University Of Alabama At Birmingham

NIH Research Projects · FY 2025 · 2025-09

In this new application, we propose the UAB Interdisciplinary Research Scholar’s Program in Women’s Health (BIRCWH) Career Development Program, dedicated to providing early career clinical and biomedical postdoctoral faculty with an interdisciplinary environment in which to attain the research skills and experience to become independent investigators in women’s health problems present across the lifespan. The primary objectives of this UAB Program will be: 1) to recruit early career faculty (Scholars) at/to the University of Alabama at Birmingham (UAB) who are motivated to develop an independent research career in interdisciplinary basic, clinical, and population research relevant to the health of women and, where appropriate, the use of both genders to understand the influence of sex as a biological variable on health and disease 2) to promote the career development of these Scholars by providing the opportunity to obtain a master’s of science in public health or other advanced training/certification in the principles and techniques of clinical and biomedical research 3) to integrate the career development of these Scholars within research projects in scientific areas of emphasis with important relevance to women’s health throughout the lifespan and 4) to assemble mentorship teams that include established, early/mid-career and peer mentors to partner with the Scholar in developing productive research programs and career development. We anticipate attracting Scholars from a variety of backgrounds involved in basic biomedical, translational, and clinical research, including the focus areas of Gynecology, Maternal-Child, Infectious Diseases and Cardiovascular health with clinical, basic science and/or population approaches. We anticipate supporting a total of 5 Scholars (maximum of 3 at any one time) over 5 years, with yearly appointments and individual support for 2-3 years, in which it is expected that independent funding will be obtained. The UAB BIRCWH Program will utilize specifically accomplished NIH and other funded, established, early/mid-career and peer program mentors, accomplished training advisory committee members, the resources of the UAB Center for Research in Women's Health (CRWH, a recognized University-Wide Interdisciplinary Research Center [UWIRC]), the UAB Center for Clinical and Translational Science (CCTS), the UAB Minority Health and Health Disparities Research Center, among other UAB campus resources including other UWIRCS, to provide an interdisciplinary matrix and guide the research career development of these early career faculty PhD/MD Scholars. The 2 Program Director/Principal Investigators (PD/PI) and third Co-PI, with the assistance of the Executive Committee and Training Advisory Committee, will be responsible for managing all aspects of the Program and formally guiding and tracking the performance of the Program and Scholars. The UAB BIRCWH Scholar’s Program will be implemented by nationally and internationally known mentors who are trained physician scientists and women’s health leaders.

NIH Research Projects · FY 2025 · 2025-09

The incidences of co-morbidities, such as obesity and diabetes, continue to rise, undoubtedly contributing to increased cardiovascular disease. This includes rising cases of heart failure (particularly HFpEF), for which in-depth understanding of the mechanisms involved in disease etiology, as well as treatment strategies, remain unmet needs. With respect to the current application, cardiac processes fluctuate dramatically over the course of the day, at molecular, cellular, and organ levels; these rhythms are mediated in large part by the cardiomyocyte circadian clock. We have recently unveiled the beginning of the sleep phase as a period of accelerated cellular constituent turnover, which is critical for cardiac growth and repair. Significance of this phenomenon is underscored by realization that cardiac growth only occurs when the heart is acutely challenged with prohypertrophic stimuli/stresses at the beginning of the sleep period. Moreover, repetitive challenge of the heart with a prohypertrophic stimulus at the beginning of the sleep period accelerates adverse cardiac remodeling and contractile dysfunction in models of heart disease. These studies highlight the importance of temporally coordinating extra-cardiac (e.g., behaviors) and intra-cardiac (e.g., circadian clocks) influences for the maintenance of normal cardiac function. The precise mechanisms promoting cardiac growth at the beginning of the sleep period remain unknown. Here, we provide evidence in support of two distinct contributing mechanisms. Our studies suggest that the cardiomyocyte circadian clock augments branched chain amino acid (BCAA) catabolism in the middle of the active period, when cardiac protein synthesis is lowest. This has led us to hypothesize that increased BCAA catabolism limits BCAA-mediated activation of mTOR and cardiac protein synthesis during the active period (Aim 1). We also provide evidence that the cardiomyocyte circadian clock activates the integrated stress response (ISR; an established translation inhibitor) in the middle of the active period. These data have led us to hypothesize that ISR activation during the active period attenuates cardiac protein synthesis at this time (Aim 2). Surprisingly, 24hr rhythms in cardiac growth appear to be antiphase during HFpEF, peaking during the active period, leading to the hypothesis that aberrant 24hr rhythms in growth mechanisms contribute to adverse cardiac remodeling and HFpEF development during cardiometabolic diseases (Aim 3). Collectively, these novel observations have led to the overarching hypothesis that temporal governance of pathways orchestrating cardiac growth (BCAA signaling and ISR) are impaired during cardiometabolic disease, leading to adverse remodeling of the myocardium, such that reinstatement of normal rhythms will attenuate HFpEF development. Successful completion of the proposed studies will reveal the mechanisms temporally governing cardiac growth, the extent to which these rhythms are impacted by cardiometabolic disease, and the efficacy of chronopharmacologic strategies for the treatment of HFpEF.

