University Of Alabama At Birmingham

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY/ABSTRACT Background: Small non-coding RNAs including microRNAs and tRNA-related fragments (tRFs) are important regulators of global gene expression and have been shown to play key roles in normal development. Recent evidence suggests small RNAs (especially tRFs) can be regulated via modifications, however global analysis of small RNA modifications in cancers is still lacking due to lack of tools. In this proposal I will test whether dysregulation of small RNA modifications play a role in cancer biology. I will focus on glioma/glioblastoma (GBM), vicious cancer types that are barely treatable. Research: The candidate's preliminary results indicate that tRFs are novel regulators of gene expression and cell phenotypes in gliomas and their activity could be regulated by small RNA modification status. The candidate already detected such small RNA modifications in GBM and GSC (glioma stem-like cells) cell lines and also GBM patients. This proposal aims to understand the biological functions of these newly identified small RNA modifications and tRFs in gliomas. If completed, this will bring novel insights to the field and be a perfect niche to launch an independent lab. Three aims are proposed, each based on preliminary data, and taking into the independent phase. Aim 1 will determine the glioma-relevant small RNA modification factors. Aim 2 will define the functional roles and targetome of glioma-prognostic tRFs. Aim 3 will elucidate novel RBP- based mechanisms of small RNA modification regulating tRF targetome and pathways in gliomas. GSC cultures and mouse xenografts, genomics and bioinformatics will be employed to tackle these questions. The proposed research plan will reveal a novel gene regulatory mechanism by small RNA modifications and identify potential therapeutic targets for glioma treatment. Candidate: The candidate's long-term goal is to utilize her background in biochemistry, small RNA and molecular biology to understand new gene regulatory mechanism in cancer biology. She already processes a lot of the skills needed to conduct proposed experiments, however she is in great need to obtain additional training in glioma biology in order to further test her hypothesis (with co-mentor who is an expert in GBM field). The K99 mentored phase will allow her to build on her current data, expand on several new areas, and learn new techniques to launch her own lab. A mentoring committee of 6 is proposed to ensure the candidate get guidance to help her achieve independence. Environment: The proposed project will be conducted at University of Virginia, which has an outstanding environment for the proposed training and research.

NIH Research Projects · FY 2024 · 2023-07

PROJECT SUMMARY Cardiovascular disease (CVD) is the leading cause of death in the United States, and obesity is one of the highest risk factors for CVD. Our lab has shown that restricting intake of high fat diet (HFD) to the 12-hour active period for the last 2 weeks in a 20-week diet induced obesity (DIO) model significantly reduces aortic wall thickness and fibrosis and restores aortic endothelial function. We also found that DIO significantly increases aortic Th17 cells, which are an inflammatory CD4+ T cell subset that are known to drive progression of autoimmunity and organ damage. Interestingly, time restricted feeding (TRF) in the final 2 weeks of the DIO protocol reduced aortic Th17 cells. Th17 cells are the main producer of the inflammatory cytokine, IL-17A. IL- 17A has been known to drive CVD risk factors, however, it is unclear if TRF reduces aortic damage via the IL- 17A pathway. Furthermore, we have preliminary data that TRF in DIO is associated with greater circulating propionate and butyrate, which are two important microbial-derived short chain fatty acids (SCFA). SCFA are important for regulating hypertension and promoting anti-inflammatory T cell subsets, however, their role in DIO induced tissue damage is unclear. DIO is associated with decreased SCFA production, which could indicate that propionate and butyrate are necessary for protection against DIO damage. This led us to hypothesize that reduction of IL-17A and increased SCFA with TRF drive aortic protection and improved endothelial function in DIO. We will use C57Bl6/J mice for our 20-week DIO model with TRF intervention in the final two weeks of feeding. During those 2 weeks, mice will receive anti-mouse IL-17A or IgG antibody daily at Zeitgeber Time (ZT) 0, the start of the inactive period. Using these groups, we will assess aortic damage via pulse wave velocity (PWV) and histology. We will also assess endothelial function via vascular reactivity by stimulating the aorta with acetylcholine to assess endothelial dependent vasorelaxation. Sodium nitroprusside is used to assess endothelial independent vasorelaxation. Furthermore, we will use our TRF intervention in DIO to assess pathogenicity of Th17 cells in the aorta via single cell RNA sequencing. Th17 cells that upregulate the IL-23 receptor (IL-23R) are known to have greater pathogenic capabilities. In aim 2, we will use our 20-week DIO model with C57Bl6/J mice. During the final two weeks, the diet will be supplemented with 5% butyrate and propionate by weight in the inactive period as that is where we see increase of circulating SCFA. We will assess how dietary SCFA affects aortic Th17 cells via flow cytometry. Flow cytometry will allow us to immunophenotype the cells to identify if SCFA have an effect specifically on Th17 cells. We will also assess aortic damage and function via histology and PWV measurements at the conclusion of the 20-week DIO protocol. Endothelial function will also be assessed via vascular reactivity experiments. The main goal of this proposal is to identify how TRF in DIO improves aortic damage and endothelial function through regulation of Th17 cell pathogenicity.

