University Of Alabama At Birmingham

NIH Research Projects · FY 2025 · 2025-08

Modified Project Summary/Abstract Section This application represents a well-integrated multi-project research program to improve and implement an emerging gene and cell therapy technology for HIV cure. Previous work demonstrated that a rhesus CMV based SIV vaccine protected 50% of macaques from persistent SIV infection with the correlate of protection being CD8+ T cells that recognized SIV peptides in the context of MAMU-E1-4. The laboratory of Dr. Goepfert demonstrated the presence of HLA-E-restricted HIV-specific immune responses. Preliminary data generated by Drs. Garcia and Wahl recently established in vivo proof-of-principle in BLT humanized mice that HLA-E-HIV-peptide TCR transduced CD8+ T cells can reduce the HIV reservoir as measured by a 50% reduction in intact proviral DNA. Additional in vitro preliminary data demonstrated that the efficacy of HLA-E-HIV-peptide TCR transduced CD8+ T cells can be enhanced by anti-HLA-E-VL9 antibodies generated by Drs. Haynes and Azoitei by preventing inhibitory interactions with the CD94/NKG2A receptor on T cells. The overall goal of this program is to demonstrate that HLA-E-peptide complexes on HIV-infected cells can be targets for antibodies, NK cells or CD8+ T cells leading to their destruction and thus, clearance of HIV infection. Our application represents a logical extension of an ongoing collaboration between a well-established group of outstanding investigators, Dr. Goepfert (Project 1), Drs. Azoitei and Haynes (Project 2) and Drs. Garcia and Wahl (Project 3). Our overall hypothesis is that cell and gene-based therapy approaches targeting the minimally polymorphic HLA-E molecules will provide a strong in vivo therapeutic effect, reducing the HIV proviral DNA load in HIV-infected myeloid and T cells. Our overall specific aims are to 1) produce novel and improved HLA-E-HIV peptide specific TCRs and CARs and evaluate their in vitro specificity and antiviral function when transduced into human T cells as cell and gene based therapy, 2) determine if HLA-E-HIV-peptide TCR transduced CD8+ T cells can target HIV-infected myeloid and CD4+ T cells in vivo in HIV-infected humanized mice, thus reducing viral loads and the HIV reservoir, and 3) determine if anti-HLA-E-peptide specific antibodies can enhance or mediate HIV suppression in vivo in HIV-infected humanized mice. Our two private sector partners T-Cypher and Accelevir will use their expertise and resources to carry out the proposed work and to assist with progressing products derived from this research for eventual FDA licensure and commercialization. The proposal also includes an Administrative Core led by Dr. Garcia that will provide management, coordination and supervision of scientific and fiscal aspects of the program. Our proposal includes a milestone plan with clear timelines and plans for an INTERACT meeting with the FDA. Accomplishment of the overall goal and specific aims of this proposal will provide the HIV cure field with a powerful new armamentarium for reducing the latent pool of HIV-infected myeloid and T cells.

NIH Research Projects · FY 2025 · 2025-08

PROJECT ABSTRACT Accurate blood pressure (BP) measurements are essential for diagnosing and treating hypertension. In clinical practice, however, BP is often not measured following a guideline-recommended protocol. This can result in inaccurate measurements, which can lead to under- or over-treatment, and clinical uncertainty about the patient’s BP, which can lead to therapeutic inertia (i.e., lack of treatment initiation or intensification), a major contributor to uncontrolled BP in the US. To obtain accurate BP measurements, clinical practice guidelines recommend a standardized series of steps, including allowing the patient to rest for >5 minutes, properly positioning the patient, using validated equipment and an appropriate-sized cuff, and performing multiple BP measurements with a 1–2-minute interval between readings. The guideline-recommended protocol takes nearly 10 minutes to complete, making it difficult to implement in clinical practice. Therefore, clinics need ways to measure BP that are both accurate and efficient to inform treatment decisions and improve BP control. Recent studies have rigorously demonstrated it is possible to reduce the rest period from 5 to 3 or even 0 minutes and the interval between measurements from 60 to 30 seconds without compromising accuracy. Further, for patients with BP below the threshold for hypertension, it may only be necessary to measure BP one time. If streamlined, standardized BP measurement protocols incorporating these elements can be implemented in primary care, this could improve hypertension treatment decisions and BP control. The objective of this proposal is to determine whether streamlined, standardized BP measurement protocols can be implemented in primary care. The project builds on the Alabama Cardiovascular Cooperative’s Heart Health Improvement Project (HHIP), a quality improvement project using a practice facilitation implementation strategy in 47 primary care practices. However, the BP measurement protocol used in the HHIP can be optimized. In a subset of 6 HHIP practices, we will adapt the HHIP practice facilitation strategy to support clinics to implement streamlined, standardized BP measurement protocols. We will evaluate the efficiency of the BP measurement procedure at baseline and after 6 months of practice facilitation. We will use mixed methods to assess factors influencing implementation of and fidelity to the streamlined, standardized protocol. To accelerate my trajectory towards becoming an independent investigator and leader in the implementation of evidence-based interventions to prevent and manage hypertension, I have developed a training plan with my mentors to increase my expertise in 1) conducting research in primary care, 2) implementation science, 3) mixed methods research, and 4) leadership skills needed to be a PI. This proposal aligns with NHLBI’s strategic objective to optimize clinical and implementation research to improve health and reduce disease and its December 2024 workshop on clinic BP assessment. Completing the research and training aims will position me to submit an R01 to test whether implementing these BP measurement protocols improves BP control.

