impact on the quality of life of millions of Americans. One and a half million people are diagnosed with cancer every year in the US, and more than 60% survive for 20 years or more. Cancer survivors have long reported cognitive dysfunction at various stages of the disease course with associated consequences upon well-being and functional independence. Several studies conducted over the past decade have indicated that cognitive impairment occurs long before cancer treatment begins and even before cancer diagnosis. Despite collective evidence for cognitive problems, far less is known about how tumor biology and cancer treatments can interact to lead to changes in the brain. The present study will use an orthotopic mouse model of breast cancer to delineate the effects chemotherapy on cognitive function. Moreover, we will test whether a novel antioxidant is capable of preventing the development of chemo/tumor- induced cognitive dysfunction. Hypothesis: We hypothesize that oxidative stress induced by chemotherapy treatment leads to changes in neuronal architecture and mitochondrial function impairing cognition which will be rescued by MnBuOE. Furthermore, Nrf2 function is critical for supporting neuronal maintenance after chemotherapy when aberrant ROS production is known to be exacerbated. Specific Aim 1: Determine if pharmacological upregulation of Nrf2 by MnBuOE protects the brain from chemotherapy induced injury. Aim 1.1) We will use a knockout model to determine if Nrf2 contributes to the protective effect of MnBuOE toward AC-T-induced brain injury. Aim 1.2) Determine if impaired Nrf2 expression plays a critical role in the pathogenesis of chemotherapy- induced brain injury. Specific Aim 2: Characterize the behavioral, neuroanatomical and morphological changes due to chemotherapy and the remediating effects of MnBuOE in a syngeneic model. Aim 2.1) Characterize mitochondrial bioenergetic changes in the brain associated with tumor ± chemotherapy and the effects of MnBuOE treatment. Specific Aim 3: Assess the influence of MnBuOE on tumor growth and susceptibility to chemotherapy (AC-T) in a patient derived tumor bearing animal model

NIH Research Projects · FY 2024 · 2021-07

SUMMARY The prevalence of extreme obesity in adults is increasing precipitously and today more than one-third (39.8%) of adults are obese. Furthermore, the obese condition is characterized by responses and hormone levels that encourage the accumulation of more fat. Obese individuals are resistant to the appetite suppressing actions of leptin and to glucose regulation by leptin and they secrete reduced levels of the lipolytic hormone, growth hormone (GH) from anterior pituitary (AP) somatotropes. There are significant gaps in knowledge about mechanisms behind the suppression in GH secretion. In light of the importance of somatotropes as metabolic sensors and the need for their production of GH, there is a critical need to improve our understanding of somatotrope responses to the stress of obesity. Like all AP cells, somatotropes display plasticity as they are remodeled to meet fluctuating hormonal and gender-specific needs of the body. Leptin may directly modulate somatotrope plasticity, although mechanisms are unknown. Furthermore, the impact of leptin is broad in that it impacts AP cell maturation. The long-term goal of this laboratory is to elucidate the mechanisms by which AP cells are regulated in order to respond appropriately to metabolic signals. The specific objectives with the studies described in this application are to determine the mechanisms by which leptin signals somatotropes, including the identification of gene expression changes and remodeling that occurs under conditions of diet induced obesity (DIO). This proposed study will test the central hypothesis that the obese state causes sex- specific somatotrope dysfunction and compromises responses to environmental stresses. A secondary hypothesis is that post-transcriptional regulation plays a key role in facilitating AP remodeling. Aim 1 studies will determine the impact of obesity and recovery to normal weight on somatotrope remodeling and plasticity. Mice will be subject to diet-induced obesity (DIO) under thermoneutral conditions and a second cohort of animals will recover normal weight after DIO. Unbiased and targeted approaches including miRNA sequencing (miRNA-seq), single cell RNA-sequencing (scRNA-seq) and multiplex protein assays will identify signaling pathway mediators and AP cellular response patterns. Aim 2 studies will ascertain the impact of obesity on somatotrope responses to stress. DIO mice will be challenged with hypothermia and responses assessed by miRNA-seq and scRNA-seq. Aim 2 will also test the impact of DIO and environmental stress on mice lacking the translational regulatory protein, Musashi in somatotropes. This study addresses the biological mechanisms regulating energy balance at the level of the AP and will clarify how somatotropes are remodeled to respond to the metabolic stress of obesity in a sex-specific manner. The introduction of targeted and unbiased state-of-the-art technologies presents a unique opportunity for broader mechanistic insights that are critical to identify targets for therapeutic intervention in the obese state.

NIH Research Projects · FY 2025 · 2021-06

Epidemiological and outcomes studies in patients, as well as studies in rodent models, reveal that renal ischemic kidney injury and unilateral obstructive uropathy brings on long-term consequences: hypertension and chronic kidney disease. Major pathophysiological contributors include impaired renal hemodynamics, endothelial dilator dysfunction, and endothelial cell inflammation. Because the renal microcirculation lacks efficient regenerative capacity, acute damage to the microcirculation can lead to long-term changes in renal hemodynamics that predispose patients to hypertension and chronic kidney disease. A class of arachidonic acid metabolites, epoxyeicosatrienoic acids (EETs) increase renal blood flow and improve endothelial cell function. Not known is the contribution of CYP2C epoxygenases, soluble epoxide hydrolase (sEH), and regioisomeric EETs to salt-sensitive hypertension and chronic kidney disease following obstructive uropathy and renal ischemic injury. We hypothesize that decreased endothelial EET levels result in endothelial dysfunction and impaired renal hemodynamics following renal ischemic injury or urinary tract obstruction. The immediate goals of this project are to determine the ability for endothelial EETs to improve endothelial- dependent afferent arteriolar dilation, to decrease endothelial inflammation, and to prevent salt-sensitive hypertension and chronic kidney disease following unilateral ureter obstruction (UUO) or ischemia/reperfusion (I/R) kidney injury. This project will utilize pharmacological as well as global and tissue-specific genetic manipulation of CYP2C, sEH, and EETs. We will obtain our immediate goals by completing three aims. Aim 1 will test the hypothesis that decreased EET levels or EET function contributes to the development of salt- sensitive hypertension and chronic kidney disease following UUO or I/R kidney injury. Aim 2 will test the hypothesis that increasing endothelial EET levels will improve renal microvascular endothelial function following UUO or I/R kidney injury to prevent salt-sensitive hypertension and chronic kidney disease. Aim 3 will test the hypothesis that pharmacological approaches to increase EET levels can prevent the long-term salt-sensitive hypertensive and chronic kidney injury following UUO or I/R kidney injury. Accordingly, our findings promise to advance the field forward by not only enhancing our understanding of the pathophysiological mechanisms whereby UUO or I/R kidney injury leads to chronic kidney disease but also leading to new therapeutic treatments.