NIH Research Projects · FY 2024 · 2023-07

Changes in the strength of GABAergic transmission is heavily influenced by posttranslational modifications and allosteric modulators like benzodiazepines and neurosteroids. O-GlcNAcylation (O- GlcNAc) is a post- translational modification that is tightly regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which add or remove the O-GlcNAc moiety of β–N-acetylglucosamine to Ser/Thr residues on proteins, respectively. Various neurodegenerative diseases like Alzheimer's disease (AD), and metabolic disorders like, diabetes exhibit dysregulated O-GlcNAc levels. Published reports from our lab have demonstrated that an acute increase in O-GlcNAcylation induces a long-term depression of evoked GABAAR mediated IPSCs (eIPSCs) and reduces the amplitude and frequency of spontaneous IPSC (sIPSC) in hippocampal principal cells, however the mechanism in which this occurs is unknown. Numerous studies have shown that serine phosphorylation of GABAAR can increase or decrease GABAAR currents depending on the neuron type and specific subunit. While O-GlcNAcylation modulates inhibitory GABA-gated currents, no studies have examined its interplay with serine phosphorylation on GABAergic transmission. Because the crosstalk between O-GlcNAcylation and phosphorylation affects the regulation of various proteins, the potential exists that O-OglcNAcylation and phosphorylation will interaction in the modulation of GABAAR function and the strength of inhibitory transmission. Furthermore, a potential interaction could impact how allosteric modulators effect GABAARs, since serine phosphorylation can either increase or decrease efficacy of these modulators. Studies proposed will investigate these hypotheses and will also test whether disease conditions where O- GlcNAc levels are chronically elevated lead to depressed GABAAR function that can be rescued via pharmacological inhibition of OGT. To determine O-GlcNAcylation's effect on GABAergic transmission in the presence of phosphorylation and allosteric modulators, I will use electrophysiological techniques, immunoblotting assays and mass spectrometry. Results will show whether the modulation of GABAAR function by PKA and allosteric modulators are shaped by the presence or absence of a co-occurring O- GlcNAc modification and if the restoration of O-GlcNAcylation levels in a disease models can restore the E/I balance.

NIH Research Projects · FY 2025 · 2023-07

PROJECT ABSTRACT This grant application is for the F31-Diversity support of Courtney Swain during her MD-PhD training. The research focus of this proposal is to establish a mechanism in which hyperglycemia and Hedgehog (Hh) signaling conspire to modulate CD8+ T cell exhaustion and regulatory T cell (Treg) immunosuppression in triple-negative breast cancer (TNBC). Breast cancer continues to threaten the lives of many women in the U.S. and worldwide as it accounts for more than 30% of all female cancer cases. Additionally, type 2 diabetes mellitus (T2D) is a highly prevalent morbidity and about a quarter of breast cancer patients are diabetic, which can increase treatment complications and limit therapy options. TNBC tumors are immunologically “cold,” characterized by the limited infiltration of cytotoxic populations and increased abundance of immunosuppressive constituents in the primary tumor. Hyperglycemia in T2D pathogenesis has been implicated to impair CD8+ T cells, lymphocytes critical in tumor killing and immunotherapy response, and their exhaustion process. Upon tumor challenge, subsets of immunologically reactive TCF1+ stem-like and TCF1- transitory effector CD8+ T cells are generated. These CD8+ T cell subsets have been found to be highly essential in tumor control despite their phenotype and nomenclature of early exhaustion. Notably, hyperglycemia exacerbates dysregulated Hh signaling in breast cancer. Initial investigations have revealed that hyperglycemia and Hh signaling may be cooperatively driving dysfunctional CD8+ T cell exhaustion in the mammary tumor milieu. Additionally, the presence of Tregs during mammary tumorigenesis correlates with poorer prognoses in TNBC. Supporting evidence in this proposal underscores that both, Hh signaling and hyperglycemia, impair CD8+ T cell exhaustion and promote Treg immunosuppression. However, the mechanisms by which these factors influence these key T cell populations are unknown. Therefore, this proposal will apply unique model systems of Hh signaling and hyperglycemia to delineate their roles in CD8+ T cell and Treg activity in TNBC. Findings will provide more relevance for combination TNBC therapies, especially for the distinct patient population of diabetic breast cancer patients. The proposed training plan for the PI is sponsored by her PhD mentor, Dr. Lalita Shevde-Samant. The goals of the training plan are to provide the PI with: (i) a rigorous research project using distinctive pre-clinical models of diabetes-associated breast cancer, novel genetically engineered mice, and tumor-immune crosstalk; (ii) opportunities in developing immunologic and bioinformatic techniques and in expanding training in responsible conduct of research, rigor, reproducibility, and principles of scientific integrity; and (iii) a scientifically enriching and equipped environment essential for developing a successful career as an oncologist-scientist. Given this project’s focus on the interaction of two major disease challenges of the U.S., breast cancer and diabetes, the PI will have exemplary guidance and a solid foundation to develop into a very competent physician-scientist.