NIH Research Projects · FY 2025 · 2025-08

Project Summary - Molecular investigation of siderophore secretion and drug efflux by Mycobacterium tuberculosis Iron is essential for growth of Mycobacterium tuberculosis, but most iron in the human body is tightly bound to proteins. The presence of many iron-sequestering proteins and other iron-restricting factors in the lung granulomas of tuberculosis patients establishes an iron-deprived environment for M. tuberculosis in the human host. To prevent iron starvation, M. tuberculosis secretes siderophores, small molecules with high iron-binding affinities called mycobactins and carboxy-mycobactins. Our extensive preliminary data revealed that siderophore secretion is mediated in M. tuberculosis by a multiprotein complex composed of the inner membrane proteins MmpL4 or MmpL5 and other proteins, whose molecular organization is strikingly different from analogous systems in other bacteria. Overproduction of this secretion system during tuberculosis chemotherapy is also the main resistance mechanism against bedaquiline, a key drug for treatment of infections with multi-drug resistant M. tuberculosis. Intriguingly, mutational analysis revealed that the mycobactin binding pocket of MmpL4 and MmpL5 is also essential for bedaquiline efflux. The proposed research will shed light on this unique secretion system and reveal the molecular mechanisms of siderophore secretion and drug efflux in M. tuberculosis.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT The University of Alabama at Birmingham (UAB) HIV Implementation Science (IS) Hub, one of the 5 inaugural resource hubs dedicated to supporting the goals of the U.S. Ending the HIV Epidemic (EHE) initiative, is a resource for investigators and community partners. Located in the heart of the U.S. Deep South region – one of the heaviest burdened with HIV and a designated “focal state” for the EHE initiative (one of 7 states with this designation) – the UAB HIV IS Hub has strengths in understanding the HIV epidemic in the U.S. South and teaching foundational implementation and dissemination science methodologies as well as advanced IS study designs, the conduct of implementation science in community and clinic spaces, community-engaged science, academic-public health department collaborations, and the integration of social determinants of health frameworks. In our four years as a regional consultative hub, we provided >125 post-award technical consultations in support of 27 funded projects led by early/mid-career investigators, training to >2,000 individuals who have joined our >24 virtual seminars live or asynchronously via our YouTube channel, and conference opportunities to ~400 people who attended the 2nd annual national EHE meeting that we hosted in 2022. Our Hub consultative services, training, and collaborative opportunities cater to the full spectrum of investigator experience with implementation science and are available to support the full span of project stages from conceptualization to operationalization to dissemination. Building on our 4 prior years of continuous funding, our goals for the next 5 years are to: 1) Provide robust services at the pre- and post-award phases to advance implementation science dedicated to ending the HIV epidemic via precision IS support offered via technical advising, coaching, and monthly “conversation hours” by faculty, community representatives, and staff; 2) Enhance skills and career development of HIV implementation scientists through the provision of seminars, interactive workshops, and programs geared towards inspiring high school, undergraduate, and medical students to learn about implementation science; 3) Nurture partnerships and collaborative opportunities with the R24-supported Coordination, Consultation, and Data Management Center, other R24-supported regional consultation hubs, and national HIV research networks.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Recurrent Glioblastoma (rGBM) displays aggressive tumor invasion throughout the brain and spinal cord. The aggressive invasive behavior of rGBM emerges following initial fractionated radiotherapy, which induces mesenchymal transition and subsequent extracellular matrix (ECM) remodeling. However, the role of this ECM remodeling in establishing the immunosuppressive tumor microenvironment of invasive rGBM remains unclear. We found that Collagen type I and III (COL I & III) showed minimal expression in the normal brain, whereas it was highly upregulated in rGBM. Through genetic knockout and pharmacological inhibition, we demonstrated that COL I & III play crucial roles in establishing the immunosuppressive tumor microenvironment (TME). Mechanistically, COL-activated PI3K signaling enhances TGFβ1 expression, subsequently promoting the induction of regulatory T cells and exhausted T cells in the TME. Based on our findings, we developed two therapeutic approaches targeting invasive rGBM. First, we used blood-brain barrier (BBB)-permeable PI3K inhibitors to suppress COL-mediated signals. We confirmed that a PI3K inhibitor improved the immunosuppressive TME and extended survival in mouse models of invasive rGBM. Second, we engineered CBD-IL-12, a fusion protein combining a collagen-binding domain with the immunostimulatory cytokine IL-12. CBD-IL-12 demonstrated selective accumulation to tumor and enhanced therapeutic efficacy in rGBM mouse model, particularly when combined with PI3K inhibitors. For clinical translation, we engineered a humanized version of CBD-IL-12 and confirmed its safety in canines. Also, we analyze the therapeutic efficacy of human CBD-IL-12 against human invasive rGBM model in humanized mouse reconstituted human immune environment. The humanized CBD-IL-12 demonstrated remarkable therapeutic effects, resulting in a significant reduction of both tumor burden and spinal dissemination. Based on these findings, we hypothesize that radiation- induced COL-PI3K-TGFβ signaling contributes to the immunosuppression of invasive rGBM, and these cells can be targeted using BBB-permeable COL signaling inhibitors and CBD- IL-12 immunotherapy. We will investigate this through three specific aims: (1) Determine how COL-PI3K-TGFβ signaling induces immunosuppressive TME in invasive rGBM using genetic knockout approaches and signal inhibitors; (2) Examine how CBD-IL-12 modulates the immunosuppressive TME by analyzing chemotactic factors and dendritic cells induction; and (3) Evaluate the therapeutic synergy between CBD-IL-12 and BBB-permeable COL signaling inhibitors in clinically relevant syngeneic rGBM mouse model and humanized rGBM mouse models. Upon successful completion of these studies, we will gain crucial insights into immune evasion mechanisms of invasive rGBM and establish a strong foundation for clinical translation. This novel therapeutic strategy could be broadly applicable to other COL-expressing invasive malignancies, potentially transforming the treatment landscape.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Short Root Anomaly (SRA) is a dental anomaly with major adverse clinical outcomes in orthodontics. SRA is a developmental disorder that affects tooth root formation resulting in short roots and unfavorable root to crown ratios. In addition, these patients have an increased risk of root resorption, a serious complication in individuals undergoing orthodontic treatment. The causal gene(s) for SRA remain largely unknown. The long-term goal of this study is to develop a body of knowledge about the critical genes guiding tooth root development that may be used to enhance diagnosis and developf novel therapies for SRA. The overall objective of this proposal is to study the human genotype-phenotype correlation in SRA patients and evaluate the role of SRA associated genes during tooth root formation. Our preliminary studies have identified a mutation in the Histone Cluster 1 H1 Family Member C (H1C) gene associated with SRA. Our central hypothesis is that the H1.2 protein (encoded by the H1C gene) is expressed at key stages of root development; is regulated by NFIC, the root master gene; and that altering its expression in vitro will dysregulate other signaling molecules involved in root formation and elongation. We further hypothesize that H1C mutation relates to a localized SRA phenotype and that mutations in additional genes will contribute to the clinical dental variations of SRA. We will achieve our objective following two specific aims. First, we will carry out in vitro studies of how H1C, the identified SRA associated gene, relates to regulatory pathways critical for tooth root formation and elongation. Second, we will correlate the dental phenotype of SRA patients with known genotype and identify new genes associated with familial SRA. Discovery of novel genes involved in the pathogenesis of SRA will broaden our knowledge about the regulatory pathways of root formation. Our data will permit creation of novel animal models that in the future can serve to develop targeted clinical therapeutics to rescue the root length of the permanent dentition. It will also be of direct benefit for the counseling, diagnosis, and clinical treatment of orthodontic patients, especially those with a high risk for root resorption. These biomarkers may be used to shed light on how SRA predisposes patients to root resorptions. Finally, these studies will facilitate the “bench-to-bedside” transition, from laboratory experiments through clinical trials to point- of-care patient applications implemented through Precision Dentistry.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Among people living with HIV (PLWH), hepatitis B virus (HBV) is a common coinfection that contributes to high rates of liver-related mortality. Even with early initiation of antiretroviral therapies that include HBV-active nucleoside analogs (NA), mortality in people with HBV/HIV coinfection remains unacceptably high. There is a strong rationale for additional HBV therapies for people with HBV/HIV infection. The HBV cure research agenda is to (1) understand HBV biology, particularly the mechanisms that lead to HBV functional cure (FC), which is defined as seroclearance of the hepatitis B surface antigen in blood, and (2) to evaluate novel antiviral and/or immunotherapies that can increase HBV FC from its current rate of ~1% per year. However, at the present, PLWH are poorly represented in HBV cure research, and HIV infection is an exclusion criterion in virtually all clinical trials of novel HBV therapeutics. To accelerate the use of novel therapies in patients with HBV/HIV coinfection, a better understanding is needed of host control of HBV in the setting of HIV. This project focuses on cellular immune mechanisms of HBV control, particularly HBV-specific T cells. Our central hypothesis is that in HBV/HIV coinfection, CD4 T cells represent a critical component of the immune response mediating HBV control, including FC. This hypothesis will be tested through 3 specific aims. In Aim 1, we will investigate the impact of HIV coinfection-associated immune dysregulation, especially CD4 depletion, on the quantity and quality of HBV-specific T cell responses. In Aim 2, we will investigate the T-cell responses mediating HBV FC in patients with HBV/HIV coinfection who are treated during inactive HBV infection (i.e., low HBV DNA, normal ALT, no-minimal liver disease). In this group, we previously reported relatively high rates of HBV FC. In Aim 3, we will characterize the evolution of HBV-specific T cell responses and the intrahepatic immune landscape during adult acute HBV infection that typically results in HBV FC, with and without HIV coinfection. The above scientific investigation will occur within a unique HBV clinical cohort in Zambia (Southern Africa), which includes adult patients with chronic and acute HBV infection, with and without HIV coinfection, and features longitudinal large volume blood and liver sampling before and during NA therapy. To date HBV FC has been ascertained >40 times in the cohort, mainly in participants with HBV/HIV coinfection. Successful completion of this project will change the field by identifying immune mediators associated with HBV FC in HBV/HIV coinfection and by defining specific immunological barriers to HBV FC in PLWH. It also will help to identify patient groups with coinfection who may be more or less amenable to cure with emerging drugs based on their current or nadir CD4 and current level of HBV control. In-depth analysis of specific CD4 T cells and the intrahepatic immune milieu will also be highly significant in our understanding of chronic HBV infection without HIV.