NIH Research Projects · FY 2025 · 2021-04

SUMMARY Aging is the most powerful risk factor for Alzheimer’s disease (AD), and it contributes to the odds of type-2 diabetes mellitus (T2D) as well. Aging is also associated with a decline in the brain’s use of glucose, its most important fuel. Astrocytes play a key role in shuttling glucose from the bloodstream to where it is needed by the neuronal units of activity deeper in the brain tissue. We find evidence of a defect in a key glucose transport molecule of astrocytes in AD and in a mouse line genetically modified to reproduce some aspects of AD. This mouse line, overproducing the β-amyloid peptide (Aβ), exhibits dysregulation of circulating glucose, as well as a decline in brain glucose use. These effects are correlated with poor performance in a test of spatial memory. Further mimicking human AD, the mice show these problems in the absence of obesity, hyperglycemia, disruption of appetite, changes in physical activity, pancreatic abnormality, or insulin resistance. Together, these findings inspire the hypothesis that Aβ, the levels of which begin to rise in the aging brain even without frank AD, perturbs the ability of astrocytes to bring peripheral glucose to neurons, where it is needed for the increased neurological activity associated with memory and other functions. This idea will be tested through studies of the status and function of glucose transport proteins in aging mouse and human brains, along with comparisons between normal aging, AD, and T2D. Through genetic modification of mice, we will modulate the levels of the most important astrocytic glucose transporter to determine if it is i) sufficient to bring about interrupted glucose delivery and memory deficits, and ii) necessary for the presentation of these problems in an AD model. These studies thus explore a novel hypothesis about a specific element of energy utilization in the aging brain and its connection to age-related cognitive impairment. As such, the project may provide innovative strategies for therapeutic intervention.

NIH Research Projects · FY 2025 · 2021-04

Project Summary/Abstract Aging is responsible for the majority of fractures in both women and men. The cellular changes in the skeleton of aged mice are similar to those observed in aged humans. In mice, trabecular bone loss is associated with low bone remodeling, while cortical thinning and porosity are associated with high bone remodeling. These findings suggest that different molecular mechanisms underlie the bone loss in these two compartments. Cellular senescence contributes to the functional decline of multiple tissues with age and DNA damage is a major cause of senescence. DNA damage causes senescence via activation of p53 and up-regulation of the cell cycle inhibitor p21 and/or p16. DNA damage also causes accumulation of the transcription factor GATA4, which promotes the senescence associated secretory phenotype (SASP). Systemic clearance of senescent cells delays several age- associated disorders and increases bone mass in old mice. We have shown that the number of osteoprogenitors in murine bone marrow declines with age and that these cells have increased markers of senescence. Cortical osteocytes also exhibit increased markers of senescence in aged mice and this is associated with elevated production of RANKL. Induction of senescence in bone organ cultures by DNA damage is sufficient to increase GATA4 and RANKL production. Moreover, overexpression of GATA4 in vitro is sufficient to increase RANKL and other components of the SASP. Administration of senolytics to old mice attenuates markers of senescence in osteoprogenitors and osteocytes. Notably, mice lacking RANKL in osteocytes are protected from the loss of cortical but not trabecular bone with age. We hypothesize that activation of p53/p21 in osteoprogenitors causes their senescence and thereby decreases osteoblast number and bone formation and that accumulation of senescent osteocytes in cortical, but not trabecular, bone increases RANKL and bone resorption via GATA4 stimulation. In Aim 1 we will determine whether DNA damage in osteoblast lineage cells is sufficient to induce senescence and reduce bone mass. To do this, we will generate mice with oxidative stress- induced senescence in either the entire osteoblast lineage or only in mature osteoblasts and osteocytes. Administration of the senolytic PZ15227 will reveal what components of the phenotype are due to senescence. In Aim 2 we will determine the contribution of the p53/p21 pathway in osteoprogenitors to skeletal aging by aging mice with p53 or p21 loss-of-function. In Aim 3 we will investigate the differential contribution of senescent osteocytes to increased bone resorption in trabecular versus cortical bone with age by aging mice with GATA4 loss-of-function in osteocytes. We will also quantify osteocyte senescence in cortical versus trabecular bone and determine whether senescent osteocytes express higher levels of RANKL. Successful completion of these studies should establish for the first time whether senescence of osteoprogenitors and osteocytes contributes to the loss of bone mass with age, and help clarify different aging mechanisms in cortical versus trabecular bone.

NIH Research Projects · FY 2025 · 2021-03

PROJECT SUMMARY ABSTRACT Long-term allograft function tends to be poor for people who receive kidneys from deceased donors, which comprise 70% of total transplants. A key contributor to these poor outcomes is cold storage (CS) of the organs, which induces injury during preservation. Accordingly, there is an urgent need to understand the mechanisms by which CS activates molecular pathways that induce renal damage in the recipient. Our long-term goal is to identify these CS-related pathways and apply targeted therapies during CS to improve outcomes and decrease transplant-associated mortality. One of the important molecular determinants of CS-induced kidney injury is abnormal protein homeostasis. During stress, heat-shock proteins and the proteasome play a concerted role in maintaining protein homeostasis. Hsp72 is the major stress-inducible homologue of Hsc70, the cognate member of the heat-shock protein 70 family that exhibits housekeeping function in all nucleated cells and is necessary for cell survival. Importantly, Hsc70 and Hsp72 play critical roles by binding damaged proteins and recruiting the proteasome for targeted degradation, preventing the nonspecific aggregation of damaged proteins. In addition to its protective roles, Hsp72 is implicated in the pathogenesis of numerous human diseases by modulating the immune system and inflammation. Using a clinically relevant rat model of renal CS combined with transplantation, we showed that CS decreases proteasome function and impairs protein homeostasis in the transplants. How CS decreases proteasome function in the transplants is not known. We hypothesize that CS- mediated activation of HSF1 and p38MAPK mediate the upregulation of Hsp72 and phosphorylation of Rpt6, leading to proteasome dysfunction and injury after transplantation. We have preliminary data supporting this hypothesis. We have also established animal models of CS/transplantation, which mimic the clinical reality more effectively than simple CS/warm perfusion and will allow us to test our hypothesis through 3 specific aims. Aim 1: Define the mechanism of Hsp72 upregulation and its impact on proteasome dysfunction during renal CS and transplantation. Aim 2: Delineate the mechanism of Rpt6 phosphorylation/aggregation and its impact on proteasome dysfunction during renal CS and transplantation. Aim 3: Determine the therapeutic utility of the Hsp72 inhibitor HS-72 using both rat and human models of renal CS and transplantation. This project uses a clinically relevant rat kidney transplant model as well as ex vivo human kidney perfusion pump to test the effects of novel CS-based therapies (e.g., HS-72) on proteasome/renal function after transplantation. We expect to identify molecular mediators of proteasome dysfunction and renal injury following CS and transplantation. These findings would be readily translatable, such as by administering drugs targeting these pathways to the CS solution to improve transplant outcomes and reduce mortality for transplant patients with end-stage kidney disease.