NIH Research Projects · FY 2026 · 2023-07

7. PROJECT SUMMARY / ABSTRACT. Gastrointestinal (GI) mucosal damage and destruction of the gut epithelial barrier are the defining features of the pathogenesis of HIV-1 infection. Accumulated evidence indicates that neutrophils play a critical role in the gastrointestinal and liver damage in HIV-1 infection. Neutrophils infiltrate the GI tract in HIV-1- infected individuals at high levels and their presence is associated with damage to the epithelial barrier, elevated epithelial permeability, and increased disease severity in animal models and HIV-1-infected patients. In this application, we propose that microbial translocation and the resulting systemic innate immune dysregulation mediated by changes in neutrophil subpopulations in circulation, gut-associated lymphoid tissue (GALT), and liver plays a fundamental role in HIV-1 disease progression. The overall objectives of this proposal are to define the role of neutrophil subpopulations and NETosis as driving mechanisms of gastrointestinal and liver damage in HIV-1 infection and to identify the mechanisms responsible for chronic neutrophilic activation in HIV-1 infection in order to reveal the specific checkpoints for intervention. Our central hypothesis is that HIV-1 infection is associated with the induction and expansion of specific neutrophilic subpopulations with increased capacity to produce reactive oxygen species (ROS) and undergo NETosis. ROS and NETs released from activated neutrophils promote damage in the GI mucosa and liver and drive the progression of HIV-1 infection. This hypothesis has been formulated on the basis of our preliminary data and recently published reports demonstrating the critical role of neutrophils in HIV-1 infection. In preliminary studies, we optimized methods for detailed neutrophil characterization and demonstrated that neutrophils from HIV-1-infected individuals display an activated phenotype, immunosuppressive properties, specific transcriptional profile, increased rate of degranulation, and a high capacity to undergo NETosis. Specific properties of the newly identified neutrophil subpopulations strongly indicate that they play a critical role in damaging GI mucosa and the pathogenesis of liver disease in HIV-1-infected individuals. We propose to determine the effect of induction of specific neutrophil subpopulations on the progression of liver disease in ART-treated HIV-1-infected individuals, to identify specific properties of neutrophil subpopulations in the GALT and liver of HIV-1-infected individuals, and determine whether the innate immune dysregulation in these tissues is associated with a shift in the ratio of tissue macrophages exhibiting M1 versus M2 phenotype resulting in lowered efferocytosis and accumulation of neutrophils undergoing NETosis. The significance of the proposed studies is that once the role of neutrophils in the progression of HIV-1 infection is defined, neutrophil activation and induction of pathogenic populations can be pharmacologically targeted.

NIH Research Projects · FY 2025 · 2023-06

Project Summary/Abstract Syphilis in women is usually a silent infection caused by Treponema pallidum (T. pallidum) that can efficiently cross the placenta during all stages of pregnancy and infect the fetus. In the absence of timely diagnosis and treatment, the natural history of infection in pregnancy includes adverse birth outcomes in 80% (spontaneous abortion, stillbirth, low birthweight, preterm delivery, congenital syphilis, and neonatal death). Our team and others have documented elevated prevalence of syphilis in pregnancy in Cameroon and Zambia (3-6%) with high HIV coinfection rates (10-40%). Despite public health efforts, syphilis is the leading preventable cause of stillbirth globally and available diagnostic testing has critical limitations in pregnant women and infants. The Syphilis in Pregnancy Study (SIPS): Molecular Diagnostics and Maternal and Infant Immune Response to Infection brings together an international team of experts in perinatal and pediatric clinical infectious diseases, syphilis molecular biology and immunology to address priority questions in the STI field about the natural history of syphilis in pregnancy and vertical transmission. The SIPS team has designed an observational cohort to enroll and follow 750 well-characterized pregnant women with confirmed syphilis and their exposed infants as well as 750 pregnant controls in Cameroon and Zambia with follow up and repeated sample collection through 12 months after delivery. SIPS participants will have pre- and post-treatment blood samples, cord blood, and placentas collected from women, neonates, and infants to assess immune responses in addition to oral and lesion swabs for PCR testing to carry out the following aims: Aim 1: Identify clinical and host factors independently associated with favorable birth outcomes among pregnant women with syphilis; Aim 2: Characterize the adaptive T. pallidum immune response before and after treatment in pregnant women and their exposed infants; Aim 3: Evaluate quantitative PCR (qPCR) testing on oral and lesion swabs to detect T. pallidum and enhance diagnostic testing in pregnancy and neonates. Aim 1 will test the hypothesis that factors associated with robust maternal immunity will be associated with favorable birth outcomes in multivariable models with clinical and host factors. Aim 2 will test the hypothesis that a robust adaptive immune response (humoral immunity and CD4 T cells) will protect against vertical transmission and assess the role of T. pallidum-specific transplacental maternal antibodies in mediating fetal and infant protection. Aim 3 will test our hypothesis that newly developed molecular diagnostic testing of easily collected oral swabs will help refine and improve the diagnosis of syphilis in pregnant women and infants. Our expected outcome is to identify T. pallidum antigens with a role in dissemination, placental attachment, and vertical transmission. Our long-term goals are to advance these newly identified antigens as potential vaccine candidates for reproductive age women and to support syphilis diagnostic testing with highly specific molecular testing and specific antigens that can discern syphilis stage and treatment response in pregnant women and infants.

NIH Research Projects · FY 2026 · 2023-06

Single amino acid variants in TREM2 have been identified by genome-wide association studies to be one of the strongest genetic risk factors for late-onset Alzheimer's disease (AD). AD-associated variants in TREM2 impair TREM2's ability to bind and signal in response to ligands in the body, further affecting TREM2-mediated immune activation in AD. Identifying the available drugs as TREM2 ligands and understanding how the drugs regulate TREM2-mediated immune activation, could reposition the available drugs to target TREM2 and aid the development of combined drug therapy for AD treatment. The central hypothesis of the proposed study is that the available drugs, including FDA-approved drugs, could bind TREM2 at either basic and/or hydrophobic binding site, allosteric effect of drugs at TREM2 either or two binding sites could regulate ligand binding at both sites to modulate TREM2-mediated immune activation in AD, and compensate for the loss of TREM2-mediated immune activities by AD-associated TREM2 variants. We will test the hypothesis with three Aims with integrated computational and experimental approaches. Aim 1 is to identify available drugs bound basic or/and hydrophobic binding sites on TREM2 with unbiased virtual screening and biophysical and biological experimental validation. Aim 2 is to characterize the interactions of the available drugs with TREM2 and determine the allosteric effect of available drugs binding at basic and hydrophobic TREM2 binding sites, and on TREM2-mediated immune activation. Aim 3 is to determine whether the available drugs bound TREM2 could counteract the loss of TREM2-ApoE binding and its mediated immune activities caused by AD- associated TREM2 variants. New knowledge gained from this study could have high impact for AD research and treatment by repositioning the available drugs to target TREM2 and further the insight into available drugs modulating TREM2-mediated immune activation, offering a molecular basis for strategy development of using available drugs including drug combinations to target TREM2 for AD treatment. Investigating novel TREM2 functional mechanism in AD at a fundamental level  how TREM2 activation by available drugs at basic and/or hydrophobic sites and whether and how available drugs compensate for the loss of TREM2 immune activity by AD-associated variants  is the necessary first step. Innovations of study include: 1) This will be the first study to identify available drugs as TREM2 ligand by targeting both TREM2 basic and hydrophobic sites in a more conclusive manner with unbiased virtual screening and validation with biophysical binding and biological cellular function experiments. 2) Results from this study will unveil novel findings about the allosteric effects of available drugs binding at either TREM2 binding site, on TREM2 binding AD pathology related ligand in the body including ApoE, and on TREM2-mediated immune activation. 3) Research outcomes could propose targeting TREM2 with available drugs currently used for other conditions to compensate for loss of TREM2-mediated immune activities by AD-associated variants for AD treatment.