NIH Research Projects · FY 2025 · 2025-08

The anterior/ventral dentate gyrus is a key gateway for mood regulation and stress responsiveness in humans and rodents. It contains a population of immature neurons throughout adulthood, providing a substrate for brain plasticity responsive to diverse physiological and pathological experiences. An extensive rodent literature establishes adult neurogenesis as a key factor for stress resilience, with independent lines of research corroborating the idea that young dentate neurons contribute to stress responsiveness by modifying the excitability of surrounding neurons. Yet the fundamental circuit mechanisms that underlie the interactions between new and older dentate neurons and how these interactions are affected by agents that enhance stress resilience are unclear. The goal of this project is to test a new mechanism to explain disparate ideas about how adult-born neurons modulate the excitability of the ventral dentate gyrus. Combining electrophysiological and pharmacological approaches along with anatomical labeling of synaptic circuits, we will determine how neurogenesis plays a modulatory role in the ventral dentate circuit and how ketamine affects the circuit interactions of adult-born neurons. Completion of the proposed experiments will reveal novel mechanisms underlying the contribution of adult neurogenesis to dentate excitability and stress responsiveness, potentially identifying new targets for treating stress-related mood disorders.

NIH Research Projects · FY 2026 · 2025-08

Elevated blood pressure (BP) is the single greatest modifiable contributor to premature mortality globally. The development of hypertension (HTN) and associated adverse cardiovascular (CV) events is contributed by an interplay of genetic and environmental factors. We constructed a genome-wide systolic BP (SBP) polygenic risk score (PRS), assimilating the risk for elevated BP conferred by over 1 million common genetic variations. In a US cohort, we have also demonstrated that the SBP PRS predicts the risk of adverse CV events beyond traditional CV risk factors, including clinic-measured BP. However, the high genetic risk for adverse CV events may be offset by controlling traditional CV risk factors and adherence to a healthy lifestyle. Young and middle-aged adults encounter unique barriers to sustained behavior change, including rapidly changing priorities with age. Young adults often prioritize education and social obligations, while middle-aged adults balance career demands and family responsibilities, resulting in a perceived lack of time for health-related goals and an underestimation of their risk for adverse CV events. Providing a comprehensive understanding of one’s genetic risk quantified by SBP PRS is likely to improve SBP control by enhancing adherence to a healthy lifestyle, which will eventually lead to a reduction in the risk of potentially fatal CV outcomes. However, this has not been evaluated in a cohort of hypertensive young and middle-aged US adults with poor CV health. We propose to conduct a randomized controlled clinical trial to assess the efficacy of SBP PRS dissemination on SBP control, adherence to a healthy lifestyle, and cardiometabolic profile. In the primary aim, we will enroll and randomize 300 adults (aged 18-55 years, including 50% females) to either receive SBP PRS results along with genomic counseling (SBP PRS disclosure arm) or routine care (regular care arm). Participants will be provided with educational materials on hypertension control at baseline in both arms, with only the SBP PRS dissemination arm participants receiving additional genomic counseling during the 3-monthly in-person follow-up visits. The main outcome will be the change in 24-hour mean SBP at 1 year between the two study arms. In our secondary aim 1, we will assess the change in diet (measured using the Healthy Eating Index), physical activity (estimated using actigraphy), medication adherence, smoking status, blood glucose, lipid profile, and body composition (lean mass and fat mass) and health-related quality of life between the two arms at 1 year. In secondary aim 2, we will assess the mediation of behavior change by SBP PRS dissemination and genomic counseling through each HBM construct. Overall, this study will evaluate the role of genomics in improving SBP control in a cohort of young and middle-aged adults with HTN and poor CV health and thereby mitigate the premature mortality burden secondary to elevated BP.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Direct pulp capping (DPC) offers an effective vital pulp therapy (VPT) for managing minimal, asymptomatic pulp exposures, with the potential to prevent disease progression and reduce the need for invasive procedures such as root canals, extractions, and extensive prosthetics. Current DPC materials, such as bioceramics and calcium silicates, show limitations in providing bioactive functions essential for pulp healing, including vascularization, mineralized barrier formation, and antimicrobial/anti-inflammatory effects. To overcome these limitations, we propose a novel biomimetic nitric oxide and hydroxyapatite (NO-HA) duo, utilizing a sequential application of NO-releasing peptide amphiphiles (PA-NO) gel and HA-fortified peptide amphiphiles (PA-HA) gel. Our team’s preliminary data indicate that PA-NO has robust antibacterial, anti- inflammatory, pro-angiogenic, and stem cell differentiation capabilities. Additionally, HA provides dimensional stability due to its low solubility, calcium and phosphate tunability, resorption resistance, and radiopacity, potentially supporting dentinogenic differentiation of dental pulp stem cells when used alongside NO. Therefore, we hypothesized that the biomimetic NO-HA duo would synergistically enhance bioactive and physical-mechanical barrier functions, providing a promising DPC solution for VPT. PA-NO will initiate repair by promoting vascularization and delivering antimicrobial and anti-inflammatory effects, while PA-HA will function as a mineralized barrier to stabilize the pulp-dentin interface and support dentinogenesis. In Aim 1, we will 1) characterize PA-HA’s physical-mechanical properties including viscoelasticity, compressive strength, solubility, and marginal adaptation, and 2) evaluate PA-NO’s bioactive functions for vascularization, dentinogenic differentiation, mineralization, and inflammation. In Aim 2, we will assess the feasibility and efficacy of the NO-HA duo in a rat pulp exposure model. The proposed biomimetic NO-HA duo aims to 1) support pulp-dentin repair through vascular network formation and dentinogenic response and 2) establish a stable, mineralized barrier with clinically relevant physical-mechanical properties. This preclinical study represents the first application of engineered NO and HA as bioactive DPC materials and will provide critical evidence for designing future large-scale studies and clinical trials. The biomimetic NO- HA duo could enable pulp-dentin repair while preserving tooth vitality, reducing invasive and irreversible tooth loss, and enhancing patient outcomes, with implications for cost savings and advancements in dental pulp regeneration.