NIH Research Projects · FY 2026 · 2020-09

Project Summary/Abstract Partnership in Cancer Research (PCAR) seeks to provide rising second-year medical students with cancer research training and education where a hands-on cancer research experience is at the heart of the program. The PCAR program will serve a class of 15 participants for 10 weeks during the summer. The research experience will be enriched by a lecture series on the molecular and cell biology of cancer alongside clinical simulations and experiences in cancer screening, treatment, and palliation. The overarching goal in this renewal of PCAR is to enhance the training of a workforce to meet the nation’s biomedical, behavioral, and clinical research needs by offering research experiences across the spectrum of basic or translational science, clinical, or community settings to medical students early in their academic careers. While students will spend most of their time training on their individual cancer research projects, the research will be put into context with a weekly lecture series on the biology of cancer. Complementary clinical experiences will expose participants to current issues in the treatment and ongoing care of people with cancer. This aspect of the program will also give participants insight into how basic and community-engaged science affect clinical practice and how clinical problems can be turned into research questions. In this renewal, we implemented a new AI-Driven In Silico Drug Discovery module that features teams of 5 participants each surveying FDA-approved drugs and natural products for potential to bind and inhibit druggable protein targets in cancer. With this integrative program we seek to spark the participants’ interest in future careers as cancer clinical specialists and researchers through the following aims: 1) Provide individual medical students an outstanding hands-on experience in cancer research. Students will perform and present on research with one of 48 faculty members including basic scientists, physician-scientists, and clinicians and participate in a team-based effort to identify putative cancer therapeutics in a parallel in silico research module; 2) Promote participants’ growth in cancer biology and research knowledge through cancer-related clinical exposures and education. Weekly lecture series will engage students in learning detailed information on molecular and cellular biology of cancer, as well as principles of community-based medicine. Clinical exposure includes hands-on medical simulations of cancer diagnostics, social media interaction with a moderated patient support group, and a visit to the palliative care clinic that will take up no more than 2 hours per week; and 3) Determine program outcomes through rigorous evaluation. Pre- and post-program testing will determine students gain in cancer research knowledge. Surveys during the program will evaluate each aspect of the program content and faculty. Long-term tracking of participants will assess efficacy of PCAR in influencing career choice in cancer research.

NIH Research Projects · FY 2024 · 2020-09

Abstract Mitochondrial apoptosis is a stress-triggered cell death pathway implicated in health and disease. This pathway is readily blocked in cancer. Mitochondrial poration is at the heart of mitochondrial apoptosis being regulated by the BCL-2 proteins. This process regulates the release from mitochondria of prodeath factors that activate the caspase cascade which dismantles apoptotic cells. Mitochondrial poration is executed by the BCL-2 protein BAK. Here we propose to delineate the mechanism of mitochondrial poration by BAK, which is elusively defined and controversial. In particular, we propose to elucidate 1) the mechanism of BAK activation, 2) BAK association with and poration of membranes, and 3) BAK recognition and sequestration by prosurvival BCL-2 proteins. To accomplish these aims we will use a multi-pronged approach including high-resolution structural biology, biophysics, biochemistry, and cell biology to generate a complete picture of mitochondrial poration by BAK. Upon successful completion we will redefine our mechanistic understanding of this process, and we will reveal innovative ways to target apoptosis in pathophysiology.

NIH Research Projects · FY 2025 · 2020-08

Abstract Since 2020, the IDeA National Resource for Quantitative Proteomics has operated as a NIGMS R24 National Resource in support of NIH-funded investigators, and other academic researchers and qualified scientists across the United States, by providing the most cost-effective access to state-of-the-art proteomics platforms and supporting a substantial nation-wide biomedical research community with unique education, outreach, and training opportunities. In this renewal, we seek to build on the high level of success during the current funding cycle by expanding access to and opportunities in service, education, outreach, and training for quantitative proteomics to a growing nation-wide userbase. Our intent is to provide broad access to investigators without regard to the specific biomedical focus of their research, while not duplicating or replacing resources supported by NIH or host institutions. With robust institutional support, we will use best-in-class practices to enable user access to the next generation of liquid chromatography-coupled mass spectrometry systems and skilled staff for data collection and analysis. We will make our capabilities and abilities broadly known to the nation-wide biomedical research community through advertisement, education, and outreach. The goals of the IDeA National Resource for Quantitative Proteomics are to provide unmatched and most cost-effective access to state-of-the- art quantitative proteomics platforms and education, outreach, and training opportunities that will increase the capacity of NIH-funded investigators, and others in academic laboratories across the United States, to perform cutting-edge biomedical research. By pursuing our goals, we will support the biomedical research mission of NIH for both fundamental and translational research focused on human diseases including cancer. We will pursue the following Specific Aims to accomplish our goals: (1) Provide state-of-the-art proteomics services to a nation- wide userbase, (2) Provide educational opportunities for quantitative proteomics to a nation-wide userbase, and (3) Provide outreach and training for quantitative proteomics to a nation-wide userbase.