NIH Research Projects · FY 2026 · 2023-06

OVERALL ABSTRACT Cancer mortality, especially for obesity-related cancers like breast, prostate, and colorectal cancer, is higher in areas of the US affected by Persistent Poverty (PP), i.e., areas with a poverty rate of 20% or higher across four consecutive decennial censuses spanning 30 years (a formal geographic classification developed by the US Department of Agriculture and codified by Congress), compared to areas in which poverty has not persisted for decades. While reasons may be multifaceted, the role of the living environments in these areas cannot be overlooked: aspects of such environments (e.g., poor walkability and low social cohesion) have downstream effects on behaviors that impact health promotion and increase cancer risk and mortality. Multi-level interventions are necessary to mitigate these effects. In 2021, Alabama ranked 8th in the US for poverty. The state includes some of the most impoverished inner-city and rural communities in the nation, and thus a considerable number of both urban and rural Census Tracts (CTs) identified as PP areas by the National Cancer Institute (NCI). The overall goal of the University of Alabama at Birmingham (UAB) Center for Cancer Control in Persistent Poverty Areas (C3P2) is to reduce the burden of cancer and cancer disparities in PP areas by expanding research and research capacity through implementation and evaluation of multi-level interventions to improve cancer outcomes across the cancer control continuum from prevention to survivorship. The C3P2 goal will be achieved through: 1) Establishment and support of two transdisciplinary, multi-level, multi-domain research projects to adapt, implement, and evaluate multilevel interventions across the cancer control continuum from prevention to survivorship, as well as pilot projects through a Developmental Core; 2) Establishment of a coordinated C3P2 infrastructure to support and strengthen the C3P2 research agenda by: a) providing overall integrated management and comprehensive evaluation, b) providing common research resources and measures to promote project integration and collaboration (Administrative and Research and Methods Cores); 3) Development of a pipeline of investigators for cancer control research in PP areas by providing training, support, and research experience opportunity to early career investigators (Career Enhancement Core); 4) Academic-community partnership building with establishment of a Community Advisory Board and engagement of Community COaCHes to support innovative and salient research in the community, and monitoring and evaluation to ensure achievement of proposed goals. (Administrative Core). Our multi-disciplinary team of established and early career investigators, working in a supportive environment with the resources and commitment to address and challenges in PP areas to cancer prevention and control, are well positioned to make an impact in PP communities of Alabama and improve cancer outcomes. The C3P2 will serve as a model to improve cancer prevention and control for other PP areas in Alabama and other states.

NIH Research Projects · FY 2026 · 2023-06

The overall goal of our proposed research is to develop robust premortem biomarkers for accurate and differential diagnosis of Alzheimer's disease (AD), non-AD tauopathies, Lewy body dementia (LBD), and their comorbidities. A pathological hallmark of AD and other tauopathies is the deposition of tau protein aggregates in the brain, whereas in LBD there is accumulation of α-synuclein (aSyn) aggregates. Strikingly, more than half of patients with clinically diagnosed AD or LBD have concomitant tau and aSyn co-pathologies at autopsy. Moreover, patients with mixed tau and aSyn pathologies often suffer from worse clinical outcomes. Currently, it is highly challenging to clinically differentiate AD, LBD, and mixed AD/LBD due to overlapping symptoms. Moreover, co-existence of aSyn pathology also occurs frequently in non-AD tauopathies. Recent advances in brain imaging and immunoassays of amyloid-β and phosphorylated tau (p-tau) have greatly facilitated diagnosis of typical AD. However, these assays fail to identify non-AD tauopathies and mixed AD/LBD. Therefore, alternative measures in easily accessible biospecimens are warranted, especially if they enable simultaneous detection of tau and aSyn aggregates in patients with mixed tauopathies and synucleinopathies. In preliminary studies, we have leveraged the newly emerged technology known as the real-time quaking-induced conversion assay (tau RT-QuIC) for specific detection of tau aggregates in the skin of patients with AD and non-AD tauopathies. In conjunction with recently established aSyn RT-QuIC, we are in a unique position to accurately diagnose patients with mixed tau and aSyn pathologies using easily accessible skin specimens. We hypothesize that skin tau and aSyn detected by RT-QuIC are novel biomarkers for early and differential diagnosis of mixed tauopathies/synucleinopathies in routine clinical practice. We propose to test this hypothesis by pursuing three Aims: 1) Establish dual skin RT-QuIC biomarker assays for mixed tauopathies/synucleinopathies using neuropathologically confirmed cases; 2) Assess skin tau and aSyn detected by RT-QuIC as reliable biomarkers for premortem diagnosis of mixed tauopathies and synucleinopathies; and 3) Evaluate skin tau/aSyn biomarker assays for improving the differential diagnosis of mixed tauopathies/synucleinopathies through longitudinal follow-up. This translational project is supported by rich clinical resources and a strong team of basic and clinical neuroscientists. The successful outcome of our proposal will establish a robust skin-based diagnostic test for mixed pathologies that is prevalent in AD and related dementias, thus facilitating better patient care and development of disease-modifying therapies.