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Bacillus anthracis is a Gram-positive soil bacterium that forms spores when starved for nutrients, and contact with these spores causes anthrax in animals and humans. B. anthracis spores are surrounded by three protective layers, the outermost of which is a loosely fitting exosporium. The exosporium plays key roles in spore survival and infectivity. Over the past two decades, there has been significant progress in identifying the proteins that comprise the exosporium and their functions, however, the assembly process is poorly understood. This proposal explores a previously unrecognized role for Ca2+ in exosporium assembly. The exosporium is a bipartite structure consisting of a paracrystalline basal layer and an external hair- like nap. Each filament of the nap is formed by a trimer of the collagen-like glycoprotein BclA. In contrast, the basal layer contains ~25 different proteins. One of these proteins is called BxpB, which appears to play two critical roles in exosporium assembly. First, BxpB trimers form an array of basal layer surface protrusions to which individual BclA-containing filaments are stably attached. Second, BxpB binds to and stabilizes the structure of an underlying basal layer scaffold formed by protein self-assembly. In the absence of BxpB, the scaffold is structurally disordered and the insertion of other basal layer proteins is aberrant. We recently published the crystal structure of the BxpB trimer. Each monomer folds into a jelly roll structure composed of two antiparallel b-sheets. An unexpected feature of the BxpB monomer was a bound Ca2+ ion hexa-coordinated by oxygen atoms of four residues located on neighboring loops that connect the two b-sheets. The bound Ca2+ appears to stabilize the relative positions of the two b-sheets thereby fixing a major element of BxpB structure. In addition, recent structural studies of the BclA-BxpB complex reveal that the BxpB-bound Ca2+ establishes the structure of a peripheral region of BxpB that closely interacts with BclA. Presumably, the activities of BxpB in exosporium assembly require the Ca2+-dependent structures. The goal of this R03 proposal is to investigate the role for Ca2+ in BxpB structure and function. Aim 1 is to produce Ca2+-free BxpB, determine its structure by X-ray crystallography (or NMR), and compare this structure to that of Ca2+-bound BxpB. Aim 2 is to assess the ability of Ca2+-free BxpB to form stable complexes with BclA and to normally insert into the basal layer scaffold. The expected outcome is the demonstration of a critical role for Ca2+ in BxpB structure and exosporium assembly in B. anthracis spores. This situation is likely to apply to many spore-forming bacterial species, including important pathogens, that possess a BxpB homolog and produce an exosporium that is structurally like that of B. anthracis. The discoveries in this proposal will significantly enhance our understanding of bacterial spore formation and potentially lead to better responses to the adverse effects of disease-causing spores.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Functional seizures (FS) are a subtype of Functional Neurological Disorder (FND). FS are paroxysmal attacks resembling epileptic seizures, but without corresponding epileptiform activity in the brain. They account for at least 20% of new epilepsy evaluations and negatively affect independence, employability, and caregiver wellbeing. FND as a whole cost the U.S. healthcare system $1.2 billion annually. Despite their significant prevalence and burden, there are no validated treatments for FS. Research has suggested that sense of control over physical symptoms, catastrophic symptom expectations, and stress reactivity may be possible novel treatment targets for reducing FS. Sense of control is the extent to which a person perceives they are in control, and is impaired in patients with FS because symptoms are perceived as involuntary. Catastrophic symptom expectations are expressed as both a tendency to interpret normal physical sensations as threatening (i.e., indicating disease) and a tendency to over-estimate the likelihood that threatening symptoms will occur, which can themselves induce the feared symptoms. Heightened stress reactivity stems from defective emotion regulation abilities and confers vulnerability for several mental health conditions, including FS. Objective outcome measures for these endpoints have not been established in this population, which limits our ability to assess the effectiveness of FS interventions. Thus, the proposed project aims to develop objective neuroimaging-based outcome measures for the above targets. We will use functional magnetic resonance imaging (fMRI) to examine neural activity in brain regions associated with emotion processing and control, including the prefrontal cortex, cingulate, insula, hippocampus, and amygdala. Forty adults with FS and 40 controls matched on age, sex, and Psychiatric comorbidities will undergo fMRI while completing two tasks: the Threat Predictability and Controllability Task (TPCT) will assess neural responses to controllable vs. uncontrollable and predictable vs. unpredictable threats, and the Montreal Imaging Stress Task (MIST) will measure neural responses to performance demand stress (induced via challenging mental arithmetic) and social evaluative stress (induced via negative auditory feedback). We will also collect expectancy ratings prior to threat presentation on the TPCT to assess potential biases in threat anticipation in FS compared to controls. Uncovering the neural substrates of abnormal behavior in FS will enhance our understanding of FS pathophysiology and provide critical tools to improve interventions for this condition. This Mentored Career Development Award will provide opportunities to acquire skills in fMRI experimental design, data acquisition, and analysis; acquire knowledge of conditioning paradigms relevant to FS development and treatment; and participate in career development activities including grant writing, lab management, and networking. The award will allow me to transition my research program to the field of FND and meet my long-term career goal of becoming an independent investigator.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Autoimmune and chronic inflammatory diseases are on the rise in the United States and world-wide. The etiology of most autoimmune and chronic inflammatory diseases is not known; however it is proposed that a combination of genetic and environmental factors influence disease susceptibility. Genome wide association studies of multiple autoimmune and chronic inflammatory disorders have identified single nucleotide polymorphisms in several immunologically relevant genes that are linked to disease susceptibility, including the members of the IL-23/Th17 family and the human STAT4 gene. How STAT4 is coupled to the etiology of autoimmune and chronic inflammation is not known, therefore it is imperative to understand the function of STAT4 in the context of disease. The overarching hypothesis that STAT4 is a master regulator to IL-23 mediated chronic inflammatory and/or autoimmune disease by promoting the differentiation of pathogenic Th17 cells and coordinately suppressing the emergence of anti-inflammatory Th17 cells. The objective of this proposal is to: Aim 1. To determine how STAT4 directs the accumulation of Th17 cells in inflamed peripheral tissues. Aim 2. To determine if the STAT4/IL-10 axis in Th17 cells governs chronic inflammation. Aim 3. To determine how STAT4 promotes pathogenic Th17 cell differentiation at the molecular level.