NIH Research Projects · FY 2025 · 2025-09

Recruitment, adherence, and retention are critical challenges in medical rehabilitation and health promotion research for people with physical disabilities. These challenges often result in small sample sizes, poor adherence, and high dropout rates, which limit the generalizability of research findings. In addition, combining data from existing and new datasets to develop research questions and analyze data across studies is a complex task. The Deep South, particularly Alabama, Mississippi, and Louisiana, has some of the highest disability rates in the nation. Chronic conditions like diabetes and obesity are significantly more prevalent in people with physical disabilities in this region, exacerbated by environmental barriers and an unsupportive environment that hinder healthy behaviors. The primary goal of this research project, supported by the Administrative, Resource, and Community Engagement and Outreach (CEO) Cores, is to apply AI and behavioral economics-based approaches to develop tools and strategies to optimize data utilization and improve retention and adherence to health promotion and secondary condition prevention (HP/SCP) interventions for PWD. These resources will be promoted to medical rehabilitation and health promotion researchers to facilitate more robust research in HP/SCP for people with physical disabilities. Aim 1 will develop AI-enabled tools to conduct data harmonization, leveraging existing data to support medical rehabilitation and health promotion researchers. Aim 2 will utilize behavioral economics–based approaches to learn participant preferences toward HP/SCP interventions. Aim 3 will develop and test the usability of an AI-enabled multichannel digital HP/SCP platform to improve adherence and retention in trial studies. Aim 4 will conduct factorial experimentation to pilot three behavioral economics–related design features in gamification and financial incentives to determine which optimizes adherence and engagement. Leveraging our ongoing digital health promotion tools at the National Center on Health, Physical Activity and Disability (NCHPAD) Data Coordinating Center, we aim to develop resources that will allow researchers to systematically address these barriers and develop their own digital HP/SCP interventions. Our research project is innovative through its use of behavioral economics and AI-enabled tools to improve intervention adherence and retention in HP/SCP trials. The resources developed will be invaluable for investigators in digital medical rehabilitation and health promotion research. They will facilitate data harmonization and analysis, incorporate user preferences to enhance intervention delivery, and ensure high usability through inclusive design and gamification. Ultimately, they will enable precision-based recruitment and adherence recommendations and support future optimization trials for digital HP/SCP interventions for people with physical disabilities. This research project aligns with the NCMRR/NICHD RFA-HD-25-001 to promote healthy behaviors and preventative medicine for secondary conditions, ultimately improving health and function for people with physical disabilities.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Abdominal Aortic Aneurysm (AAA) repair is typically recommended when the aneurysm diameter reaches 5.5 cm, based on studies that primarily included men. Women, however, face a fourfold higher risk of AAA rupture at smaller diameters and nearly double the mortality following surgery. This discrepancy raises critical questions about whether women should undergo elective AAA repair at smaller diameters than men to improve survival and quality of life. The WARRIORS trial (Women’s Aneurysm Research: Repair Immediately Or Routine Surveillance) is an international, randomized controlled trial designed to address this issue by comparing early elective endovascular aortic repair (EVAR) with routine surveillance in women aged 50+ with small (4.0-5.4 cm) asymptomatic AAAs suitable for EVAR. The trial will enroll 1,112 women globally, including 350 in the United States, with 1:1 randomization stratified by age, country, and aneurysm size. The primary outcome is AAA-related mortality and rupture over five years, while secondary outcomes include quality-adjusted life years (QALYs), operative mortality, loss of EVAR eligibility, and cost-effectiveness. The trial’s innovative design incorporates registry-supported data collection, novel electronic health record screening for patient identification, and extensive patient and community engagement to ensure broad representation and minimal loss to follow-up. The trial meets criteria for NHLBI’s strategic goals and objectives i.e. Objective 3: Investigate factors that account for differences in health among populations. By determining whether women should have different criteria for AAA repair, the WARRIORS trial aims to establish sex-specific clinical guidelines, ultimately advancing health equity and improving outcomes for women with AAAs.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY / ABSTRACT People with HIV on antiretroviral therapy (ART) have a higher prevalence of hypertension than HIV seronegative adults. In the last decade, integrase strand transfer inhibitors (INSTIs) have become the preferred ART class to pair with nucleoside reverse transcriptase inhibitors (NRTIs) to durably suppress viremia in people with HIV. In addition, INSTI-based ARTs and NRTIs backbone agents like tenofovir alafenamide (TAF) are associated with higher BP and increased incidence of hypertension compared with non-INSTI-based ART. Potential mechanisms contributing to higher blood pressure (BP) in people with HIV include off-target effects of ART. INSTI-based ARTs and NRTIs backbone agents like TAF are associated with weight gain, which may lead to chronic conditions including hypertension. Besides traditional risk factors, HIV conditions may also increase the risk of developing hypertension. However, unknown is the incidence of hypertension, if weight gain is a mechanism of hypertension incidence and if HIV and non-HIV risk factors cause hypertension incidence across different INSTI- based ARTs, especially second generation (which are more commonly used) including bictegravir and dolutegravir-based ART overall and with NRTI backbone combinations including TAF, tenofovir disoproxil fumarate (TDF) and others. The objective of the proposed study is to assess hypertension incidence in ART naïve people with HIV after initiation of bictegravir versus dolutegravir-based ART overall and with NRTI combinations (Aim 1); determine if weight gain is associated with incident hypertension in ART naïve people with HIV initiating bictegravir and dolutegravir-based ART overall and with NRTI combinations (Aim 2); and determine if HIV and non-HIV risk factors for incident hypertension in ART naïve people with HIV initiating bictegravir and dolutegravir-based ARTs (Secondary aim). The proposed study, titled “Role of Integrase Strand Transfer Inhibitors on Hypertension in People with HIV” will achieve the aims by analyzing data from Center for AIDS Research Network (CFAR) of Integrated Clinical Systems (CNICS) study. The proposed study is unique in that it will leverage the CNICS study, a well-established diverse large cohort of patients with HIV, that includes clinical data and patient-reported outcomes from 10 sites across the US. The study will evaluate hypertension incidence, weight gain as a mechanism and risk factors (HIV and non-HIV) within 2 years after initiation of bictegravir and dolutegravir-based ART overall and with NRTI combinations from 2018 to 2023.The proposed study can inform strategies to prevent and manage hypertension in people with HIV on second generation INSTIs-based ART. We anticipate that the results from this study will prepare us to propose and lead R01 grants testing risk factors, mechanisms and interventions to prevent the development of hypertension and reduce cardiovascular risk in people with HIV taking INSTI-based ART.

NIH Research Projects · FY 2025 · 2025-09

Modified Project Summary/Abstract Section HIV disproportionately affects the Southern United States with the highest burden of new infections. While biomedical HIV prevention strategies, such as pre-exposure prophylaxis (PrEP) and treatment as prevention can effectively prevent HIV acquisition and transmission, innovative strategies are still needed to ensure these tools are employed in the communities most impacted by the epidemic. Alabama, one of seven priority states in the U.S. Department of Health and Human Services Ending the HIV Epidemic initiative, recently permitted collaborative practice agreements between physicians and pharmacists. Over half of all pharmacies operating in Alabama are community-based with many operating in areas of the state of higher HIV incidence. Rapid status neutral approaches can improve linkage to HIV service delivery, and pharmacy-based HIV testing in pharmacies has been effective in other regions. However, critical gaps remain in understanding how to effectively incorporate HIV testing and service delivery in pharmacy settings in Alabama and other regions of the Southern US. To close that gap, this proposed study will pursue two specific aims: (1) Evaluate key determinants for implementation of a test-to-treat, status neutral rapid antiretroviral (ARV) intervention into independent pharmacy settings through concurrent mixed-methods; (2) Develop and refine a multi-component implementation strategy to integrate HIV testing, PrEP, and ART in routine pharmacy-based practice. Upon completion of our proposed research, our inter-disciplinary team, which includes experts in infectious diseases and HIV PrEP/ARV service delivery, implementation science, community-engaged research, and pharmacy care delivery, will lead to a multi-site type III implementation trial of PrEP service delivery at community pharmacies across the South.

