Univ Of Arkansas For Med Scis

NIH Research Projects · FY 2025 · 2010-07

PROJECT SUMMARY It is estimated that human papillomavirus (HPV) is responsible for 42,700 cancers in the US each year and that it caused more than 90% of anal and cervical cancers and about 70% of oropharyngeal, vaginal, and vulvar cancers. The increases in incidences of HPV-associated anal and oropharyngeal cancers in the US are notable, and cervical cancer is the fourth most common cancer among women globally. This is the second competitive renewal of this R01, which has the long-term goal of developing therapeutic vaccines for HPV. This is significant because currently available prophylactic vaccines are effective only for preventing HPV infections, but not for eliminating them once they are established. The estimated lifetime probably of acquiring HPV is 91.3% for men and 84.6% for women. We developed and are testing PepCan, a therapeutic vaccine that consists of four “current good manufacturing grade” synthetic peptides that cover the E6 protein of HPV type 16 (HPV 16), along with a Candida skin-test reagent as a novel vaccine adjuvant. Our dose-escalation single- site Phase I clinical trial of PepCan to treat women with cervical high-grade squamous intraepithelial lesions (HSILs) was recently completed. It demonstrated safety, a significant decrease in HPV 16 viral load, and a significant increase in circulating T-helper type 1 cells after vaccination. A randomized (to two treatment arms), double-blind, Phase II clinical trial is on track to complete recruitment soon. Furthermore, in a double-blind, placebo-controlled (3:1 ratio) Phase I/II clinical trial, PepCan is being tested to reduce recurrence of squamous cell carcinoma of head and neck in patients who reach “no evidence of disease” status after curative treatment. The following aims will test our hypothesis that PepCan induces HPV-specific immune responses, resulting in reduced recurrence of head and neck cancer (HNC) and increased regression of HSILs when the effector cells (i.e., T-cells) reach the disease sites. Aim 1: Assess efficacy and safety of our HPV therapeutic vaccine for HNC recurrence reduction and cervical HSIL regression Aim 2: Examine immune factors that influence PepCan response and vaccine mechanisms Aim 3: Examine how microbiomes of gut and of disease sites (cervix and mouth) contribute to vaccine efficacy Results of the proposed investigations may lead to FDA approval of a therapeutic vaccine for two HPV-related cancers and to an improved understanding of immunotherapy mechanisms.

NIH Research Projects · FY 2025 · 2009-07

PROJECT SUMMARY/ABSTRACT This proposal seeks competitive renewal (years 16-20) of the UAMS NIDA T32 training program “Translational Training in Addiction.” Spanning six academic departments and three Colleges, the program provides multi- level, cross-disciplinary, team science training that spans the translational research gamut from animal models to population-based approaches to solutions to curb or halt drug addiction. With program priorities of training innovation, diversity, connectivity, and outcomes, this renewal seeks further support for a program of training excellence that is dynamic and evolving in response to the rapidly changing societal, legislative, research, clinical, and community responses to addiction. The program Co-Directors, Governance and Steering Committees, and external evaluators/advisers enact the roles of program administration, connectivity, and oversight. A program evaluation plan is based on progress towards eight training objectives: (1) foster a shared knowledge of the broad societal and health impacts of drug use disorders, and of the diversity of engaged scientific disciplines, (2) provide an individualized path to diverse addiction impact career areas and maximize post-training outcomes, (3) foster diversity as a strength for maximizing program impact, (4) provide career building environments emphasizing interdisciplinary, team science, and translational research, (5) innovate advances in training approaches to research ethics, professional development, and program connectivity, (6) enhance awareness of and impact on translational outcomes, (7) evaluate both bibliometric and translational science benefit outcomes of the program, and (8) foster the engagement of physicians and other clinicians in the career building processes of the program. A Progress Report details significant outcomes for each objective; quantitative and qualitative data support the claim of program excellence in the current funding cycle. Continued support is requested for three levels of trainees involving three predoctoral students, four postdoctoral fellows, and four annual M2 summer addiction research interns, complemented by institutional support of one annual PGY3 psychiatry resident. Program-wide courses, faculty-facilitated seminar and presentation series, professional development lectures and workshops, and elective mentored research training emphasis/impact areas would support translational research training opportunities across the spectrum of T1 to T4 translational science. Mechanisms of trainee and program evaluation will focus on both scientific bibliometric and translational human health and society benefit indicators of program impact. Other feedback- driven new initiatives will include a redesigned grant writing skill development course and workshop, as well as a well-developed leadership succession plan. Significant institutional commitment and resources support the accrued value and continued success of the training program.