NIH Research Projects · FY 2025 · 2025-08

In the United States, 60% of adults have a chronic disease and 40% have two or more. Collectively these diseases are the leading causes of death and disability, accounting for >90% of our nation's $3.3 trillion annual health care costs. Genome-wide association studies (GWAS) have identified genetic underpinnings of disease and enabled the development of polygenic risk scores (PRS) that may help to predict the occurrence and progression of common diseases. Working with the eMERGE team, we will select the fifteen diseases of public health impact. For these diseases, we will finalize the PRS to be adopted including adaptations (if any) for various race groups, the genotyping array, the family history (FHx) tool and key clinical variables to be used in calculating genomic risk estimates (GRE). We will identify GRE thresholds at which genomic risk assessment (GRA) with risk reduction recommendations (RRR) in concordance with practice guidelines. To strengthen the evaluation of race-specific PRS, we bring an additional cohort of 30,0000 African Americans. We will conduct a pilot ethical legal social implications study, to explore patient perspectives on use of FHx and PRS for estimating disease risk among Alabama Genomic Health Initiative (a statewide cohort) participants. The results will inform the development of consent, educational materials and a communication strategy to enhance recruitment and retention of eMERGE participants. We will prospectively recruit 2,500 patients with >75% patients from primary care, incorporate PRS, FHX and clinical data to compute GRE for the selected fifteen diseases for all patients. For high-risk patients, where GRE exceeds pre-specified thresholds (n~ 5000 of the 20,000 recruited across the network), deploy clinical decision support (CDS) and present the GRA and RRR. We expect ≥50% uptake of RRRs. We will assess whether the uptake of GRA-RRR improve outcomes. We will assess three outcomes: uptake of GRA-RRR (implementation outcome), adherence to clinic visits (engagement outcome), and surrogates of disease / control (clinical outcome, e.g. blood sugar, cholesterol). Although research has identified genomic signatures of common diseases, genomic risk assessments to identify, and if appropriate, pre-treat at-risk patients have not been implemented in clinical care. This is the vital first step to leverage the power of genomics to prevent disease. We bring our expertise and experience to collaborate with the eMERGE investigative team to take this vital first step.

NIH Research Projects · FY 2025 · 2025-08

Heart failure (HF), a condition associated with increased hospitalizations, cost, and mortality, is a large and growing contributor to the mortality gap between rural and urban populations in the United States. Individuals living in rural communities face significantly higher mortality from HF than those in urban communities. Without the development of effective HF management strategies tailored to rural populations, these individuals will continue to experience higher rates of morbidity and mortality. Rural-dwelling patients with HF face numerous obstacles to receiving appropriate outpatient care. Thus, there is a critical need to identify feasible, cost-effective, and scalable delivery strategies for HF care in rural areas. To this end, we plan to: 1) elicit feedback on remote intervention strategies to inform implementation of HF care within rural communities; 2) conduct a pilot 2³ factorial trial to examine the feasibility and acceptability of three intervention strategies for delivering HF care to rural-dwelling participants; and 3) characterize contextual factors relevant to the delivery and implementation of these remote care strategies. Our central hypothesis is that these intervention strategies (video-based visits, remote patient monitoring, and remote self-care education) will be feasible and acceptable, and that combinations of these components will show preliminary effectiveness in caring for rural-dwelling individuals with HF. Through this proposal and the Multiphase Optimization Strategy (MOST) framework, we will identify an optimal combination of intervention components to facilitate remote HF care, and combine with stakeholder input, we will develop a larger randomized trial. Additionally, the PI will use this proposal to focus a career on rural health as a physician-scientist through the following training aims: 1) Gain experience with qualitative research methods; 2) Develop skills in innovative trial design (factorial trials) and implementation frameworks; and 3) Advance expertise in intervention development for rural populations. This training plan will be supported by a multidisciplinary mentorship and advisory team to guide the successful completion of the research and training aims.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract The vascular endothelium, lining the inner surface of the arterial wall, responds dynamically to shear stress from blood flow. Atheroprone shear stress reduces atheroprotective gene expression and induces endothelial cell (EC) dysfunction, initiating atherosclerosis. Over the past decade, we and others have identified epigenetic and epitranscriptional regulations that are integral to shear stress-regulated gene expression. Although epigenetic regulation and histone post-translational modifications (PTMs) have been identified in ECs and other cells, the full extent of histone PTMs, as well as novel histone codes, remain to be fully understood. Recently, we discovered that O-GlcNAc occurs at the histone H3T32 site (H3T32OG) under atheroprone shear stress. A loss- of-function mutation (H3T32A) decreased H3 O-GlcNAc and increased H3K27ac in promoters of atheroprotective genes, suggesting systemic effects on chromatin accessibility and gene expression. To investigate the role of H3T32OG in atherosclerosis, we created a mouse model with a tissue-specific H3T32A mutation. These preliminary results led to the hypothesis that histone H3T32OG, as a novel histone code in ECs, mediates atheroprone shear stress-induced EC dysfunction and atherosclerosis. Mechanistically, H3T32OG competitively interacts with H3K27ac, ultimately restricting chromatin accessibility and downregulating atheroprotective genes in ECs. To test this hypothesis, we propose the following three specific aims: Aim 1: To elucidate the epigenetic features of H3T32OG in ECs under shear stress. Specifically, the shear stress-induced H3T32 O-GlcNAc modification site will be validated by mass spectrometry. Then, the enrichment of H3 O-GlcNAc will be identified by H3 O-GlcNAc ChIP-seq. Additionally, we will integrate H3 O-GlcNAc ChIP- seq data with existing datasets to understand the shear stress-governed epigenetic features of H3T32OG. Aim 2: To delineate the role of shear stress-regulated H3T32OG in EC function. Specifically, step flow channel- induced shear stress will be applied to mouse aortic ECs isolated from H3T32A mutation mice and their H3T32T littermates. Gene expression profiles and cell lineage mapping will be elucidated by single-cell RNA-seq. Furthermore, EC functional alterations between H3T32A and H3T32 will be evaluated in vivo and ex vivo. Aim 3: To investigate the effect of shear stress-regulated EC H3T32OG on atherosclerosis. We will evaluate the potential differences in atherogenesis in male and female iEC-OGT KO ApoE-/- mice vs. their wildtype littermates, as well as in iEC-H3T32A ApoE-/- and H3T32T ApoE-/- mice, by feeding them a high-fat diet or using a partial carotid artery ligation model. This research will enhance our understanding of epigenetic mechanisms in ECs and challenge current paradigms of histone modifications in health and disease.