NIH Research Projects · FY 2026 · 2023-06

Mental disorders are among the most common causes of disability, and the disease burden is among the highest of all illnesses. Thus, there is an urgent need to develop not only novel therapeutic approaches but also the next generation of research scientists who can meet the challenges of the growing field of mental health research. The overarching goal of this “Predoctoral Training in a Multifaceted Translational Approach to Mental Illness (AMI)” program (Adrienne Lahti, MD, and Yogesh Dwivedi, PhD as Directors) is to provide the students with an environment of cross-cultural training where they will be exposed to the clinical challenges, biological mechanisms, and cutting-edge research approaches used across mental illnesses, rather than the kind of single-disease training they might obtain by working in an individual research laboratory. The AMI T32 training program will uniquely provide an interdisciplinary training environment that will integrate basic and translational research training of predoctoral students to foster the development of critical thinking, communication, and in-depth research skills. Built on a strong foundation and supported by a large infrastructure of outstanding basic, translational, and multidisciplinary programs in mental health research, the AMI training program will take advantage of interdisciplinary mental health research investigative efforts led by strong, internationally renowned clinical and educational resources within the UAB Department of Psychiatry, dynamic mental health research efforts by the Comprehensive Neuroscience Center, university-wide interdisciplinary initiatives of the UAB Depression and Suicide Center, the Comprehensive Center for Translational Sciences, and UAB graduate programs within the thematically based Graduate Biomedical Sciences and the Psychology Doctoral Program affiliated with the Department of Psychology. The collaborative environment at UAB, embodied by various cores, centers, programs, and departments, will provide extensive support for invigorating research efforts. The training program is requesting three predoctoral training slots per year and will take advantage of well-established best practices for the successful recruitment of trainees. The plan will include required didactic courses, laboratory and clinical research, journal clubs, seminars, scientific presentations both locally and at national meetings, and training in the responsible conduct of research. Trainees will also benefit from courses on grant writing and professional skills development. Together, the trainee and mentoring team will craft an individual development plan. Internal and External Advisory Committees will evaluate the overall performance of the AMI training program. A series of benchmarks for progress will be formulated for each trainee and mentor and reviewed on a semi-annual basis. As a top 25 NIH-funded academic medical center with state-of-the-art scientific core facilities and university-wide, interdisciplinary research centers, the University of Alabama at Birmingham is remarkably well-positioned to cultivate a new generation of translational scientists who will advance and transform mental health research.

NIH Research Projects · FY 2026 · 2023-06

Project Summary/Abstract Albeit periodontal disease is a local chronic infectious inflammatory process affecting tissues supporting teeth, it can also have systemic consequences. Along these lines are reports that Alzheimer’s disease (AD) is epidemiologically associated with periodontal disease. Yet, the mechanisms underlying this association are not delineated. Our preliminary studies provide new evidence that a keystone periodontal pathogen Porphyromonas gingivalis (Pg) could enter the brain and exacerbate amyloid-b (Ab) accumulation, neuroinflammation, microglia activation, synapse loss, and cognitive and behavioral impairments in AD mice upon oral gavage infection. Microglia are the primary innate immune cells in the brain, and microglial activation is an invariable feature of AD pathology. The complement system also represents a major part of innate immunity, and microglia have been identified as the dominant source of C1q, the initiation factor of the classical complement pathway, in the brain. The objective of this application is to understand the importance of periodontitis in regulating microglial in AD, and the role of complement component C1q in microglial activation and AD progression. Based on the literature and our preliminary results, we hypothesize that periodontal infection and inflammation not only increase the severity of AD, but also increase the risk of AD, via potentiating Ab-primed microglial activation and sensitizing microglia for a heightened inflammatory response to subsequent pathogenic stimuli. In addition, periodontitis-associated persistent C1q activation is critical for microglial priming and activation, and the increased neurodegeneration in AD. We will test our hypothesis by pursuing two specific aims. Aim 1 will determine how periodontitis regulates microglial activation in AD using three different models of periodontitis. Aim 2 will determine the role of complement component C1q in microglial activation and AD development following Pg infection. Our proposed studies will provide novel and significant insights into the association between periodontal infection and AD. Understanding how a prevalent chronic infection like periodontitis modulates complement and microglial activation will advance our understanding of the mysterious etiology of AD. The knowledge obtained from these studies will provide a basis for targeting microbial etiology and periodontal therapy to ameliorate the clinical manifestations of AD and lower AD prevalence.