NIH Research Projects · FY 2024 · 2020-08

PROJECT SUMMARY/ABSTRACT Mechanical stimuli promote bone growth and are critical for skeletal homeostasis during adulthood. Loss of mechanical signals decreases bone mass and increases fracture risk. Osteocytes, which are cells buried in the bone matrix and derived from osteoblasts, are able to sense changes in mechanical load and orchestrate bone remodeling. Several lines of evidence suggest that calcium channels are involved in the sensing of mechanical load by osteocytes. For example, calcium influx is one of the earliest responses of osteocytes to mechanical stimuli in vitro and in vivo. Consistent with a functional role for calcium signaling in the response to mechanical forces, the response of osteocytes to mechanical stimuli can be inhibited by blocking calcium channels using chemical blockers. Moreover, load-induced bone formation in the rat ulna is significantly blunted by calcium channel inhibitors. However, the identity of the calcium channels activated by mechanical forces and their functional role as mechanosensors in bone remain unclear. We have found that Piezo1 calcium channel is highly expressed in osteocytes, and that its expression and activity are increased by mechanical stimulation in osteocytes. In addition, deletion of Piezo1 in osteoblasts and osteocytes decreases both bone mass and bone strength in mice, consistent with loss of skeletal responsiveness to mechanical stimulation. Moreover, the skeletal response to anabolic loading is blunted in mice lacking Piezo1 in osteoblasts and osteocytes. Wnt1, a ligand for Wnt signaling that is known to be upregulated by mechanical signals and stimulate bone formation, is downregulated in Piezo1 conditional knockout mice. Importantly, activation of Piezo1 by its chemical agonist, Yoda1, mimics the effects of fluid flow on osteocytes and increases bone mass in mice. Based on this evidence, we hypothesize that osteocytes sense changes in mechanical signals through Piezo1 and thereby promote bone formation in part by activating signaling pathways that increase the expression of Wnt1. To test this hypothesis, we will determine whether Piezo1 expression by osteocytes is required for mechanical sensing in the murine skeleton. We will generate mice in which Piezo1 is deleted from osteocytes, but not osteoblasts, and compare their skeletal phenotype to that observed in mice lacking Piezo1 in osteoblasts and osteocytes. We also will delete Piezo1 postnatally in adult mice and investigate their response to mechanical loads by tibia compression (Aim 1). In addition, to understand how Piezo1 promotes bone formation, we will determine the role of Wnt1 in Piezo1-mediated bone formation in vivo using a mouse genetic approach (Aim 2). In Aim 3, we will determine whether Piezo1 is responsible for the skeletal response to unloading using a tail-suspension model. Lastly, we will determine whether pharmacological activation of Piezo1 prevents bone loss associated with unloading or increases bone mass in old mice. Successful completion of this work should establish a new model for understanding the skeletal response to anabolic mechanical loading and may suggest new strategies to develop anabolic therapies for bone loss related to disuse or aging.

NIH Research Projects · FY 2024 · 2020-06

Doxorubicin, an inhibitor of DNA topoisomerase 2a (Top2a), is routinely used in the treatment of breast cancer, sarcoma, and pediatric leukemia. Of the two topoisomerase 2 isozymes, Top2a is highly expressed in cancer cells and is required for cell division. However, adult cardiomyocytes express only topoisomerase 2b (Top2b), which is involved in DNA transcription, but not DNA replication. Long-term cancer survivors who were treated with doxorubicin and other anthracyclines often suffer from dose-dependent cardiotoxicity. Laboratory data showed that Top2a mediates doxorubicin’s tumoricidal activity, whereas Top2b mediates doxorubicin’s cardiotoxic effect. At present, dexrazoxane is the only FDA approved drug for cardio-protection. The cardio-protective effect of dexrazoxane is due to its ability to bind to the ATPase domain of Top2b to inhibit Top2b’s catalytic cycle. Currently, dexrazoxane is given concurrently with doxorubicin. Because dexrazoxane also binds to Top2a, it has the potential to interfere with doxorubicin’s tumoricidal effect. However, subclinical doxorubicin-induced cardiotoxicity is known to occur much earlier, perhaps at the initiation of doxorubicin therapy. Thus, dexrazoxane has limited clinical utility as specified by FDA’s approved indication. In preliminary studies, dexrazoxane induced an ubiquitin/ proteasome- mediated degradation of Top2b, but not Top2a. By administering dexrazoxane eight hours before doxorubicin, Top2b will be degraded to avoid cardiotoxicity, whereas Top2a will remain intact to preserve tumoricidal efficacy. Because the half-life of dexrazoxane is two hours, 93.75% of dexrazoxane will be eliminated eight hours (four half-lives) after administration. Indeed, dexrazoxane pre-treatment eight hours before doxorubicin provided complete protection against doxorubicin-induced cardiotoxicity in an animal model. In this proposal, this novel strategy will be tested in breast cancer patients prescribed doxorubicin- containing regimens. Two specific aims will be studied. Aim 1: To determine whether dexrazoxane given at a lower than FDA-approved dose is effective in degrading Top2b and the time-course of Top2b degradation in human volunteers. Aim 2: To test a mechanism-based hypothesis that early administration of dexrazoxane prevents doxorubicin-induced cardiotoxicity in non-metastatic, HER2- negative female breast cancer patients. HER2-negative, stage I-III female breast cancer patients will be enrolled in this prospective randomized, placebo-controlled, double-blind study. Patients will be monitored by cardiac MRI, Top2a, Top2b, and biomarkers before and after dexrazoxane/doxorubicin therapy. Tumor regression will be followed by oncologists clinically. Overall survival, event-free survival, and overall response (using response evaluation criteria in solid tumors -RECIST) will be collected to compare outcomes of cancer therapy with or without pre-treatment of dexrazoxane. Successful implementation of these trials will provide a novel and cost-effective strategy to prevent doxorubicin-induced cardiotoxicity.

NIH Research Projects · FY 2026 · 2020-06

PROJECT SUMMARY/ABSTRACT This application is a renewal of R01 CA236814-01, entitled “Novel NEK2 Signaling Pathway in Myeloma Progression.” The long-term objective of this work is to develop novel treatments for multiple myeloma (MM) that overcome drug resistance and prevent relapse. MM is the second most common hematologic malignancy, with an estimated 35,780 new cases in the United States in 2024. In cancer, drug resistance is a major cause of treatment failure and disease relapse, and our group has a long history of using genomic and genetic tools and leveraging data derived from a large clinical sample database to explore mechanisms of drug resistance. Through these efforts, we identified 10 chromosomal instability (CIN) genes, including NEK2, that are associated with poor prognosis in MM. During the funding period since June 1, 2020, we showed that NEK2 interacts with another CIN gene, TRIP13, to accelerate B-cell tumor development and progression. Importantly, we made novel discoveries and generated preliminary data to support this renewal application: (1) Using mass spectrometry proteomics analysis of human primary MM samples, we identified CDK11A as a potential master regulator of CIN genes in MM cells. (2) We showed that high NEK2 expression in the tumor microenvironment suppresses T-cell immunity. (3) We discovered that MM cells that survive BCMA-CAR-T therapy or conventional chemotherapy highly express both CIN genes and CD24 and represent distinct populations of drug-resistant MM cells. In this proposal, we hypothesize that CDK11A acts as a master regulator of the 10 CIN genes, promoting drug resistance, and that combination therapy involving Bi-BCMA-CD24-CAR-T cells and a NEK2 inhibitor will improve therapeutic efficacy by eliminating both bulk and drug-resistant MM cells while enhancing immune responses. To rigorously test this hypothesis, we propose the following Specific Aims: (1) Determine the mechanisms by which drug-resistance genes are regulated in MM cells. (2) Determine the role of NEK2 in controlling regulatory T cells in MM. (3) Develop a novel combination therapy to overcome drug resistance and improve immune responses in MM. This application proposes the use of vertebrate animals. Because we explore the potential mechanism whereby inhibiting Nek2 in the tumor microenvironment improves the immune response to MM and evaluate therapeutic effects of Bi-BCMA/CD24- CAR T cells using immune competent mice, there is no alternative system for performing such experiments. Supported by our high productivity and strong preliminary data, which provide a sound rationale for this renewal application, the proposed research will likely yield a better network-based understanding of resistance mechanisms to chemotherapy and immunotherapy. This work has the potential to also provide novel insights and facilitate the development of novel targeted therapies to overcome drug resistance and immune suppression in MM.