NIH Research Projects · FY 2025 · 2025-08

Project summary/abstract Individuals with frequent exacerbations of COPD (ECOPD) experience increased risk for mortality and accelerated lung function decline. We have shown that reduced total IgG, IgG subclasses, and pneumococcal antibody levels and function are associated with increased ECOPD risk. However, the roles of underlying genetic variants in IgG and its receptor are not well-known. Our preliminary studies have shown that a distinct set of IgG are associated with exacerbations among African American participants in a large COPD cohort study. Our study will investigate the hypothesis that variants in the IgG heavy chain (IGHG) and Fc receptor for IgG (FCGR) interact to enhance susceptibility to functional antibody deficiencies and ECOPD in African American patients. Specific Aim 1 will investigate interaction between G3m6 variant of IgG3 and low- functioning FcγRIIIb alleles as a risk factor for severe ECOPD in African American participants in the SPIROMICS and COPDGene cohorts. To investigate the hypothesis that G3m6 allotype, in the presence of the ‘NA2’ FCGR3B variant predict increased risk for severe ECOPD, we will first use novel genomic analyses to determine haplotypes (combinations of alleles inherited from a single parent) for these variants. We will then confirm these variants using conventional qPCR-based methods. Associations with ECOPD will be analyzed using longitudinal follow-up data available in both cohorts. Specific Aim 2 will evaluate IgG3 hinge length as a mechanism for discordance between antibody levels and function, investigating the hypothesis that short hinge length will be associated with impaired antibody function with preserved antibody levels. We will first measure antibody levels and function in African American participants in SPIROMICS. We will then compare IgG3 hinge region length between participants with impaired vs intact antibody function in the presence of normal antibody levels. This investigation will be used to facilitate further studies of immunogenetic variation as a risk factor for antibody deficiencies and exacerbations in COPD, and will represent the most detailed study of these variants in African American cohorts to date. This study will also serve to address a knowledge gap regarding characterization of IGHG and FCGR variants in people of non-European ancestry. Ultimately these studies will contribute to our overall goal of developing personalized diagnostic and therapeutic approaches to mitigate the detrimental effects of frequent ECOPD.

NIH Research Projects · FY 2025 · 2025-07

53 million U.S. family caregivers provide critical daily unpaid assistance to individuals with chronic and/or life-limiting illnesses, 3.3 million of whom provide care to patients with cancer. Despite providing complex care, these cancer caregivers receive little to no support or training. While there has been a high standard and increasing success in testing interventions to support cancer family caregivers over the past two decades, less rigor and thoughtfulness have been given to developing implementation strategies to integrate these interventions into “real world” practice. Translation of evidence-based caregiver interventions to “real world” practice faces considerable challenges, including: lack of intervention testing in “real-world” delivery settings, lack of trained staff, limited outcome data on costs and healthcare utilization, limited funding sources for translation, limitations in provider knowledge, limited understanding of reimbursement and payment, and mechanisms to support caregiver programs. Based on our own national survey data of U.S. cancer centers, this has resulted in the near non-existence of evidence-based formal support services for cancer caregivers. To address this gap, the overall objective of this R25 project is to test a comprehensive national accelerator program, called INCITE (INcreasing Caregiver support Implementation through Training and Education), to train cancer centers and their staff in identifying, implementing, evaluating, and sustaining evidence-based cancer caregiver programs. The INCITE program is designed to work with health systems’ existing cancer center service lines and departments to develop new caregiver services. This is accomplished by providing implementation training, education, coaching, and technical assistance on: selecting, planning, and tailoring evidence-based cancer caregiver interventions for implementation into specific practices; start-up and launch processes; day-to-day operations and workflow; billing and business model planning, and long-term sustainability. Aim 1 will finalize and establish the INCITE program in partnership with experts and constituents from leading caregiver organizations. Aim 2 will test the INCITE Program in the form of two national traineeships/year to competitively selected interdisciplinary teams at U.S. cancer centers that will include pre-preparation learning activities, a 3-day in-person workshop, and post-workshop monthly virtual technical assistance for 6 months. Aim 3 will evaluate the impact of the INCITE Program by measuring a) program outcomes and b) cancer center team outcomes, including family caregiver programmatic development, at their institutions. Aim 4 will disseminate research products through interprofessional conferences, submission of peer-reviewed manuscripts related to program outcomes, and a website hub highlighting program achievements. This high impact project is expected to exponentially increase the presence of evidence-based cancer caregiver interventions and caregiver-focused support programs in U.S. cancer centers.