NIH Research Projects · FY 2025 · 2025-09

Neuroimaging of Neuroinflammation in Temporal Lobe Epilepsy Project Summary/Abstract Epileptogenesis, a dynamic and adaptive process, is associated with focal neuroinflammation (NI). This, in turn, is accompanied by glial activation and corresponding focal temperature increases. Methods of visualizing NI have been tested mostly in animal models of epilepsy and are not readily translatable to in vivo human imaging. Advanced positron emission tomography (PET) has been used for human in vivo NI visualization. However, advanced PET methods are underdeveloped, unreliable for identification of NI, riddled with many technical, genetic and logistical obstacles, expensive, and readily available to only few investigators. A less technically challenging technique of in vivo NI visualization is greatly needed. We, thus, propose to investigate and validate a technique called magnetic resonance spectroscopic imaging and thermometry (MRSI-t) {via biomarkers in brain tissue and peripheral blood. MRSI-t measures} in vivo brain temperature (T) increases in response to focal NI; it relies on measuring the location of creatine (CRE) and H2O peaks on the ppm chemical shift distribution in multiple and relatively small voxels encompassing the whole brain. While the location of the CRE peak is stable on the ppm spectrum, the location of the H2O peak changes with temperature (TCRE) fluctuations. The first step towards implementing MRSI-t as a tool for in vivo assessment of NI is to determine the degree of focal TCRE elevation in treatment-resistant temporal lobe epilepsy (TR-TLE) and whether MRSI-t can differentiate TR-TLE from controlled TLE (C-TLE). It is also important to show that the TCRE measures are stable over time. Finally, the key is to examine the relationship between the results of MRSI-t and biomarkers of NI in the resected brain tissue from epilepsy surgery and in peripheral blood. To address this, we propose three specific aims: AIM 1: To quantify the TCRE distribution patterns in TR-/C-TLE participants and compare them to healthy controls, AIM 2: To assess the 12-week stability of the focal TCRE measurements in patients with TR-/C-TLE, and AIM 3: To determine the relationship between focal increase in TCRE and 1). Focal changes in NI biomarkers in surgically resected temporal lobe tissue and 2). Blood biomarkers of inflammation. Via completion of this project, we will determine the utility of MRSI-t for detecting TCRE elevations as a proxy for chronic low-grade NI that is the underlying cause of treatment resistance in TLE and the stability of the MRSI-t signals in TR-/C-TLE over time. We expect that this will lead to further development of MRSI-t as a biomarker for treatment resistance and allow for development of MRSI-t as a method for monitoring treatment response in focal TR-/C-TLE and its use in the presurgical evaluation of patients with TR-TLE.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Bacteria must be able to sense and coordinate an appropriate response quickly to ensure their continued survival in their constantly changing environments. Bacteria must be able to respond to a wide variety of stressors including DNA damage, nutrient starvation, heat, cold, acid, toxins, and others. To survive, bacteria have developed several conserved stress response pathways such as the well-known stringent response triggering production of (p)ppGpp in response to amino acid starvation and other stressors. Another stress sensing system found in nearly all living cells, from bacteria to eukaryotic cells, is inorganic polyphosphate (polyP), which contributes to the survival and virulence (ability to cause infection or harm) of bacterial cells. In E. coli, there was a long-standing hypothesis that that (p)ppGpp directly stimulated the production of polyP, based on the observation that (p)ppGpp inhibits exopolyphosphotase (PPX), reducing the degradation of polyP. Recent work from our lab, however, has found that polyP production is not dependent on (p)ppGpp, but now suggests previously unknown interactions between polyP and the stringent response. Both ∆relA ∆spoT mutants lacking (p)ppGpp and ∆ppk mutants lacking polyP are well-known for their multiple amino acid requirements. We were therefore surprised to find that an E. coli triple ∆ppk ∆relA ∆spoT mutant fails to grow on MOPS minimal media even when supplemented with casamino acids (CAA). Growth of the ∆ppk ∆relA ∆spoT strain is rescued by a currently unknown small molecule component of yeast extract, but under these conditions, our preliminary data shows severe and unexpected morphological defects in the bacterial cells, including filamentous and branching cells, and a strikingly high rate of mis-localized FtsZ rings. These data suggest unexpected and possibly redundant roles for polyP and (p)ppGpp outside of their canonical roles in stress response, survival and virulence. This suggests these two disparate, yet fundamentally conserved stress response pathways may be linked together and play a novel role in controlling the fundamental processes of cell division, elongation, and cell wall synthesis. Notably, these core biological functions tend to be highly conserved among bacterial species and essential for cell survival and are the primary targets of antibiotic therapies. The essentiality of polyP, SpoT and the RelA/SpoT homologs found in other bacteria make these attractive targets for antibiotic development, as an interruption of the stringent response or polyP makes cells at least unable to respond properly to cell stress and host defenses and can, under some circumstances, kill bacterial cells outright. Our goal is to elucidate the molecular mechanism of the interactions between (p)ppGpp and polyP and how they affect the growth, division, and metabolism of the bacterial cell.

NIH Research Projects · FY 2025 · 2025-09

Project Abstract Postoperative pain occurs in 80% of patients undergoing surgical procedures, with nearly 90% of these patients reporting moderate, severe or extreme pain1,2. Despite the attempts to understand and prevent severe pain after surgery, the percentage of patients who still suffer has remained unchanged for over 30 years4. For most patients, acute pain peaks between 24 and 48 hours after an operation6 and remits as the tissues heal, but for some patients, this unpleasant sensory and emotional experience can persist for months or even years7. Postoperative pain is complex and multifaceted, however, It has been suggested that if risk factors (biological and psychosocial) associated with chronic pain are recognized early in the preoperative period, then a patient is less likely to develop chronic postoperative pain (CPOP)5. Though preclinical pain models have provided evidence for some of the processes that might underlie the chronification of pain, postoperative pain in humans is complex and remains poorly understood10. General surgery provides a unique opportunity for researchers to examine the potential underpinnings of this transition (via human/clinical model) in a relatively controlled environment (I.e., operating room with procedures that are standard for specific operations). Thus, the proposed projects will employ the use of the biopsychosocial model, in the perioperative setting, to gain a deeper understanding of mechanisms that underlie nociception and the pain experience in humans. This will be achieved by examining aspects of endogenous pain modulation/ pain neurocircuitry (using quantitative sensory testing to assess diffuse noxious inhibitory control and pain facilitation), blood-based biomarkers (cytokines, chemokines, acute-phase reactants, pain-relative hormones, etc.) as well as relevant psychological features and social determinants of health (using standardized psychosocial and demographic assessments) in the preoperative setting that could potentially be used to predict which patients might experience more severe, frequent, and disabling pain in the postoperative setting and during other phases of recovery (follow-up). We will also examine biological markers in the immediate postoperative phase to assess immune response to surgical insult/injury. We anticipate that our work will ultimately identify novel biological and psychological correlates of postoperative pain that can be used to improve risk stratification and inform treatment decisions for patients who suffer from CPOP.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Pluripotency is a fleeting state in the embryo that is the source for all the cell types of the body. This enormous developmental potential is facilitated by a permissive genome structure globally depleted for the nucleosomal compaction and heterochromatin that direct lineage acquisition. Amazingly, embryonic stem cells (ESCs) derived from the inner cell mass capture the pluripotent state and its specialized chromatin signature in vitro. As expected, ESCs are enriched for activating histone lysine acetylations, but surprisingly are the most depleted for modifications associated with ongoing transcription found at gene bodies. The epigenome is causal in developmental potential as maintenance of pluripotency-associated modifications inhibits their differentiation and removal of somatic-associated modifications enhances reprogramming to induced pluripotent stem cells (iPSCs). Therefore, dynamic cell state transitions are a powerful platform that will be used mechanistically interrogate the epigenetic contribution to cellular identity. In both the embryo and in ESCs, the global depletion of heterochromatin permits widespread amplification of transcription, despite the near absence of transcription-associated gene body epigenetic modifications. The relative increase in transcriptional output was recently observed in adult stem cells and cancer stem cells, but the connection of developmental potential and the calibration of RNA output is currently unknown. The goal of this research program is to parse the interconnected network of cellular identity, the epigenome, and the global transcriptome. To identify how transcription is amplified, we will examine the regulation of RNA polymerase II checkpoints across cell states. We will define how gene body modifications that enforce the somatic fate regulate transcriptional output using specialized genetic depletion and targeting tools. We will uncover how ESCs interpret their uniquely high levels of histone acetylation to sustain pluripotency. Using acute degradation technologies, we will interrogate how acetylation directs RNA polymerase II across early developmental stages when transcription commences. The findings of our proposed studies extend to regenerative medicine and cancer biology as transcriptional output is a scalable feature of developmental potential across tissue type and cellular identity.