NIH Research Projects · FY 2026 · 2020-04

PROJECT SUMMARY This proposal seeks to renew a pre-doctoral training program “Arkansas Center for Health Disparities T32 Pre-doctoral Research Training Program” (ARCHD-T32) in the Department of Health Policy and Management at the University of Arkansas for Medical Sciences (UAMS). The program builds on the research infrastructure of the UAMS Translational Research Institute and five social science PhD programs across the College of Public Health, the College of Pharmacy, and the College of Nursing with support from the Department of Biomedical Informatics in the College of Medicine. ARCHD-T32 provides a formal structure for integrating advanced analytics into social science programs through didactic and applied settings with a focus on reducing health disparities and improving health consistent with the priorities of NIMHD. ARCHD-T32 scholars benefit from the rich data resources, experienced mentors, and didactic coursework in natural language processing, machine learning, data visualization, and data mining. ARCHD-T32 leverages the unique data assets available to trainees, especially the Arkansas All Payer Claims Database to address three specific aims: 1) Provide a formal structure for training social scientists in disparities research using advanced data analytics and a team science approach; 2) Develop formal externship programs with key partners in the state; and 3) Collaborate with the UAMS Translational Research Institute, other key institutes in Arkansas, and the TADA-BSSR consortium. A formal organizational structure including a Multiple Program Director plan that combines expertise from the social sciences, analytics, biostatistics, and informatics is proposed to meet five primary objectives: to recruit strong trainees with quantitative backgrounds/capabilities and an interest in disparities research; to develop a high-quality, individualized training program in advanced analytics directed at identifying and eliminating healthcare disparities; to increase the workforce in Arkansas and the nation that has advanced analytics capabilities and can contribute to identifying and eliminating healthcare disparities; to foster a training environment based on interdisciplinary expertise and team science that responds to community needs; to evaluate the breadth of the training program with respect to the overarching goal of sustaining a strong training program that meets the needs of the state and the nation. Support is requested to maintain four slots for pre-doctoral students with two-year training commitments. With technical and financial resources from UAMS and state partners, the ARCHD-T32 training program serves as a national model for addressing health using advanced analytics in an environment with pronounced health disparities.

NIH Research Projects · FY 2025 · 2020-04

Project Summary The consequences of irradiation- and/or Cisplatin (IR/CisP)-induced neuronal toxicity, i.e., neurological function deficits, often irreversible and permanent, represent a daunting challenge when treating patients with cancer. The underlying mechanisms of toxicity remain poorly understood and the ability to selectively protect neuronal survival while not compromising tumor control following IR/CisP is lacking. This proposal aims to determine the mechanisms protecting neurons from IR/CisP-induced cytotoxicity, with the overarching goal to provide evidence supporting novel strategies to decrease their neurotoxicity, while maintaining therapy efficacy and improving patient quality of life. NAD+-dependent deacetylase sirtuin 2 (SIRT2), which is highly expressed in differentiated neurons, is involved in diverse cellular processes including metabolism, response to oxidative stress, and tumor suppression. Our preliminary study has discovered a novel signaling network that connects SIRT2 to transcription coupled- homologous recombination repair (TC-HRR) and -nucleotide excision repair (TC-NER) of DNA damage and neuronal cell resistance to IR/CisP-induced cytotoxicity. Furthermore, our data revealed that CSB, the key mediator for TC-HR/TC-NER, is directly deacetylated by SIRT2. Moreover, the cyclin-dependent kinase 5 (CDK5), which is involved in DNA damage signaling in neuron cells, phosphorylates and inhibits SIRT2 function in DNA repair and neuronal survival following IR/CisP. We hypothesize that SIRT2 activity, which is suppressed by CDK5-mediated phosphorylation, protects neurons against IR/CisP-induced DNA damage by enhancing CSB- directed TC-NER and TC-HRR, thereby attenuating neuronal cytotoxicity and neurological deficits. A series of in vitro and in vivo experiments are proposed to test this hypothesis: Aim 1 will determine whether CSB mediates SIRT2 promotion of TC-NER/TC-HRR and neuron survival following IR/CisP. Aim 2 will determine how CDK5 negatively regulates SIRT2 function in TC- NER/TC-HRR and neuron survival following IR/CisP. Aim 3 will test if pharmacologically targeting SIRT2 specifically attenuates neuronal deficits following IR/CisP-based cancer therapy. Results from these studies will provide insights into the biological role of SIRT2 and the molecular mechanisms regulating the repair of IR/CisP-induced DNA damage. We expect this study to lay the foundation for future research investigating the targeting of the CDK5/SIRT2-CSB signaling axis as a novel strategy to alleviate and/or prevent neurotoxicity in cancer patients who need IR/CisP therapy.