NIH Research Projects · FY 2026 · 2008-08

PROJECT SUMMARY/ABSTRACT Intracellular membrane trafficking mediates the intracellular delivery of proteins and lipids. The process is bidirectional and consists of the anterograde (secretory) and retrograde (endocytic) branches. Intracellular membrane trafficking is evolutionary conserved, and its machinery is modular, with functionally homologous components operating on different trafficking steps. Therefore, a detailed understanding of one trafficking step will help in understanding the entire intracellular membrane trafficking process. The Conserved Oligomeric Golgi (COG) complex operates as a vesicular tether for intra-Golgi trafficking. The Golgi is the central hub for protein posttranslational modifications, mostly glycosylation. Consequently, the primary job of the COG is to tether vesicles that recycle resident enzymes and cargo receptors. To achieve its function, the COG interacts with SNAREs, Rabs, and other tethers, but the detailed understanding of these interactions is an enigma that we propose to solve by pairwise probing of COG/partner interactions, their kinetics, and by defining their molecular environment through proximity-labeling studies. Depletion of COG causes accumulation of specific transport intermediates – COG complex dependent (CCD) vesicles that are likely to represent a major class of Golgi vesicles that recycle Golgi enzymes and cargo receptors. Mutations in COG subunits result in congenital disorders of glycosylation (CDG) type II category, which belong to a group of autosomal recessive multi-systemic disorders with several distinguishable symptoms that include global developmental defects and microcephaly. These deficits are often accompanied by neurological and liver impairment. COG-CDG defects are studied in patients’ fibroblasts, which do not represent the most affected tissues; a more flexible cell base model will benefit our progress in developing a cure for this disorder. We hypothesize that a revealing of the molecular basis of COG/partner interactions will help in deciphering the mechanisms of assembly/disassembly of vesicle docking platforms and that a detailed analysis of different populations of CCD vesicles will uncover their specific origin, budding and tethering machinery and a complete set of proteins that traffic in a COG-dependent manner. The development of cell-based models for COG-CDGs will allow us to test the effects of different COG mutations without the need for patient involvement and pave the way for the development of treatment protocols. To test this hypothesis, first, we will characterize in molecular interactions between COG and its key partner proteins (Aim1). Next, we will use a degrone-assisted COG depletion to accumulate, purify and characterize CCD vesicles (Aim2). Finally, we will develop and characterize a novel iPSC-based cellular model for COG CDGs (Aim 3). Success in accomplishing these aims will provide a mechanistic understanding of COG complex function, characterize COG-dependent trafficking intermediates, and create a set of isogenic stem cell lines bearing human COG mutations. Moreover, these results will be necessary for a functional understanding of Golgi dynamic and vesicular trafficking in general.

NIH Research Projects · FY 2026 · 2003-09

Abstract Osteoclast formation depends on the cytokine receptor activator of NFB ligand (RANKL), whose actions are inhibited by the decoy receptor osteoprotegerin (OPG). Osteocytes are an important source of RANKL and we have recently shown that osteoblasts, but not osteocytes, are an essential source of the OPG that suppresses resorption of cancellous bone. In contrast, osteoblasts and osteocytes provide only a portion of the OPG protecting cortical bone. Thus, the identity of the cells providing the OPG that protects large regions of cortical bone remains unclear, but may involve osteoblast progenitors and vascular endothelial cells, both of which express OPG. Previous studies suggest that a major function of beta-catenin is to promote OPG expression in osteocytes. Our finding that osteoblasts, but not osteocytes, are a major source of OPG necessitates a reevaluation of the role of beta-catenin in osteocytes. Previous beta-catenin loss-of-function studies have been hampered by the lack of Cre driver strains that can distinguish between osteoblasts and osteocytes and by the dramatic bone loss caused by beta-catenin deletion in late-stage osteoblastic cells. That osteoblasts are an important source of OPG also suggests that the rapid increase in resorption and rebound bone loss following discontinuation of anti-RANKL (denosumab) therapy may be due, in part, to the absence of osteoblasts, and thus OPG, during the period following discontinuation. Based on these findings, we propose the hypotheses that osteoblast progenitors or vascular endothelial cells are important sources of the OPG protecting cortical bone and that the beta-catenin pathway in osteocytes contributes to bone remodeling independent of its control of OPG expression. We also propose that the lack of osteoblasts, and thus OPG, contributes to the rebound resorption following discontinuation of denosumab. Aim 1 will identify cellular sources of OPG that control cortical bone resorption by deleting a conditional OPG allele in mesenchymal progenitors using Prx1-Cre mice, and vascular endothelial cells using Tek-Cre mice, and compare the effects on cortical bone to those seen in OPG- null mice. Aim 2 will determine the role of beta-catenin in osteocytes by deletion of beta-catenin using Sost-Cre mice, which delete target genes in osteocytes but not osteoblasts. Aim 3 will determine whether the rebound resorption caused by discontinuation of denosumab results in part from the profound lack of osteoblasts producing OPG using a novel humanized RANKL mouse line treated with denosumab. These mice will be used to map the cellular and molecular conditions associated with discontinuation of denosumab and to determine whether promotion of osteoblast formation via anti-sclerostin antibody administration can restore OPG levels and ameliorate rebound resorption.