NIH Research Projects · FY 2025 · 2025-09

Project Summary This research program seeks to understand the fundamental mechanisms underlying the production, regulation, and function of microbial appendages, such as flagella and pili, and to use this knowledge to design self-assembled nanofibers for various biochemical applications. Microbial appendages, including flagella and pili, are essential structures that prokaryotic cells invest significant energy in producing. These appendages extend microns from the cell surface and play crucial roles in bacterial survival, adaptation, and virulence. Our recent work has focused on elucidating the structural and functional diversity of flagellar outer domains, revealing their roles in diverse functions such as surface attachment, colonization, and biofilm formation. We have also discovered new types of appendages, such as the extracellular cytochrome nanowires in both bacteria and archaea, which expands our understanding of microbial electron transfer mechanisms. Additionally, we have made progress in understanding the dynamics of pili production, demonstrating how a single pilin subunit can assemble into distinct pilus structures under different conditions, highlighting the adaptability of these structures. In the next five years, we plan to investigate several key areas that align with the overall vision of this project. One focus will be to uncover the interaction between the membranous sheath and a particular class of flagella outer domains in H. pylori. Understanding this interaction could lead to novel strategies for disrupting bacterial colonization and reducing the risk of severe complications. We also aim to discover and characterize a new class of pili in cyanobacteria, exploring their role in colony formation, toxin interactions, etc. Finally, we will combine our knowledge of cytochrome nanowires with self-assembled peptides to design self-assembled conductive nanowires. Our research program has the potential to significantly advance our understanding of microbial appendages and their roles in bacterial physiology and pathogenesis. Furthermore, the development of self-assembled peptide nanofibers could lead to innovative biomaterials with broad applications in biomedicine, opening new avenues for treatment and technological advancement.

NSF Awards · FY 2025 · 2025-09

Phytoplankton provide essential services such as oxygen production, but they are threatened by environmental perturbations including elevated light stress, warming temperatures, and ocean acidification. Less is known about how these changes will impact microscale interactions within the marine microbial community. These interactions warrant investigation as they influence key global biogeochemical processes. This research will test how climate change may shift cycling of extracellular reactive oxygen species (ROS) such as hydrogen peroxide. ROS production is projected to increase due to changing environmental conditions. Because ROS influence biogeochemical cycling and microbial interactions, changes in ROS production could have broad implications in future oceans. These efforts will advance current understanding of phytoplankton-bacteria relationships under current and future ocean conditions and how these microscale interactions will impact global processes. Through this project, educational resources will also be developed to provide hands-on research experiences and training in computational skills for undergraduate students. The goals of the proposed research are to 1) determine shifts in ROS dynamics and 2) assess plastic and evolutionary responses of co-cultures due to warming temperatures, elevated light stress, and ocean acidification. To address these goals, the postdoctoral fellow leading this project will conduct an evolution experiment wherein representative phytoplankton and heterotrophic bacteria are coevolved using a “scenario-based approach” consisting of a combination of climate change perturbations while tracking responses and resulting biogeochemistry. Phytoplankton used in the experiment will be a prokaryotic representative Prochlorococcus marinus and a eukaryotic representative Thalassiosira oceanica. Each phytoplankton will be paired with Alteromonas macleodii, which is widespread throughout temperate and tropical oceans. The experiments will be maintained for at least one year. In the first three weeks of the experiment, a factorial design approach will be used to help disentangle plastic responses to specific stressors. Throughout the experiment, changes in fitness, ROS, and culture conditions will be measured routinely. At specific points during the experiment, the investigator will also assess the metatranscriptome, metagenome, and metabolome of the model phytoplankton and heterotrophic bacteria community. Finally, a reciprocal transplant experiment will be conducted, wherein ancestral and evolved cultures will be exposed to control and climate change conditions while measuring fitness, ROS, culture conditions, as well as the metatranscriptome of co-cultures. This project is jointly funded by the Ocean Sciences Postdoctoral Research Fellowships Program and the Established Program to Stimulate Competitive Research (EPSCoR). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Alzheimer’s disease (AD) is the most common neurodegenerative disease, affecting more than 6 million Americans. As AD only continues to increase in prevalence, new therapeutic approaches are needed to combat this disease. A combination of clinical, neuroimaging, and neurophysiological studies have provided converging evidence that network hyperexcitability, including mostly subclinical epileptiform activity, is an important aspect of the early stages of AD. Many AD models exhibit similar network hyperexcitability that is dependent on both APP/Aβ and tau. Because network hyperexcitability can potentially be targeted by a variety of treatment approaches, a better understanding of the underlying mechanisms is needed. Circadian variation is a prominent aspect of AD-related network hyperexcitability, which occurs mainly during the inactive phase in both AD patients and mouse models. Emerging data from both human and animal models indicate that neural excitability is under circadian control. Diurnal changes in inhibition may drive this, as there is a relative increase in levels of cortical inhibition during the inactive phase corresponding to lower cortical excitability. Parvalbumin- positive (PV) interneurons are one of the most abundant interneuron types in the hippocampus and cortex; however, they are one of the multiple subtypes of inhibitory interneurons derived from the medial ganglionic eminence that interact to maintain cortical network dynamics. Preliminary data suggests altered clock gene expression in PV interneurons, increased epileptiform activity, and behavioral disinhibition in the hAPPJ20 model. Many important questions remain, including the functional and molecular mechanisms in MGE-derived inhibitory interneurons that contribute to circadian- and tau-mediated EA in AD models with increased levels of APP/Aβ. Thus, the current proposal will test the novel concept that circadian rhythms in cortical MGE-derived interneurons play a critical role in modulating network excitability and behavior. My overarching hypothesis is that altered clock gene rhythms in MGE-CINs contribute to network hyperexcitability and behavioral abnormalities, which can be corrected by tau reduction. I will test this hypothesis using single-molecule fluorescent in situ hybridization to quantify clock-gene transcript expression, electroencephalography to assess network hyperexcitability, and machine learning pipelines to analyze open-field videos for behavior. For these studies I will use hAPPJ20 mice, a commonly used model of AD with overexpression of APP & Aβ crossed with Tau+/- mice for my experimental groups for Aim 1. I will use Lhx6-Cre mice crossed with Bmalfl/fl to create a line of mice with the circadian clock ablated in only cortical MGE-interneurons, which will then again be crossed with Tau+/- for Aim 2 experiments. Overall, the work proposed will provide insights into the circadian mechanisms driving network hyperexcitability and behavioral changes in AD.