NIH Research Projects · FY 2026 · 2019-04

PROJECT SUMMARY / ABSTRACT Hypertension is a prominent public health problem and a major risk factor for other cardiovascular diseases. Major clinical challenges in the management of hypertension are insufficient blood pressure control and the recurrence of hypertension after discontinuing medications. Thus, it is important to identify the unknown mechanisms that drive its pathogenesis. Immune cells, particularly CD8+ T cells (CD8Ts), play a crucial role in hypertension. Our recent findings revealed inappropriate activation and infiltration of CD8Ts into the kidneys during the initial elevation of blood pressure, which exacerbated hypertension by enhancing renal salt retention. However, the underlying mechanisms driving this "inappropriate CD8T activation in hypertension" remain unclear, hindering the development of effective treatment strategies. Our initial studies showed that CD8T activation in hypertension does not necessitate specific antigens, suggesting an antigen-independent mechanism. Building on this premise, we hypothesize in this competing renewal application that P2X7-mediated calcium influx activates CD8Ts during the onset of hypertension, and this event is sustained by an extracellular ATP autocrine positive feedback loop. Moreover, this process promotes the formation of kidney resident memory CD8Ts (kidney-CD8Trms), thereby intensifying the progression of hypertension and hypertensive memory of salt sensitivity. Specifically, Aim 1 will test the mechanism of P2X7-mediated antigen-independent activation of CD8Ts in hypertension and the critical role of the autocrine positive feedback loop in maintaining this CD8T activation to become long-lasting. Aim 2 will determine the underlying mechanisms and critical molecular pathways that mediate the establishment of CD8Trms in the kidney during the development of hypertension. Proof-of-principle studies in Aim 2 will determine whether kidney-CD8Trms contribute to the memory of salt sensitivity that underlies the recurrence of hypertension. Our experiments will rely on genetically modified animals including a knockout of purinergic receptor P2X7, CD8T-specific gene deletion of pannexin 1 (Panx1), and T cell-specific knockout of transforming growth factor β (TGFβ) to implicate these molecules in the activation and establishment of kidney-CD8Trms that fuel the progression of hypertension and hypertensive memory of salt sensitivity. Vertical integration of complementary in vitro and in vivo studies are further incorporated into this proposal to elucidate the important molecular mechanisms that cause T cell activation and homing to the kidney, thus impairing salt and volume homeostasis to cause hypertension and its recurrence. We propose that salt- sensitive hypertension is caused and maintained, at least in part, by a resident memory immune disorder in the kidney. Moreover, the key molecules identified in this study may represent novel targets for future immunotherapies to mitigate hypertension and its recurrence.

NIH Research Projects · FY 2026 · 2018-02

PROJECT SUMMARY/ABSTRACT - OVERALL Conditions such as osteoporosis and osteoarthritis, and malignancies such as breast cancer, negatively affect the musculoskeletal system, leading to substantial disability and health care costs. Thus, there is an ongoing need to better understand the causes of these conditions and to support development of more effective and well-tolerated therapies. The Center for Musculoskeletal Disease Research (CMDR) was established at the University of Arkansas for Medical Sciences (UAMS) during Phase 1 to meet this need. The scientific theme of the CMDR is that identification of molecular contributors to musculoskeletal dysfunction and disease will guide development of effective therapies. To study these conditions, we have assembled teams of junior and established investigators and supported development of junior investigators to the point of achieving independent R01-level funding. We also utilize state-of-the-art technologies to analyze gene expression, genetically manipulate animals, and analyze the skeleton. These complementary approaches, together with access to clinical investigators and patient samples, have synergized to create a unique and productive research environment. A key to the continued success of the Center will be to increase the number of investigators whose research is aligned with our scientific theme via development of more junior investigators and recruitment of new and established investigators. To accomplish this, in Phase 2 we propose to support the development of 3 Project Leaders by providing structured mentoring, financial resources, and collaboration with other CMDR investigators (Aim 1). We will also continue to strengthen the biomedical research infrastructure at UAMS by increasing the capabilities and utilization of 4 research cores that provide access to rapid, high-quality services and that develop new approaches, such as CRISPR interference for in vivo loss-of-function studies (Aim 2). To continue building a critical mass of musculoskeletal investigators and teams, the Center will utilize a Pilot Project Program, targeted recruitment of investigators with complementary expertise, and incorporation of new and established center investigators into synergistic and productive research teams (Aim 3). Successful implementation of this Organization and Management Plan will, in the long-term, lead to a self-sustaining Center of Biomedical Research Excellence that will generate novel and important results leading to more effective therapies for the numerous conditions that involve the musculoskeletal system.

NIH Research Projects · FY 2022 · 2017-07

ABSTRACT Tumor has been described as the wounds that do not heal. The two share some common features, such as loss of polarized tissue structure and chronic inflammation. We showed that disruption of tissue polarity induced macrophage infiltration. However, little is known of how disruption of epithelial cell polarity at early stage of breast cancer development induces macrophage infiltration. We have identified the RAR-related orphan nuclear receptor α (RORα) as a potent tumor suppressor by analyzing global gene expression profiles in polarized and non-polarized mammary epithelial cells. Our recent findings show that RORα inhibits ROS generation and macrophage infiltration in the syngeneic mouse mammary tumor model. These results suggest that RORα is a potent suppressor of macrophage infiltration in mammary epithelial cells. We found that knockdown of RORα significantly induced ROS production in mammary epithelial cells. Reactive oxygen species (ROS) are the driver of cancer progression and critical regulator of the NF-κB pathway. Based on these novel findings, the central hypothesis of our proposal is that downregulation of RORα in non-polarized breast cancer cells increased ROS generation in mitochondria, thereby inducing NF-κB and macrophage infiltration. We integrate high-throughput metabolic analysis, a novel 3D co-culture system, and global gene expression profiling to delineate mechanisms by which RORα inhibits ROS production and macrophage infiltration. The long-term goal of this proposal is to define the impact of the RORα/ROS axis in mediating mammary epithelial cell-macrophage crosstalk and in regulating breast cancer progression. We have proposed following specific aims to test the hypothesis: Aim 1. To elucidate the molecular mechanisms by which RORα reduces ROS levels and NF-κB activity in polarized mammary epithelial cells; Aim 2. To determine how reduced RORα expression in non-polarized breast cancer cells induces macrophage infiltration and M2 polarization; Aim 3. Define the impact of RORα in suppressing breast cancer formation and metastasis. The proposed study is high impact for its inherent scientific importance and its translational potential. This study will elucidate the molecular mechanism by which disruption of tissue polarity induces macrophage infiltration/differentiation. Determining roles of RORα in reducing ROS generation and inhibiting NF-κB activation may identify a novel strategy to inhibit breast cancer development and progression.