NIH Research Projects · FY 2025 · 2025-07

Hypertension, defined as systolic blood pressure (SBP) ≥ 130 mm Hg or diastolic BP (DBP) ≥ 80 mm Hg, is a leading cause of morbidity and mortality in the US and affects nearly half of US adults. Hypertension is also associated with substantial healthcare costs. In 2016, hypertension cost the US healthcare system $71 billion, and the total cost of cardiovascular disease (CVD) was $320 billion. Controlling BP among adults with hypertension can limit these negative consequences. Among adults with hypertension, those with controlled BP, defined as an SBP < 130 mm Hg and DBP < 80 mm Hg, have a lower risk of CVD events and all-cause mortality, and cost the US healthcare system less compared to those with uncontrolled BP. Antihypertensive medication and lifestyle changes (i.e., diet and exercise) have been shown to lower BP and improve BP control among adults with hypertension. Despite the effectiveness of these treatments, barriers to their adoption and utilization exist and contribute to low rates of BP control. Research reports only 43.7% of US adults had controlled BP in 2017-2018. In response to low rates of BP control, the US Surgeon General released a Call-to-Action to Control Hypertension to address the negative consequences of uncontrolled BP in the US. One of the recommendations contained in this Call-to-Action was to identify barriers which may undermine effective treatments for hypertension including antihypertensive medication use, lifestyle changes, and regularly attending visits with a healthcare provider. A vast proportion of US adults face barriers to BP control and the Call-to-Action recognizes that these need to be addressed. To improve rates of BP control for adults in the US, first, tools need to be created for health systems to more easily identify barriers to BP control. To address the gaps in identifying barriers to BP control, the objectives of the major study proposed in this R03 application are to first, develop a clinical decision support (CDS) tool that identifies patient barriers to BP control (i.e., medication nonadherence, diet). To do this, we will use qualitative methods and input from clinicians and patients with hypertension, separately, to develop an easy-to-administer questionnaire that will consist of clinical barriers and patient centered barriers to BP control identified through key informant interviews with clinicians and focus group sessions with patients. Second, we will administer the CDS tool to clinicians and patients in the University of Alabama at Birmingham Health System to determine the feasibility and acceptability of the tool and identify common self-identified barriers to BP control among patients.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY Gout coexisting with advanced chronic kidney disease (CKD) poses a complex and under-researched medical challenge. There is scant evidence and an important knowledge gap to guide gout management in patients transitioning from advanced CKD to end-stage kidney disease (ESKD), where dialysis or kidney transplantation (KT) becomes necessary. Understanding the burden of gout during the transition from non- dialysis CKD to ESKD and subsequently to KT is essential for optimizing treatment strategies and improving patient outcomes. This research, utilizing data from the United States Renal Data System (USRDS), aims to explore the evolution of gout burden (including flares and healthcare utilization) from advanced CKD to ESKD, and for those undergoing KT. Our overarching goal is to test the central hypothesis that individuals with concomitant gout and CKD progressing to dialysis (ESKD) will have an increased burden of gout (flares, emergency room visits, hospitalization, and cardiovascular disease) during the period of transition into dialysis. In addition, gout burden after kidney transplantation has decreased after the transition of anti-rejection regiments to those not using cyclosporine (primarily) and calcineurin inhibitors in general. We will test this hypothesis using data from the United States Renal Data System (USRDS) and the United Network for Organ Sharing (UNOS). For this, we will apply a self-controlled case series (SCCS) method, where individuals act as their own controls, reducing the influence of between-person confounding variables. We will also conduct a retrospective cohort study examining the change in the incidence of gout, immunosuppressive regimes, and related patient outcomes in Kidney Transplantation. The two aims will rigorously evaluate the natural history of the gout burden in critical phases of CKD and ESKD . The goal of Aim 1 (CKD to ESKD aim) examine the trajectory of gout burden and treatment patterns as patients transition from advanced CKD to ESKD. The goal of Aim 2 (Kidney transplantation aim) is to assess changes in gout incidence, gout flares, and outcomes including cardiovascular hospitalizations and mortality among KT recipients.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT: Exposure to early life stress (ELS), including abuse, neglect, and household dysfunction, significantly increases the risk of mental illness, chronic kidney disease, and cardiovascular disease (CVD) later in life. The previously characterized effects ELS and chronic disease development in adults may have their origins in ELS- dependent effects on composition and functions of the gut microbiota. The gut microbiota interact directly with the host’s immune and neurological systems and microbial derived metabolites have been shown to mediation cardiovascular function. My recently published research using a mouse model of ELS has determined that ELS alters the gut microbiota independent of maternal inheritance. This suggests ELS-medicated endogenous factors within the offspring are responsible for the ELS microbial phenotype. However, it remains unknown whether ELS-mediated changes in the gut microbiota play a direct role in the genesis risk factors for CVD. This proposal will address these knowledge gaps by identifying ELS-medicated factors that regulate the gut microbiota and elucidating microbial-mediated pathways that lead to increased CVD risk due to ELS. Adolescents and young adults with ELS have increased arterial stiffness and systemic vascular resistance. Using an established mouse model of ELS involving maternal separation, our novel data indicate that ELS is also associated with increased arterial stiffness in adolescent and adult mice. Furthermore, ELS induces superoxide production and endothelial dysfunction in adult mice. This suggests that vascular dysfunction is an important mediator of ELS-induced CVD risk. Our new data in mice show that ELS leads to reduced gut microbial diversity, lower circulating short-chain-fatty acids (SCFAs), and impaired gut barrier function during adolescence. Gut microbial diversity is negatively associated with arterial stiffness in women and reduced SCFAs are associated with hypertension and impaired gut barrier function. This suggests a role for the gut microbiota in ELS-induced vascular dysfunction, though exact mechanisms remain undefined. Therefore, the overall goal of this proposal is to elucidate mechanisms by which microbial metabolites mediate ELS-induced aortic stiffening and endothelial dysfunction and examine the potential of diet in the early intervention of CVD risk.

NIH Research Projects · FY 2025 · 2025-07

The overall mission of the Medical Scientist (MD-PhD) Training Program (MSTP) at the University of Alabama at Birmingham (UAB) is to train the next generation of physician-scientists who do rigorous translational research in academic or industry settings and who promote safety and rigor in their careers. Although the ultimate career pathway for individual trainees extends a broad spectrum from the conduct of basic biomedical research to clinical trials of novel therapeutic agents or procedures, the net effect of this cadre of investigators will be to increase the translation of basic biomedical understanding into clinical practice. Our Program focuses on the following objectives: 1) training students to master clinical knowledge and skills of medicine; 2) training students to master knowledge of a scientific discipline, including training in quantitative methods; 3) promoting the development of rigorous experimental and critical thinking skills; 4) promoting responsible conduct of research and ethical behavior; 5) training students in communication skills in science and medicine; 6) promoting supportive mentorship; 7) training students in leadership skills; 8) promoting resilience, wellness, and professional development; and 9) developing graduates who continue in the physician-scientist workforce. The UAB MSTP curriculum has three distinct phases: two years of basic science course work and summer research rotations (Preclinical Phase), an extended research period culminating in the PhD degree (Research Phase), and final clinical training leading to the MD degree (Clinical Phase). Each year, our MSTP will matriculate 12 students into the first program year and accept another one or two students through Advanced Transfer pathways (the NIH MD-PhD Partnership Training Program pathways, and MD or PhD to MSTP Advanced Transfer pathways). Our program currently has 82 students. Unique aspects and strengths of the UAB MSTP include high numbers of funded NRSA awards, 97% program completion rate, a lower (7.7 year) time to degree average than the national average, 100% residency match rate for MSTP graduates, exceptional faculty mentors across a broad array of specialties, options for research in non-traditional research programs, vertical integration of students, extensive student involvement and ownership in the program, strong clinical continuity training during the PhD years, and Advanced Transfer options. Our program will build on these strengths and nurture new ones, including a new alumni mentoring program and a new MSTP-focused learning community. Strong MSTP recruiting, leadership, and institutional support will ensure continued success of the UAB MSTP.