NIH Research Projects · FY 2025 · 2025-09

Project Summary The purpose of this proposal is to add to prior in silico and in vitro results, to support our novel finding that vitamin D3 is a ligand for TREM2, by conducting experiments in vivo. Alzheimer’s disease (AD) is the most common neurodegenerative disease and affects more than 6 million Americans. A rare loss-of-function-like variant in triggering receptor expressed on myeloid cells 2 (TREM2), TREM2R47H, causes a 2–4-fold increased risk of developing AD. TREM2 is a receptor on microglia, and other myeloid cells, that binds notable molecules involved in AD pathogenesis such as apoE and Aβ. Additionally, TREM2 plays an important role in microglial response to Aβ plaques by increasing microglial plaque coverage, phagocytosis, and proliferation while also altering their transcriptional response. We identified, via a virtual screen, and supported, via biolayer interferometry, that D3 and several of its derivatives bind TREM2 and, with less affinity, its deleterious variant TREM2R47H. Next, we conducted in vitro experiments on different myeloid cells, derived from rats and mice, that supported that D3 signals through TREM2. We observed an increase in downstream effects associated with TREM2 signaling like increased phagocytosis of Aβ and increased cell survival against toxic Aβ oligomers. To support these results, we propose experiments using hAPPJ20 mice, a transgenic AD mouse model that overexpresses human amyloid precursor protein (hAPP) and has increased Aβ production. Prior research has also established a link between D3 and AD. Studies have found that D3 deficiency increases, while supplementation decreases, risk of developing AD. D3 deficiency and supplementation in Aβ mouse models of AD have similarly found that lower D3 levels can exacerbate Aβ pathology. We will use normal, deficient, and supplemented D3 diets to alter D3 levels in hAPPJ20 mice over a ~5.5-month treatment period to examine interactions between Trem2 genotype and D3 level. Our hypothesis is that D3 protects against Aβ-induced dysfunction by increasing Trem2 signaling in vivo. We have planned two aims to test our hypothesis. Aim 1 determines if D3 deficiency exacerbates Aβ-induced dysfunction by decreasing Trem2 signaling while aim 2 determines if D3 supplementation ameliorates the detrimental loss-of-function-like effects of TREM2R47H by increasing Trem2 signaling. Trem2-targeted outcome measures were selected and grouped into three categories: Trem2 signaling, Trem2-dependent microglial functions, and neuronal health. Experiments utilize methods such as Western blots, immunohistochemistry, and behavioral assays to examine Trem2 signaling outcomes. This project and training plan are sponsored by Dr. Erik Roberson and Dr. Yuhua Song, who have a history of mentoring other successful MD/PhD students. The training for this grant provides me with the skill set and experience to help me achieve my career goal of becoming a physician-scientist who identifies and validates therapeutic targets to help the patients I treat.

NIH Research Projects · FY 2025 · 2025-09

Type 2 Diabetes (T2D) affects over 37 million people in the United States, signi ficantly contributing to healthcare costs and reducing quality of life. While lifestyle interventions have shown some success in reversing T2D, fewer than 20% achieve full remission. Bariatric surgery, particularly Roux-en-Y gastric bypass, leads to rapid T2D reversal, suggesting that neuro-hormonal factors play a role beyond mere caloric restriction. Understanding the nature of neural signaling between the stomach, pancreas, and brain may lead to novel solutions for diabetes treatment. This proj ect aims to develop and evaluate an Application-Specific Integrated Circuit (ASIC)-Based Edge Artificial Intelligence (Al) Wireless Vagus Ne rve Implant to investigate and modulate neural signaling between the brain, stomach, and pancreas. By recording vagus nerve activity and identifying correlations between neural patterns and diabetes progression, this intervention seeks to restore metabolic function and provide a drug-free therapeutic option for T2D management and reversal. The proposed research addresses key scientific and engineering challenges in neuromodulation by designing (1) a flexible electrode array and implant capable of withstanding continuous movement over the stomach for long-term use, (2) a low-power, min iaturized edge computing system within the implant to process neural signals, and (3) reliable machine learning (ML) algorithms adaptable to digital and analog edge computing within the implant for adaptive closed-loop neuromodulation without reliance on continuous external data connectivity. Through a controlled experimental design with test and control groups, the study will evaluate the implant's effectiveness in restoring glucose homeostasis and mitigating T2D progression. Clinical outcomes will be assessed based on metabolic improvements, insulin sensitivity, and overall glycemic control. This research advances a non-pharmaceutical intervention that integrates cutting-edge neurotechnology with whole-person health approaches. By contributing to neuromodulation, metabolic health, and edge Al-d riven biomedical applications, the findings may lead to groundbreaking, minimally invasive treatments for metabolic disorders and other neurological conditions. RELEVANCE (See instructions): This research explores a drug-free, implant-based Artificial Intelligence (Al) at edge approach to reversing Type 2 Diabetes (T2D), a condition affecting millions and driving significant healthcare costs. By targeting the vagus nerve, which connects the brain, stomach, and pancreas, this innovative intervention aims to restore the body's natural ability to regulate blood sugar, potentially reducing the need for medication or insulin. If successful, this technology could offer a safer, more accessible alternative for diabetes 11

NIH Research Projects · FY 2025 · 2025-09

Title: Studying The Mechanisms of Delayed Lung Injury Post-Arsenical Exposures Abstract In this study, we aim to investigate the mechanisms of delayed lung injury after a single exposure to trivalent arsenic chemical agents: Lewisite, Phenyl arsenic oxide, and arsenic trioxide. Our research using murine models has shown that skin exposure to Lewisite and Phenyl arsenic oxide, as well as single inhalation exposure to arsenic trioxide, leads to persistent systemic inflammation and fibrotic airway-centered chronic bronchitis. Additionally, in our model, we observed that single exposure to arsenic trioxide exposure led to hemolytic anemia-like lung disorder. We hypothesize that trivalent arsenic injury triggers the release of self- double-stranded DNA in the form of NETs, which activate IRF7 in airway epithelial cells. This activation leads to the transcription of type I interferons, initiating a feed-forward loop of IL-33 signaling that contributes to airway fibrogenesis in Lewisite/Phenyl arsenic oxide-exposed mice and persistent IFN-type I inflammation in arsenic trioxide-exposed mice. We are investigating how a single dose of trivalent arsenic induces mechanisms of NETs-IRF7-IL33 signaling, leading to persistent inflammation and implicating chronic lung disorders.