NIH Research Projects · FY 2025 · 2001-09

PROJECT SUMMARY Individuals with a family history of alcoholism (FH+) are 4 to 8 times more likely to develop an alcohol use disorder (AUD) compared to individuals with no such family histories. We developed the Family Health Patterns project to characterize risk-related phenotypic characteristics of FH+ young adults. During our recent funding period, we have identified robust links between increased early life adversity (ELA) in FH+ and their (a) blunted stress reactivity, (b) increased antisocial tendencies, (c) poor affect regulation, and (d) impaired cognitive performance. In our neuroimaging studies, we identified diffusivity changes in frontal white matter tracts in both FH+ young adults and children, suggesting decreased myelination and axon damage in underlying neural circuitry. We interpret these collective findings to suggest that increased ELA in FH+ individuals induces lasting neurobiological changes and consequent behavioral effects that increase AUD risk. To guide the present proposal, we developed a heuristic model of how ELA contributes to risk-related phenotypic characteristics in FH+ persons. We propose that convergent epigenetic and transcriptomic dysregulation of immune genes increase inflammation and immunoreactivity, thereby impairing myelination and/or damaging axons in developing frontal white matter tracts. The resulting impaired communication to and from the prefrontal cortex contributes to phenotypic characteristics of increased antisocial tendencies and poorer affect regulation and cognitive performance, increasing AUD risk. Here we propose to test this model by examining inflammatory gene expression, functional changes in immunoreactivity, and cerebral white matter myelin levels and axon damage markers in FH+ and FH– young adults. We will then examine relationships of these variables with ELA exposure and risk-related phenotypic characteristics. This proposal rigorously builds on our extensive findings on FH+ behavioral and biological phenotypes by testing a novel, overarching model of AUD risk. While extensive preclinical evidence exists illustrating ELA induces long-lasting dysregulation of the immune system and resulting neural and behavioral sequela, our proposal breaks new ground by comprehensively examining these relationships in humans using advanced immunology and multimodal neuroimaging together with in-depth behavioral and clinical assessments.

NIH Research Projects · FY 2026 · 2001-09

OVERALL PROJECT SUMMARY/ABSTRACT The goal of the Arkansas IDeA Network of Biomedical Research Excellence (INBRE) is to expand biomedical research capacity in Arkansas. Scientific leadership for the network is provided by 2 research-intensive lead institutions: the University of Arkansas for Medical Sciences (UAMS) and the University of Arkansas, Fayetteville (UAF). In addition, the lead institutions, and Arkansas Children’s Research Institute (ACRI) provide resources and mentoring to 16 statewide primarily undergraduate institutions (PUIs), that range from a large urban university to small liberal arts colleges and universities. To achieve its goals, the Arkansas INBRE administers programs with objectives to: i) support PUI faculty research and mentoring, ii) support and promote student participation in biomedical research, and iii) grow biomedical research infrastructure across the network. The programs are managed by 4 interactive and synergistic network components. The Administrative Core provides operational support, opportunities for undergraduate students to participate in research, support for PUI faculty development, support for an annual research conference, and programs that expand participation in biomedical research. A Developmental Research Project Program provides competitive research funding that enhances success in biomedical research at PUIs. A Data Science Core provides cloud computing resources, training modules, and workshops, all designed to enhance research skills for PUI faculty and students. A Research Technology Core manages a Core Facility voucher program that allows PUI faculty and student researchers to access core facilities located at UAMS, UAF, and ACRI. The External Advisory Committee, along with the Executive and Steering Committees that represent the major stakeholders in the Arkansas INBRE provide oversight and ensure continued engagement and commitment of network institutions. An internal evaluation program coupled with periodic external evaluation provides additional information to leadership about the impact and effectiveness of the Arkansas INBRE components and programs. Through further enhancement of research infrastructure, particularly at undergraduate institutions, the Arkansas INBRE will continue to improve the ability of academic researchers to make discoveries that improve human health, increase the number of undergraduate students who choose careers in biomedical research, and stimulate the growth of biomedical research in Arkansas.