NIH Research Projects · FY 2026 · 2023-06

Project Summary High asleep systolic blood pressure (SBP) and a non-dipping blood pressure (BP) pattern (a <10% decrease in SBP from being awake to asleep) are very common, each with a prevalence >30%, and both are associated with a 1.5 to 3-fold increased risk for cardiovascular disease (CVD) morbidity and mortality. Circadian and sleep-related factors are two of the most likely contributors to high asleep SBP and non-dipping BP. A better understanding of both circadian and sleep contributions, as well as the alignment between sleep behaviors and chronotype, to asleep BP levels and rhythms will allow for the development of interventions to lower asleep BP, restore BP dipping, and reduce BP-related CVD. The overall objective of the proposed study is to determine the associations of chronotype and sleep-related factors with mean BP, and BP dipping (Aim 1); the association of alignment between sleep timing and chronotype with mean BP, and BP dipping (Aim 2); and the association of circadian phase and amplitude with BP dipping under constant conditions (Aim 3). The proposed study, titled “Sleep and Circadian Contributions to Nighttime Blood Pressure (SCN-BP)” will achieve Aims 1 and 2 by collecting sleep and circadian data using questionnaires and wrist actigraphy as part of a large, diverse cohort of research participants at 3 sites (the University of Alabama at Birmingham [UAB], Columbia University Medical Center, and Kaiser Permanente Southern California). SCN-BP will then enroll participants who successfully complete Aims 1 and 2 at UAB to complete a 30-hour Constant Routine (CR) Protocol to determine circadian phase and amplitude, as well as BP levels under constant conditions. Findings from the proposed study will provide data that are critical to understand two of the most likely factors that contribute to high asleep BP and non-dipping BP, as well as generate preliminary data to examine the impact of non-sleep factors (e.g., feeding) on asleep BP levels and dipping. The proposed study is unique in that it will combine population science approaches in Aims 1 and 2 with basic/clinical science approaches in Aim 3 in a large, diverse sample sufficiently powered to examine differences by age, sex, race/ethnicity, and antihypertensive medication use. The proposed study will allow for the development of interventions to lower asleep BP, restore BP dipping, and reduce BP-related CVD.

NIH Research Projects · FY 2024 · 2023-06

Abstract Background: Glaucoma is a leading cause of blindness worldwide. While the potential mechanisms of glaucomatous injury are incompletely understood, it is clear that the incidence of glaucoma increases with age and with intraocular pressure (IOP). Several biomechanical studies have indicated that the sclera is a critical mediator of the biomechanical response of the optic nerve head (ONH) to changes in IOP, showing a significant progressive stiffening with aging in the regions around the ONH (peripapillary sclera) most susceptible to glaucomatous injury. While prior studies have provided valuable insight into the role of IOP, cerebrospinal fluid pressure, blood pressure, and structural stiffness of the ONH and lamina cribrosa , as determinants of the ONH‘s mechanical environment, the role of the vitreous humor, filling the space between ONH- retina and lens, has still not been investigated as being part of the ONH’s environment. Significantly, the vitreous undergoes progressive structural degeneration with aging showing increasing liquid and decreasing gel volumes throughout life that impairs its viscoelastic properties. We therefore propose that such an age-related vitreous degeneration along scleral stiffening is determinant to ONH biomechanics. The Objectives of this study are: 1) to determine the impact of vitreous in modulating the biomechanical scleral response during dynamic IOP variations in human donor eyes; 2) To determine how scleral response can be biomechanically improved with a biomimetic designed hydrogel. Design: In a group of 20 human donor eyes over age of 40, we will measure the sclera’s response during physiological IOP variations induced in the anterior chamber. We will compare the scleral biomechanics in four conditions of the vitreous chamber: i) with the natural vitreous, ii) after replacing the liquid part of the vitreous with saline, iii) after replacing the remaining vitreous gel with saline, iv) and after replacement with a biomimetic hydrogel designed to match the viscoelastic properties of young vitreous. Impact: Elucidating the complex mechanical relationship between the sclera and vitreous will not only inform and improve mechanistic models of glaucoma, it will also provide a potential translational mechanism to develop novel approaches to attenuate the mechanical insult caused by dynamic IOP variations on the ONH. This project will be the first to define this relationship, filling a scientific gap. Vitreous replacement based on the ONH-sclera response can be further explored in clinical longitudinal studies and animal models based on the data obtained herein. .

NIH Research Projects · FY 2026 · 2023-06

ABSTRACT All-trans-retinoic acid (RA) is the main physiologically active derivative of vitamin A, which serves as a ligand for nuclear transcription factors, RA receptors. During development, RA is produced in a quickly changing spatiotemporal pattern to control the expression of precise sets of genes at different developmental stages. Critical RA-sensitive processes during development are RA-concentration dependent, which underscores the importance of the precise control over RA synthesis in a strictly defined and rapidly regulated manner. Biosynthesis of RA includes reversible rate-limiting oxidation of retinol to all-trans-retinaldehyde, followed by irreversible oxidation of all-trans-retinaldehyde to RA. Multiple studies examined the roles of the enzymes catalyzing the oxidation of retinaldehyde and degradation of RA in establishing the dynamic pattern of RA concentration. However, the mechanism regulating the upstream rate-limiting step, which supplies the immediate RA precursor, retinaldehyde, in a precise spatiotemporal pattern remains unknown. It has been established that two proteins, retinol dehydrogenase 10 (RDH10) and short-chain dehydrogenase/reductase 3 (DHRS3), are critical for the control of retinaldehyde levels during development. We have recently discovered that DHRS3 binds to RDH10 and upon binding reduces the output of retinaldehyde by RDH10 by recycling retinaldehyde back to retinol. As a result, the formation of the bifunctional retinoid oxidoreductase complex (ROC) that consists of an oxidative RDH10 and reductive DHRS3 attenuates the RA biosynthesis. Whether this mechanism works in vivo and whether ROC exists in animal tissues is unknown, but if proven to be true, this finding will have a paradigm-shifting effect on our understanding of the mechanisms that regulate embryogenesis through vitamin A. The major hypothesis driving this proposal is that ROC represents a previously unrecognized universally conserved mechanism that can both provide the RA synthesis with robustness (Aim 1) and enable the dynamic changes in RA spatiotemporal pattern by regulating the levels of RA precursor (Aim 2). The hypothesis will be tested using a zebrafish embryogenesis model to take advantage of external fertilization and transparency of zebrafish for intra-vital visualization of RA synthesis and formation of the complex. Successful completion of these studies will advance the field at the conceptual level by demonstrating a mechanistically novel model of producing strictly controlled spatiotemporal gradients of small molecules. These findings will lay the foundation for a better understanding of the mechanisms of congenital diseases associated with dysregulation of RA homeostasis.