NIH Research Projects · FY 2025 · 2025-09

Stroke is a leading cause of disability and death with ischemic strokes (IS) accounting for more than 85% of strokes. After consideration of thrombolytics at presentation of IS, treatment of patients is limited to supportive care (e.g., blood pressure and glucose control) for neuroprotection. This represents a large gap in our management of patients with IS. The neuroinflammatory response after stroke is a major determinant of tissue injury and is triggered within minutes by activated microglia and astrocytes. These cells produce and secrete cytokines and vasoactive factors that exacerbate tissue injury either by direct cytotoxicity or indirectly by disruption of the blood brain barrier with increased vascular permeability, edema, and hemorrhagic transformation. The inflammatory cascade is further accelerated by glial production of chemokines which recruit peripheral immune cells, including neutrophils, monocytes, and T cells, within the acute phase of IS. Past failures in targeting neuroinflammation after IS likely stem from the multiple and overlapping pathways driving it. A major determinant of the glial inflammatory response is the RNA regulator, HuR, which promotes the expression of diverse pro-inflammatory mediators. Key drivers of inflammation after IS, such as IL-1β, TNF-α, COX-2, and iNOS, contain adenine- and uridine-rich elements (ARE) in the 3’ untranslated region to which HuR binds and positively regulates their expression. Our team has developed a novel class of small molecule HuR inhibitors that block induction of pro-inflammatory mediators in glial cells. Our preclinical studies indicate excellent and rapid penetration of SRI-42127 into the CNS after systemic administration. In middle cerebral artery (MCAO) models of IS, we observed significant reductions in IS volume after SRI-42127 treatment. We hypothesize that HuR drives a pro-inflammatory and toxic secretome in IS, initiated by glial cells, and then amplified by recruited peripheral immune cells. Furthermore, HuR inhibition will reduce secondary injury and improve functional outcome. We propose 3 aims: (1) Further characterize the beneficial effect of HuR inhibition by SRI- 42127 after IS, including aged mice, (2) Assess molecular and cellular mechanisms by which HuR inhibition improves recovery after IS, and (3) Assess the contribution of glial and macrophage HuR to neuroinflammation and secondary tissue injury after IS using mouse knockout models. The long term objectives are to gain mechanistic understanding of how HuR-mediated post-transcriptional regulation in microglia, astrocytes and other key cellular constituents impacts neuroinflammatory responses and secondary tissue injury after IS. The innovation of this proposal is the investigation into RNA regulation of inflammatory responses in glia and other immune cells (to date underexplored), including in aged models, and the development of a novel class of inhibitors for neuroprotection. The ultimate goal would be to fill a large clinical gap in the management of IS. The significance extends beyond IS as the same HuR-regulated pathways drive inflammation in other acute (e.g., traumatic brain injury or spinal cord injury) and chronic (e.g., ALS and Alzheimers) neurological diseases.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY This NIH F30 application describes a plan for mentored research and career development for the PI, Daniel Minassian. Community-acquired pneumonia (CAP) has increasingly been recognized as a significant risk factor for MACE such as new or worsening heart failure, arrhythmia, and myocardial infarction in hospitalized patients. Streptococcus pneumoniae (Spn) is the leading cause of CAP and models of Spn-induced chronic heart failure have been well-established by the sponsor of this proposal (Dr. Orihuela) in non-human primates and mice. The mechanisms through which Spn infection leads to heart failure are unclear, as it occurs despite appropriate antibiotic therapy, mirroring what is observed clinically; patients who survive treatment for pneumonia are at elevated risk for MACE even 10 years following admission to the hospital. Our preliminary data suggests that post-infection inflammation is causative of cardiac dysfunction as mice treated with a combination of steroids and antibiotics do not suffer reduced ejection fraction, and mice lacking T cells and B cells show a strong trend toward reduced or no chronic cardiac dysfunction following infection. Analysis of RNAseq data obtained from the hearts of mice acutely infected with Spn suggests that the CXCR3 ligands CXCL9 and CXCL10 are particularly upregulated; we have confirmed their production in reporter mice. These chemokines are highly pro-inflammatory and it is the objective of this proposal to determine how CXCL9 and CXCL10 contribute to subsequent heart failure. We hypothesize that CXCL9/10 signaling following pneumonia initiates an inflammatory cascade which leads to chronic inflammation and adverse cardiac remodeling. We will test this hypothesis by examining the impact of Spn infection on CXCL9 and CXCL10 production in the heart (Aim 1) and determining the role of CXCL9/10 signaling in modulating cardiac inflammation and long-term fibrosis (Aim 2). Aim 1 will primarily be accomplished through single nuclear RNA sequencing (snRNAseq) of hearts from infected or antibiotic-treated mice at different times. Aim 2 will be accomplished by blocking CXCL9, CXCL10, and their cognate receptor, CXCR3, through neutralizing antibodies or genetic knockouts and assessing cardiac inflammation through flow cytometry and cardiac damage through echocardiography, histopathology, and relevant biomarkers. All experiments will be performed at the highly funded University of Alabama at Birmingham which is equipped with faculty expertise in Spn and cardioimmunology and all the tools necessary for this proposal. Included in the training plan for the PI are experiences that will support Daniel’s career and professional development, such as 1) rigorous scientific training in the application of advanced flow cytometry, snRNAseq, and next-generation sequencing analysis; 2) presentation of findings at national conferences; 3) continuing clinical education. This proposal drives the development of skills supporting the PI’s future career as a cardiologist-scientist studying how immunological and infectious insults drive the development of heart failure.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with decline in memory and cognitive skills, eventually leading to the loss of ability to perform simple tasks. While genetics and a family history of AD are major risk factors, age remains the most critical risk factor for late onset AD (LOAD) as the percentage of individuals with AD increases dramatically with age. Accelerated aging in space provides unique opportunities to exacerbate aging related declines in tissue/organ function and amplify pathogenic signaling pathways associated with disease onset and progression. In this project, we are interested in how aging contributes to development and progression of AD. We are also interested in how onset of AD perpetuates dysfunction of other organs and systems, specifically, the heart and the cardiovascular system. To accomplish this, we will use cerebral organoids derived from AD human induced pluripotent stem cells (hiPSCs) cultured in Low Earth Orbit (LEO) (microgravity and ionizing radiation) to promote accelerated aging to study the effect of aging on cellular processes critical in progression of AD. To model how progressive neurodegenerative diseases affect other organs and systems, and vice versa, we will focus on the brain-heart axis. Thus, we will also utilize cardiac organoids generated from hiPSCs (control and AD patients) to study bi- directional communication in the setting of neurodegenerative disease. Finally, as a therapeutic strategy, we will evaluate if elimination of senescent cells with senolytic treatment in aged cerebral organoids can slow progression of hallmarks of AD including accumulation of beta-amyloid peptide (Aβ) and Tau tangles. Using an organoid model of accelerated aging, we hypothesize: (a) Aging exacerbates pathogenic APP processing and pTau resulting in enhanced Aβ deposition and Tau tangles, as well as DNA damage/loss of repair, (b) bi- directional communication between the heart and the brain in the setting of progressive neurodegenerative disease results in cardiac dysfunction, and (c) elimination of senescent cells will slow or mitigate progressive neurodegeneration associated with aging. Completion of the UG3 phase will result in: (a) successful terrestrial development of an AD cerebral organoid system and associated pathology, (b) confirmation that accelerated aging associated with LEO increases pathogenic APP processing, hyper-phosphorylation of Tau (pTau) and DNA damage, resulting in accumulation of Aβ and Tau tangles, and (c) demonstration that culture medium from AD cerebral organoids can perpetuate cardiac dysfunction. Results from the UG3 phase will inform studies proposed in the UH3 phase and technical milestones for the UH3 phase will include (a) establishing co-culture of AD cerebral and cardiac organoids in space and (b) determining if elimination of senescent cells via senolysis can be used as an effective therapeutic strategy to mitigate or slow progressive neurodegeneration associated with aging and prevent cardiac dysfunction.