NIH Research Projects · FY 2025 · 2017-03

Summary Multiple myeloma (MM) is characterized by the growth of malignant plasma cells in the bone marrow supported by increased angiogenesis. Despite significant advances in treatments, MM remains incurable due to frequent relapses originating from MM cells refractory to therapy. Further, MM induces a devastating bone disease, increasing fracture risk and decreasing quality of life. The long-term goal of this proposal is to improve clinical outcomes in MM by defining targetable mechanisms underlying MM growth, responses to therapy, and bone destruction. The rationale stems from work from the previous funding period demonstrating that osteocytes (Ots) are an abundant and long-lived source of signals in the MM tumor microenvironment (TME) that supports MM growth and promote bone destruction; and that targeting Ot-MM cell interactions decreases MM growth and improves bone health. In studies leading to this application, we found that MM cells upregulate the expression of Fibroblast growth factor (FGF) 23 in Ots and discovered that Ots support angiogenesis and promote resistance to Bortezomib-based therapies. The specific goal of this proposal is to evaluate the efficacy of targeting local FGF23 derived from Ots to decrease tumor growth, repair damaged bone, and improve responses to therapy in MM. The central hypothesis is that Ot-derived FGF23 promotes MM progression, bone destruction, and refractory disease via local TME autocrine and paracrine signals mediated by the FGF23 co-receptor α-Klotho (αKL). This hypothesis will be tested in three specific aims: (1) Determine the contribution of Ot-derived FGF23 to MM tumor growth and bone disease by interfering with paracrine and/or autocrine FGF23-αKL signaling; (2) Determine the impact of Ot-derived Vascular endothelial growth factor A (VEGFA), a downstream target of FGF23, and other osteocyte-derived pro-angeogenic factors on the pathological angiogenesis in the MM-TME; and (3) Determine the role of FGF23 and the FGF23 target gene Heparanase (HPSE) on TME-induced resistance to Bortezomib-based therapies in MM cells. These aims will be pursued using a combination of innovative in vitro, in vivo, and in silico approaches, including cell-specific genetic tools, pharmacological approaches, human MM xenograft and immunocompentent mouse models of MM, primary cells from MM patients, scRNAseq analysis, and mining of MM patient genetic/clinical databases.

NIH Research Projects · FY 2024 · 2016-09

PROJECT SUMMARY Eligibility for the Institutional Development Award (IDeA) program is based on historically low levels of NIH funding. IDeA states differ from non-IDeA states with respect to the rural/urban distributions of the population and access to medical care. Compared to children in non-IDeA states, children in IDeA states are more likely to live in rural areas and are less likely to have access to or receive medical care. Since multi-center pediatric clinical trial networks are concentrated in centers in non-IDeA states, there are limited opportunities for children living in IDeA states to participate in clinical research activities. The ECHO IDeA States Clinical Trials Network (ISPCTN) was established in 2016 with 17 clinical awardee sites and the Data Coordinating and Operations Center (DCOC) at the University of Arkansas for Medical Sciences (UAMS) in Little Rock, Arkansas. The objectives of the Network are to develop and implement clinical research in the IDeA states in the ECHO priority areas: upper and lower airway disease; obesity; neurodevelopment; pre-, peri-, and post-natal outcomes; and positive child health; and to develop capacity within the IDeA states to conduct clinical trial research. This proposal is for UAMS to continue to serve as the DCOC for the ECHO ISPCTN. The specific aims of the Data Coordination and Operations Center are to 1) Provide scientific, operational, administrative and logistical infrastructure support to the ECHO IDeA States Pediatric Clinical Trials Network (ISPCTN) to facilitate the development, implementation and dissemination of clinical research activities in the ISPCTN; and 2) Build pediatric clinical research capacity in the IDeA states to enhance the potential for conducting clinical trials that address health issues of relevance to children in IDeA states. We will work collaboratively with clinical investigators at the ISPCTN sites, Project Scientists and Project Officers at the NIH ECHO Office, and other participating NIH staff, and collaborating multicenter clinical trials groups to design and implement studies that will address health issues that disproportionately affect rural and medically underserved children.

NIH Research Projects · FY 2024 · 2015-06

PROJECT SUMMARY/ABSTRACT The objectives of the Center for Studies of Host Response to Cancer Therapy are to (1) form a self-sustaining multidisciplinary research center within the University of Arkansas for Medical Sciences (UAMS) to increase the understanding of mechanisms of side effects of cancer therapy, identify methods for early detection, and develop strategies to prevent or treat such side effects and (2) help junior investigators with research programs in this common theme establish themselves as independent scientists. Achieving these goals will create a vibrant, multidisciplinary yet synergistic research environment. To our knowledge, few research centers focus on cancer survivorship, and none take the paradigm-shifting approach of proactively addressing treatment-related toxicities to improve overall cancer treatment outcomes. Specifically, this Center will provide an environment for young investigators to succeed as independent scientists (Aim 1); strengthen the overall research infrastructure at UAMS and the Winthrop P. Rockefeller Cancer Institute (Aim 2); and ensure that the Center becomes self- sustaining (Aim 3). All 6 project leaders recruited to the Center in Phase 1 have built well-funded, productive research programs and close collaborations with each other and several of the pilot project grantees. In preparation for Phase 2, we have recruited 4 promising new/early-stage independent investigators. During Phase 1, the Center focused heavily on radiation therapy. To increase the impact and scope of the Center while retaining its overall theme, project leaders recruited for Phase 2 have a research focus on both radiation and chemotherapy. To increase the likelihood that project leaders will successfully secure independent extramural research funding, individualized mentoring and faculty-development plans will be implemented, and support from an administrative core and 2 research service cores will be integral. To replace project leaders who achieve independence and graduate from COBRE support, a pipeline of new project leaders is ensured through institutional support for recruiting junior faculty combined with a structured pilot project program. Strengthening our interactions with the 5 other COBRE Centers and additional NIH-supported programs that enhance biomedical research on the UAMS and affiliated campuses will also contribute to establishing the Center as a self-sustaining research program that is well-integrated in the institution. The Center's progress will be guided by highly qualified External and Internal Advisory Committees. Strong institutional support combined with active interest from funding agencies in improving uncomplicated cancer cure rates and the quality of life of cancer survivors ensures a high likelihood of success for the Center for Studies of Host Response to Cancer Therapy.

NIH Research Projects · FY 2025 · 2015-06

SUMMARY ABSTRACT We have demonstrated that mutation of the staphylococcal accessory regulatory (sarA) in Staphylococcus aureus results in an increase in the production of extracellular proteases to a degree that limits biofilm formation, limits cytotoxicity for mammalian cells including osteoblasts and osteoclasts, and limits the accumulation of both surface-associated and extracellular virulence factors. We have also demonstrated that this can be correlated with decreased virulence in animal models of sepsis and osteomyelitis. Moreover, we have confirmed that all of these phenotypes are evident in diverse clinical isolates of S. aureus and that they can be reversed by eliminating the ability of sarA mutants to produce extracellular proteases. In this proposal, we will expand on these observations to identify the specific extracellular proteases that are most relevant in the context of our underlying scientific hypothesis in diverse clinical isolates of S. aureus (Aim 1) and use the information gained to interrogate the impact of these proteases on the virulence factor repertoire on these clinical isolates, define the impact sarA and these proteases on bone remodeling and the host response in bone infection, and ultimately identify and evaluate the contribution of specific S. aureus virulence factors alone and in combination with each other on these phenotypes (Aim 2).