NIH Research Projects · FY 2026 · 2023-05

Kidney stone disease (KSD) results in billions of dollars in healthcare costs per year, creates large economic losses due to decreased work productivity, and negatively impacts quality of life. Diet and lifestyle clearly influence KSD risk. It is important to describe how these factors, as well as their temporal changes, contribute to KSD risk. The overall objective of this project is to assess factors associated with KSD risk in adults, the contribution of dietary quality to these associations, and the effect of adopting a healthy dietary pattern on KSD risk. To achieve this objective, we aim to: 1) Identify risk factors for KSD prevalence in a pooled cohort from five observational studies; 2) Measure the associations of temporal changes in risk factors (e.g., dietary pattern, anthropometrics, and associated chronic medical conditions) with KSD incidence among participants of Coronary Artery Risk Development in Young Adults (CARDIA; a cohort of adults with over 30 years of follow-up); and 3) Determine the extent to which adopting a healthy dietary pattern, namely a Dietary Approaches to Stop Hypertension (DASH)-style diet, improves 24-hour urinary stone risk parameters among individuals with KSD through a controlled diet study enrolling CARDIA participants. The proposed research leverages key resources at our institution, including the Birmingham Field Center for CARDIA and the Bionutrition Unit of the Center for Clinical and Translational Science (CCTS). We expect to elucidate the basis for KSD risk in cohort studies and determine the effect of a DASH-style diet on urinary stone risk factors. We also expect that this will provide the foundation for future independent grant efforts to develop more effective preventive care strategies for patients with KSD. This K23 award will provide the PI with training in biostatistics/epidemiology, nutrition/dietetics, and patient-oriented kidney stone research, which will be critical for his career development and long-term goal of becoming an independent investigator. Career development activities will include a Masters of Science in Public Health in Applied Epidemiology, which will incorporate coursework in population-based and nutrition research; the Clinical Investigator Training Program which offers training on clinical trial oversight; and regular interactions with a team of mentors and collaborators with complementary expertise in nutrition, analysis of cohort studies and clinical trials, and KSD epidemiology/prevention.

NIH Research Projects · FY 2026 · 2023-05

Parkinson’s disease dementia (PDD) and Dementia with Lewy bodies (DLB) are two neurodegenerative diseases characterized by cognitive impairments that include executive dysfunction, visual-spatial processing difficulties and impaired working memory. Cognitive impairments are among the most debilitating symptoms of these diseases, often leading to institutionalization and severe decline in health. In PD, cognitive symptoms are often present at diagnosis, but can appear over the course of the disease. In DLB, cognitive changes appear first followed by the development of motor parkinsonism. Both diseases, collectively termed Lewy body dementias, are pathologically characterized by aggregates containing the protein α-synuclein, called Lewy pathology. Lewy pathology is found in brain areas important for cognition including the cortex and hippocampus where it correlates with cognitive decline. Genetic variations in the gene, GBA1, also associate with LBDs. GBA1 encodes for glucocerebrosidase an enzyme that metabolizes glucosylceramide. Mutations in glucocerebrosidase reduce its enzyme activity. Up to 12% of PD cases involved genetic variations in GBA1. The GBA1L444P mutation, which represents about 35% of all PD-GBA1 mutations, increases risk of cognitive decline in PD by 5X. We have found that mice heterozygous for GBA1L444P show impaired performance in behavioral tasks of hippocampal function, and reduced synaptic markers in the hippocampus but not other brain regions. In addition, GBA1L444P heterozygous mice injected with pre-formed α-synuclein fibrils to induce formation of inclusions from endogenous α-synuclein, show more abundant inclusions in the hippocampus compared to wild type mice. In addition, we and others have found that the lipid, glucosylsphingosine but not glucosylceramide is increased in GBA1L444P heterozygous mice, suggesting this lipid causes pathology and should be the target of PD-GBA1 therapies. The combined impact of increased GlcSph and enhanced α-syn aggregation in the hippocampus could be a mechanism by which cognition is impaired in LBDs, which will be explored in this proposal. First, we will determine if glucosylsphingosine is elevated in brain tissue from individuals with PD-GBA1 and controls. We will also utilize a model of human α-synuclein aggregation to determine if pathologic α-synuclein causes changes in glycosphingolipid metabolism in hippocampal and cortical brain regions. Because reduced glucocerebrosidase has been shown to impair lysosome function, we will use primary hippocampal neurons to determine if glucosylsphingosine impairs lysosome activity, leading to a build-up of abnormal α-synuclein. Finally, we will use independent methods to reduce GlcSph in GBA1 L444P heterozygous and wild type mice with and without α-synuclein pathology to determine if decreasing this lipid prevents defects in hippocampal physiology and related behaviors. Overall, this project will help determine mechanisms by which GBA1L444P contributes to cognitive decline and help identify therapeutic strategies to prevent development of cognitive symptoms.