NIH Research Projects · FY 2025 · 2025-09

Project Summary The PI3K-AKT pathway is one of the most implicated pathways in disease. AKT is the main regulator of the pathway through its interactions with over one hundred protein partners to accomplish specific cellular outcomes including cell proliferation, survival, metabolism, and protein synthesis. To accomplish these cellular outcomes, AKT must first undergo a conformational change in the cytoplasm towards an active conformation, then associate at the plasma membrane, and finally interact with its binding partners. Despite its prominent role in major cellular functions and knowledge of AKT’s activation process, real time mechanistic information regarding how AKT becomes active, associates at the plasma membrane, and interacts with its binding partners under physiological and pathological conditions is not well understood. We hypothesize that biophysical differences in each of these steps of AKT’s activation process underlie pathway dysregulation in disease. Knowing this information is critical to understand the basic biology of the pathway under physiological and pathological conditions, characterize/reveal important kinetic vulnerabilities associated with AKT conformational bias/membrane association, and identify AKT-protein partner complexes that can be exploited in the long-term to treat disease. To interrogate this hypothesis, we have developed novel live-cell bioluminescent- and bioluminescence resonance energy transfer-based assays that will be applied to measure how 1) conformational changes and membrane association, and 2) populations of AKT-protein partner complexes vary between physiological and pathological conditions. These approaches overcome major limitations associated with studying purified protein and complex results from standard cell-based viability and signaling assays. The results of this proposal will be the first to reveal the kinetic differences in AKT activation as cells respond to pathological conditions, and can be applied to any system. The prosed work over the next five years will generate substantial data and represents a hypothesis generating platform to propel the field forward.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Endothelin-1 (ET-1) is a vascular protein that promotes cardiovascular disease by contributing to hypertension, inflammation, and diabetes. Masashi Yanagisawa was the first described ET-1 in 1988. Realizing the importance of ET-1 in human physiology, the First International Conference on Endothelin Research was held the same year that brought together internationally renowned scientists working in the endothelin field to exchange and disseminate research findings. The Conference has been held every two years and has naturally morphed into a highly interdisciplinary event. The Conference attracts both basic and clinical researchers with expertise in nephrology, neurology, cardiology, oncology, comparative physiology and anatomy, and more. The aim is to review advancements in basic, translation and clinical research on the endothelin system in health and disease. This meeting was last held in 2023 in Rome, Italy. Since then, major clinical advances have been made, including the first FDA approved ET-1 antagonist for uncontrolled hypertension. The purpose of this proposal is to seek support for the “19th International Conference on Endothelin: From New Discoveries to New Treatments” scheduled on September 21-24th, 2025. The program will be organized into nine distinct sessions themed in fields where major recent advances have been made in endothelin research. These include 1) renal physiology and pathophysiology, 2) oncology, 3) vascular biology and hypertension, 4) nervous system, 5) inflammation and rheumatology, 6) women’s health, 7) cardiology, 8) endocrinology and metabolism, and 9) clinical trials/health disparities. Each session will include an invited keynote lecture intermingled with four abstract based talks. Both invited and abstract based talks will be given by early stage and senior investigators. There will also be two poster sessions which will have “on call times” for presenters to give their 3 min poster presentation followed by a Q&A period. Moreover, the meeting will have a strong emphasis on trainee involvement with efforts to promote development of young scientists, including faculty/trainee pair mentoring to facilitate lunch and coffee break discussion and a trainee mixer to promote networking and comradery.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Dr. Pankaj Arora is an Associate Professor of Medicine (Tenured), the Director of the Cardiovascular Genomics Clinic, and the Director of the Clinical and Translational Research Program at the University of Alabama at Birmingham (UAB). His ultimate career goal is to establish a Center for Precision Medicine that will provide multidimensional training incorporating clinical epidemiology, big data analysis, designing and conducting clinical trials, genomic studies, and precision medicine to young trainees to develop them into well-rounded physician- scientists. He has established a successful, federally-funded (3 R01 awards) laboratory that focuses on assessing the genetic determinants of natriuretic peptide (NP) levels, unraveling the pathophysiological pathways through which NPs cause cardiometabolic disease, and developing targeted approaches centered on the NP system to treat cardiometabolic diseases. Apart from NP-based projects, his research team has a consistent output of mentee-led projects ranging from epidemiological studies on cardiovascular health to the disparities in clinical outcomes in cardiovascular diseases, which have been published in prestigious journals. Dr. Arora has trained >20 mentees at various career stages, including undergraduate students, medical students, residents, cardiology fellows, and T32 fellows. The K24 award will provide Dr. Arora with protected time to mentor trainees and develop individualized plans to help his mentees achieve their research career goals. He would also work on improving his mentorship skills through the experiences of his mentorship team, comprised of previous K24 awardees with decades of mentorship experience, and through formal didactics on mentorship offered by the UAB Center Clinical and Translational Science. Furthermore, he will expand his research focus to include advanced genomics, proteomics, and implementation science. Dr. Arora will learn specialized genetic analytic techniques (rare and structural variant analyses) and gain hands-on experience in conducting targeted mass spectrometry to study the bioactive levels of NPs. Recognizing the challenges of implementing the results of research in clinical practice, Dr. Arora will attend didactics and work with an implementation scientist to devise a plan for the clinical implementation of polygenic risk scores in the Cardiogenomics Clinic. Dr. Arora proposes 3 unique projects that cover the range of clinical research including a post-hoc analysis of an ongoing R01 study to assess the racial differences in response to NP augmentation on correcting a non-dipping BP profile, examine the bioactive levels of NPs and their response to physiological perturbations using blood samples collected in 2 R01 studies, and determining the contribution of genomics to NP levels using data from a multi-ethnic cohort of US individuals. Therefore, these projects would not only expand the current knowledge on NPs and their role in cardiometabolic disease but also provide mentees with unparalleled training in clinical research.