NIH Research Projects · FY 2024 · 2025-07

PROJECT SUMMARY Although acute viral replication has been well controlled with combination antiretroviral therapies (cART) in the early stage of HIV infection long-term HIV-1 viral protein exposure within the CNS causes dysregulation of monoamine transmission, which has been implicated as a key factor in HIV associated neurocognitive and depression-like behavior deficits with concurrent cocaine abuse. Cocaine abuse has been shown to enhance the incidence of HIV-1 associated cognitive depression and exacerbate its severity. Dopamine (DA) plays a significant role in the prefrontal cortex, which is an important brain region for higher cognitive function. Both DA transporter (DAT) and norepinephrine transporter (NET) are responsible for maintaining dopaminergic homeostasis. While serotonin transporter (SERT) can transport not only serotonin but also DA, DA release is increased by inhibition of SERT. Among the viral proteins, Tat protein plays a significant role in viral replication in the early stage of HIV infection and in the pathophysiological effects on the development of cognitive depression impairments. Our published work has demonstrated that in vivo expression of Tat protein dysregulates monoamine transmission by its allosteric interaction with DAT and NET in inducible Tat transgenic (iTat-tg) mice. Furthermore, our preliminary studies demonstrate that in vivo Tat expression increases serotonin release and decreases serotonin uptake through SERT in the midbrain of iTat-tg mice. We have identified SRI- 32743, a novel allosteric modulator, which attenuates Tat-inhibited DA transport via DAT or NET and alleviates Tat-potentiated cognitive impairments and cocaine reward in iTat-tg mice. Through further structure activity relationship studies, we identified four analogs of SRI-32743 with improved solubility and metabolic stability. The four analogs display partial inhibitory capability for monoamine transporters and attenuate Tat-induced inhibition of DAT-mediated DA uptake through an allosteric mechanism. This R01 renewal application proposes to expand our ongoing studies of allosteric modulators interacting with DAT by identifying the unique allosteric modulatory sites on monoamine transporters for Tat and cocaine binding. We hypothesize that attenuating Tat and cocaine binding to monoamine transporters through novel allosteric modulators with minimal effects on physiological changes in monoaminergic transmission preserve neurocognitive function in HIV-infected individuals with the concurrent use of cocaine. Three specific aims are proposed in investigating this hypothesis: (1) Design and synthesize novel allosteric ligands in recognition for Tat and cocaine binding sites on monoamine transporters as potential probes for in vivo pharmacological studies; (2) Characterize the in vitro pharmacological profile of the compounds to identify optimized probe molecules; and (3) Determine the therapeutic role of novel allosteric modulators in alleviation of Tat-mediated cognitive deficits and rewarding effects of cocaine in iTat-tg and EcoHIV mice. Collectively, this proposal is anticipated to provide mechanistic insights into how allosteric modulators reverse Tat-induced dysregulation of monoamine transmission.

NIH Research Projects · FY 2025 · 2025-07

Abstract: Electronic cigarettes (e-cigarettes/vapes) have exploded in popularity over the past several years with approximately 11.1 million (2021) U.S. adults and 2.13 million (2023) U.S. youths using e-cigarettes. Of particular concern has been the meteoric rise in the prevalence of vaping amongst pregnant women, where the prevalence ranges from 3 – 15%. Pregnant women may be at greater risk for vaping due to their perceived safety and may be more vulnerable to the risks due to the physiological and hormonal changes they undergo during pregnancy and fetal exposure. Despite the rise in prevalence and increased risk there is currently a paucity of research on the health effects of vaping during pregnancy. Limited prior studies on the topic have linked exclusive vaping during pregnancy with adverse birth outcomes such as lower birth weight and being small for gestational age; however, findings remain mixed. Prior studies on the topic have been limited by a lack of data on exposures and inflammation. Furthermore, most studies that have investigated the effects of vaping during pregnancy have been comparative studies with combustible cigarette use during pregnancy. Therefore, this study aims to investigate the health effects of exclusive vaping during pregnancy and determine the prevalence and characteristics of exclusive vaping during pregnancy in Birmingham, Alabama. To accomplish this, we will leverage the infrastructure and resources available through the University of Alabama at Birmingham (UAB) Hospital and Center for Women’s Reproductive Health. Participants recruited from UAB OB/GYN prenatal care clinics will self-report their tobacco product use during pregnancy via their standard hospital intake survey and the survey developed by our team. The results of these surveys will then be validated for 100 randomly recruited participants using urinary cotinine and exhaled carbon monoxide tests, which in combination will allow us to differentiate between vapers, smokers, and non-users. Data on the agreement between participants self-reported and biologically validated tobacco use will then be used to determine the prevalence of vaping during pregnancy in Birmingham, Alabama. We will then recruit a total of 120 pregnant participants to compare the exposure and inflammatory biomarker concentrations found in blood and urine, which will include (N=60) validated pregnant exclusive vapers and (N=60) validated pregnant non- users to determine whether pregnant vapers have significantly elevated levels of e-cigarette specific exposure and inflammatory biomarkers. Finally, exposure and inflammatory biomarker concentrations found in the umbilical cord blood of a subset of the pregnant vapers (N=20) and pregnant non-users (N=20) will be compared to see if maternal vaping related chemicals can make their way into fetal circulation and if they are elevated in e-cigarette users. This study will fill important current knowledge gaps on the health effects of vaping during pregnancy and will provide strong evidence which physicians and policy makers can use to make informed decisions.

NIH Research Projects · FY 2025 · 2025-07

Abstract Human immunodeficiency virus 1 (HIV-1) targets the human immune system and can lead to the development of acquired immunodeficiency syndrome (AIDS), increasing susceptibility to opportunistic infections and tumors. Current HIV-1/AIDS treatments involve the utilization of combination antiretroviral therapies (cART) that target and inhibit multiple steps of the HIV-1 replication cycle. People living with HIV must stay on treatment for the rest of their lives, which increases the risk of HIV-1 developing resistance to antiretrovirals. As a result, there is a need for the development of novel antiretrovirals. One target for possible antiretroviral treatment is the HIV-1 protein called Rev (regulator of expression of virion proteins). Rev functions as a nucleocytoplasmic shuttling protein for the nuclear export of viral mRNA necessary for virus assembly. To properly mediate the export of this mRNA, Rev must be able to translocate back and forth through the nuclear pore complex (NPC). Rev contains a nuclear localization signal and a nuclear export signal able to bind host importins and exportins, which are responsible for host cargo nucleocytoplasmic trafficking. This F31 proposal seeks to decipher how HIV-1 Rev is recognized, bound, and trafficked through the NPC by the host nuclear transport machinery. We hypothesize that Rev hijacks human importins and exportins, specifically importin-β and Crm1 (or exportin), for trafficking Rev through the NPC and preventing Rev aggregation and non-specific RNA binding. Aim 1 of this proposal explores binding determinants between HIV-1 Rev and importin-β. We will utilize cryogenic-electron microscopy (cryo-EM) and pull-down and turbidity assays to visualize and characterize the importin-β:Rev structure. Aim 2 explores the mechanisms of Crm1 nuclear export of Rev alone and bound to the HIV-1 genome. To better understand these mechanisms, we will use cryo-EM to determine the structures of Crm1 bound to Rev before and after adding viral mRNA.