NIH Research Projects · FY 2025 · 2015-03

PROJECT SUMMARY/ABSTRACT In the United States, trauma is the leading cause of death for individuals under the age of 45 and was responsible for $671 billion in economic damage in 2013. Despite growing standardization of clinical trauma care, at Level I and Level II trauma centers, there remains significant variability in patient outcomes across trauma centers on both levels. To resolve this issue, two knowledge gaps will be addressed: a) which organizational features impact patient outcomes and b) which organizational features are indicative of institutional commitment. Our global hypothesis is that variability of organizational features in Level I and Level II trauma centers is a significant factor in the variability of patient outcomes across those trauma centers. We will also collect data on which organizational features are indicative of institutional commitment from the perspective of trauma experts. In Aim 1 we will collect data about the organizational characteristics and patient outcomes at 230 Level I and Level 2 trauma centers. These centers will also provide us with their Trauma Quality Improvement Program data, which includes patient outcomes. To support our global hypothesis, we will use these data to test whether organizational features of the trauma centers show an impact on patient outcomes, specifically patient mortality, length of stay, and risk-adjusted major complications. In Aim 2 we will use the data about organizational characteristics to assess which organizational features of trauma centers are indicative of institutional commitment using Latent Class analysis. This will allow us to represent the dependencies between organizational features and institutional commitment and add this information to the TIPTOE database. We will use these data to create automatic inferences on patterns of institutional commitment to represent, group and analyze factors indicative of institutional commitment using data collected in the present project. This provides an additional source of knowledge guiding trauma center planning and decision-making. In Aim 3 we will extend the Ontology of Organizational Structures of Trauma Centers and Trauma Systems (OOSTT) to include institutional commitment and patient outcomes. We will set up the TIPTOE Knowledge Base and create the Knowledge Path tool for users to explore, analyze, and visualize TIPTOE data. We will test the hypothesis that the TIPTOE Knowledge Path is perceived to make a positive impact on knowledge discovery and decision making in the user community. This project will initialize a novel resource of patient outcome information for the trauma care community. The purpose of this project is the next evolution of trauma center quality improvement allowing change based on scientific evidence of which components of trauma centers affect patient outcomes.

NIH Research Projects · FY 2026 · 2014-04

PROJECT SUMMARY Gammaherpesviruses (GHVs) establish lifelong chronic infections that place the host at risk for numerous cancers. During chronic infection, GHVs express viral gene products that stimulate host-cell proliferation and differentiation, processes thought to facilitate long-term latent persistence and contribute to tumorigenesis. However, GHVs are not acutely transforming, and cancer is rare given the high incidence of infection among adult humans, estimated at more than 95% for Epstein-Barr virus (EBV). This suggests that host cells are equipped with an intrinsic resistance to GHV-driven proliferation and cellular immortalization. In work performed during the previous funding period, we identified the tumor suppressor p53 as a protein that is activated during the establishment of GHV latent infection. p53 is frequently considered a “guardian of the genome”, working downstream of multiple mutagenic pathways to halt cell-cycle progression, stimulate DNA repair, or promote apoptosis. p53 is frequently mutated in human cancers, including endemic Burkitt lymphoma, an EBV-associated lymphoma that is characterized by a chromosomal translocation between the immunoglobulin heavy-chain promoter and cellular proto-oncogene c-myc. It is hypothesized that EBV synergizes with malaria, to promote the survival of cells that harbor IgH/c-myc translocations. Using murine gammaherpesvirus 68 (MHV68) infection of mice as a small animal model to enable a multi-system analysis GHV pathogenesis, we demonstrated that p53 limits cellular proliferation, especially of germinal center (GC) cells. We also found that p53 inhibits IgH/c- myc translocations in B cells of infected mice, an event that correlates with enhanced B cell lymphoma development in p53-deficient mice infected with MHV68. Moreover, we provide preliminary data indicating that co-infection of mice with MHV68 and a murine malaria parasite also promotes IgH/c-myc translocations. Experiments proposed in this competing renewal will build on our previous progress, harnessing the powerful mouse and MHV68 genetic systems, to (i) define viral genes and molecular pathways that promote genomic instability and lymphoma development, (ii) identify viral and host-factor dependencies in GHV-driven lymphomas, and (iii) determine the mechanisms through which MHV68 and murine Plasmodium parasites facilitate chromosomal translocations. In addition to providing a better understanding of how GHVs cause disease, we anticipate that results of this work will inform new therapeutic approaches that target lymphoma dependencies and reduce the mutagenic potential of GHVs and related co-infections.

NIH Research Projects · FY 2025 · 2011-06

U.S. institutions of higher education have failed to successfully attract, enroll, and graduate students with disadvantaged personal histories from rural, low income and high poverty areas who later pursue research and health professional careers. The University of Arkansas for Medical Sciences (UAMS) has a number of faculty who engage in research that fulfills the NHLBI mission, with more than $20 million in total research funding from NIH and $5 million in research funding from other agencies. Thus, UAMS is well positioned to help address the shortfall of researchers in cardiovascular, pulmonary, or hematologic areas by providing an active pool of potential research mentors for undergraduate students from rural, low-income areas who have disadvantaged personal histories. The UAMS Summer Undergraduate Research Program (SURP) was implemented in 2012 to increase the number of students from rural, low income and high poverty areas entering NHLBI sponsored research fields; program funding was renewed in 2016 and 2020. The overall goal of the SURP is to provide students with research, mentoring, and networking experiences; real-life surgical observations; and simulated cardiovascular demonstrations to increase their interest in careers in cardiovascular, pulmonary, and hematologic research. During the first funding period, approximately 95% of participants were expected to complete a bachelor’s degree, with 75% continuing education in a graduate or health profession program. During the second funding period, several SURP participants obtained their bachelor’s degrees and enrolled in graduate or medical school. Since the program started in 2012, 78% of all participants have completed a bachelor’s degree program; 54% are currently enrolled or have completed graduate or medical school programs. Most program participants who have not continued in a health-related or graduate degree program are either preparing to apply to a graduate/health profession program or still actively engaged in research. The SURP has been successful at providing students with positive summer research experiences and long-term mentor-mentee relationships. To continue to build on the program’s success, we propose the following aims: 1) recruit a heterogenous group of academically talented and enthusiastic undergraduate students interested in pursuing careers in cardiovascular, pulmonary, or hematologic research; 2) support and cultivate successful and rewarding mentor-mentee relationships; 3) develop and promote student leadership and communication skills; 4) stimulate low income, disadvantaged, and rural students’ interest in research and health-related careers; and 5) evaluate the program and its activities annually to ensure student satisfaction and program success. Exposing rural, low-income and disadvantaged students to basic, clinical, and/or translational research will provide a firm introduction and foundation to foster interest in research and health-related careers.