NIH Research Projects · FY 2025 · 2025-09

Moderate-to-severe cancer pain is common in patients with advanced cancer and is often effectively treated with prescription opioids. Effective pain management is crucial for optimal quality of life and health outcomes in these patients. However, the emergence of the opioid crisis in the United States has sparked widespread fears about the use of opioid pain medications, given the potential for negative outcomes such as addiction and overdose. Despite being exempted from restrictive opioid policies, patients with cancer experience adverse consequences of efforts to address the opioid crisis, including stigma associated with prescription opioid use (“opioid stigma”). Based on our recently published Opioid Stigma Framework, we anticipate that opioid stigma results in several proximal (e.g., impaired patient-provider communication, suboptimal health behaviors, emotional distress, maladaptive coping skills) and long-term health consequences (e.g., less effective pain management, reduced health-related quality of life). Emerging evidence indicates that opioid stigma is common, pervasive, and has the potential to seriously impact patient well-being. However, there are no known interventions to mitigate opioid stigma in patients with advanced cancer. Thus, the proposed project will develop and test a novel behavioral intervention for opioid stigma in an effort to fill this unmet need. Together with her mentors, Principal Investigator Dr. Bulls will explore opioid stigma experiences and treatment priorities reported by 75 patients with advanced, painful cancer using rigorous concept mapping methodology (Aim 1). Next, Dr. Bulls will design a theory-based intervention to reduce negative proximal impacts of opioid stigma in patients with advanced cancer, soliciting feedback from patients and community-engaged institutional resources prior to piloting (Aim 2). Finally, Dr. Bulls will conduct a pilot trial of the intervention with 45 patients with advanced cancer pain to evaluate feasibility and acceptability in preparation for a full-scale randomized controlled trial (Aim 3). This project will facilitate training crucial to Dr. Bulls’ career development: advanced skills in participatory and stakeholder-engaged research methods, in-depth training in behavioral intervention development, and expertise in conducting clinical trials. Dr. Bulls has convened a dedicated, multidisciplinary mentorship team with expertise in essential content and methodological areas including palliative oncology, opioid pain management, health-related stigma, concept mapping, behavioral intervention development and testing, and recruitment of patients living with advanced cancer, among others. This proposal represents a comprehensive training, mentoring, and research plan to support Dr. Bulls’ transition into a successful independent investigator. At the end of the award period, Dr. Bulls will contribute substantially to the field as a leader in behavioral approaches to improve opioid stigma in patients with advanced cancer.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The purpose of this NIH F30 application is to support the PI, Skye Opsteen, and her mentored research and career development for the next three years. The proposed activities will strengthen her potential to become a successful physician scientist. The major goal of this project is to develop her experimental immunology skills to inform the biologic basis of post-COVID syndromes, particularly in people with HIV (PWH) given their increased baseline immune activation. The primary objectives of the research proposal are to investigate if the monocyte and T cell population shifts typical of chronic HIV infection are exacerbated during long COVID, and how the immune features of long COVID in PWH compare to people without HIV. Chronic inflammation has been implicated in long COVID development and is known to drive increased rates of comorbidities in PWH; therefore, studying long COVID in PWH offers a unique opportunity to characterize long COVID phenotypes driven by chronic inflammation. This project will investigate monocyte-mediated inflammation, specifically the role of CD16+ monocytes and inflammatory cytokines IL-1 and TNF in recovery versus long COVID development in PWH, and how these responses contribute to clinical symptoms such as fatigue (Aim 1). The project will also determine the contribution of adaptive immune responses during long COVID in PWH (Aim 2). Our long-term objective is to inform future long COVID studies of potential diagnostic markers and therapeutic targets for patients with long COVID phenotypes driven by persistent inflammation. The proposed training plan for the PI is sponsored by her primary PhD mentor, Dr. Nathan Erdmann, and co- mentor, Dr. Paul Goepfert. Included in the training plan are experiences that will help her develop in three major areas: 1) rigorous immunological research in HIV and SARS-CoV-2, which includes developing familiarity with the existing literature, critically evaluating published studies, and training in principles of scientific integrity and responsible conduct of research; 2) competence in bioinformatic techniques and biostatistical analysis; and 3) career and professional development, including grant writing, manuscript review, clear communication through presentation and manuscript preparation, and translation of research findings to clinical applications. After completion, this training plan will provide the PI with the foundation necessary for a successful career as a physician scientist. Her ultimate career goal is to one day lead a translational research laboratory that studies human immune responses to emerging and reemerging pathogens in the setting of chronic immune dysregulation to assist in the clinical prevention and treatment of various infectious diseases in at-risk populations.

NIH Research Projects · FY 2025 · 2025-08

There is no current curative therapy for asbestos-induced fibrosis. Recruited monocyte-derived macrophages (MDMs)play a critical role in the pathogenesis of asbestos-induced disease progression. The activation of MDMs is dependent on their metabolic profile. Metabolic reprogramming is a key feature in macrophage activation; however, the regulation of metabolic reprogramming of macrophages in asbestos-induce fibrosis progression is poorly understood. Other than causing an alternative phenotype in certain macrophages, little is known about ER stress and UPR in lung macrophages. The effect of ER stress and UPR on metabolic reprogramming in lung fibrosis has not been investigated in any cell type, including lung macrophages. Our preliminary data show that lung macrophages from asbestosis subjects have activation of PERK (p-PERK) and absence of p-IRE1a. Asbestosis subjects also express significantly more PGC-1a in lung macrophages than normal subjects. Silencing PERK (Eif2ak3) completely abrogated PGC-1a expression in the nucleus. Asbestosis lung macrophages have increased metabolites associated with metabolic reprogramming to OXPHOS. Over expression of PERK in macrophages markedly increased OCR, while a dominant negative PERK reduced OCR. Moreover, mice harboring a conditional deletion of Eif2ak3 in MDMs are protected from asbestos-induced lung fibrosis. Based on these observations, we hypothesize that macrophage ER stress and UPR have a crucial role in asbestosis progression by increasing PERK-mediated metabolic reprogramming. Aim 1 will determine if metabolic reprogramming has a role in asbestosis progression using mice with a conditional deletion of PERK (Eif2ak3) in monocyte-derived macrophages or with a PERK inhibitor. In Aim 2, we will determine the mechanism(s) by which ER stress and UPR activates PGC-1a to mediate metabolic reprogramming. Aim 3 will determine if activation of PERK is required for FAO in lung macrophages from subjects with asbestos-induced toxicity. The studies in this proposal will provide: (a) new insights into the effect of ER stress and UPR in progression of fibrotic disease; (b) an understanding of the molecular mechanism(s) by which ER stress and UPR modulate lung macrophages to undergo metabolic reprogramming; and (c) proof-of-concept by targeting UPR genetically to disrupt metabolic reprogramming and regulate or reverse established asbestos-induced fibrosis.