NIH Research Projects · FY 2025 · 2023-05

PROJECT ABSTRACT/SUMMARY. The population of people with HIV (PWH) is aging, and are at higher risk for Alzheimer’s disease and related dementias (ADRD) than seronegative counterparts. Although physical activity (PA) is a promising protective factor to mitigate ADRD risk, few well-powered PA intervention studies have rigorously tested cognitive outcomes among older PWH, a population with rates of moderate to vigorous PA well below recommended guidelines. Further, given that adherence to habitual PA diminishes after supervised interventions, identifying mechanisms of adherence (MoA) to habitual PA among older PWH is germane to develop effective and durable interventions to protect cognitive health. The proposed R01 will leverage the High-Intensity Exercise Study to Attenuate Limitations and Train Habits in Older Adults With HIV (HEALTH), a two-site RCT (University of Washington [UW], University of Colorado Denver [UCD]) of 100 older PWH examining: 1) if 4 months of supervised high-intensity interval training (HIIT) mitigates physical function impairments and fatigue to a greater extent than continuous moderate exercise (CME); 2) the effects of a 3 month text-messaging intervention on PA adherence. In contrast to CME, where aerobic exercise is performed continuously for a specified duration, HIIT, which uses repeated alternating bouts of high- intensity and lower intensity aerobic exercise, has shown superior efficacy in improving physiological and cognitive outcomes, and is associated with superior enjoyment which may increase adherence to PA regimens. The proposed R01 (HEALTH-COG) will leverage the two HEALTH sites, add a new racially diverse UAB site, and add new measures (psychological MoA measures, cognitive function assessments, biomarkers) and a few 12 month follow-up to the parent study. We estimate that of our planned sample of N=100, n=50 will be enrolled at UAB and n=50 total at UW and UCD. Our primary aim is to compare the effects of a 4 month supervised HIIT or CME intervention on (1°) cognitive functioning and (2°) subjective cognitive symptoms. Our exploratory aim is to evaluate putative biomarkers underlying the effect of PA on cognition (blood markers: e.g., BDNF, VEGF, IL-6 and neuroimaging markers: cerebral blood flow, resting state functional connectivity, and brain volume). Our secondary aim is to determine MoA to long-term PA maintenance at 12 months. This aim will examine distal predictors of long-term PA, including sociodemographic, clinical, and intervention factors (i.e., changes in parent R01 physical outcomes [cardiorespiratory fitness], condition [HIIT vs CME], [coaching vs control]), as well as proximal psychological MoA assessed in real-time, using EMA (e.g., self-efficacy, perceived benefits, motivation, social support). Testing efficacy and mechanisms of exercise interventions on cognitive outcomes and understanding psychological MoA of habitual PA following supervised interventions will aid in the development and implementation of personalized medicine approaches for the treatment and prevention of cognitive impairment and ADRD in older PWH.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Alcohol-related liver disease (ALD) is the number one cause of death from long-term and excessive alcohol use in the United States. One early and primary target of alcohol hepatotoxicity is the mitochondrion. Chronic alcohol consumption severely compromises liver mitochondrial bioenergetic function; however, the specific molecular mechanisms responsible for mitochondrial damage are not well understood. We also do not know the full contribution of mitochondrial dysfunction in pathobiology of ALD. Accumulating evidence supports the concept that an intrinsic biological mechanism known as the molecular circadian clock regulates how organs respond to external environmental factors, as well as internal physiological stimuli and abnormal pathologic stresses. There is a growing body of evidence that circadian rhythms are disrupted by chronic alcohol use, which likely contribute to disease as genetic mutation or deletion of clock genes increase metabolic dysfunction and liver pathology in alcohol models. Regarding this scientific premise, we discovered that chronic alcohol significantly deceases liver clock amplitude and disrupts the timing of the liver clock. Alcohol-fed mice with liver-specific deletion of Bmal1 exhibit impaired glucose and glycogen metabolism rhythms, a dysregulated hepatic triglyceride lipidome, and a greater liver disease pathology score compared to control genotype mice fed an alcohol diet. We also have exciting new preliminary data showing chronic alcohol significantly dampens and disrupts rhythmicity of critical hepatic mitochondrial bioenergetic functions, including activity of cytochrome c oxidase, the rate-limiting enzyme of mitochondrial respiration. Building on these exciting new observations, we offer a new paradigm where loss in circadian control of mitochondrial bioenergetic function during chronic alcohol consumption plays a key causal role in the pathogenesis of ALD. We will test this hypothesis through three Specific Aims. In Aim 1, we will establish that chronic alcohol consumption disrupts 24-h rhythms in hepatic mitochondrial bioenergetic function. In Aim 2, we will define the roles of hepatocyte BMAL1 and E4BP4 in alcohol-induced mitochondrial bioenergetic dysfunction and liver injury. In Aim 3, we will test if reinstating liver clock activity during alcohol use prevents mitochondrial dysfunction and liver injury. These results will provide the first insights into the relationship between the circadian system and alcohol on mitochondrial bioenergetics and organ damage. Project findings will have direct translational impact by advancing pre-clinical scientific knowledge required for stimulating drug discovery in the areas of mitochondrial and chronobiology based therapeutics for treating patients afflicted with ALD and other serious liver diseases.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Foregut (esophageal, gastric, liver, biliary and pancreatic) cancers account for approximately 20% of new cancer deaths in the United States each year, with an incidence that is projected to increase by almost 70% over the next ten years. These are aggressive malignancies, with complex therapies that require coordinated, specialized multidisciplinary care. However, up to 70% of patients with foregut cancers do not receive guideline-concordant treatment (GCT). Patient demographic characteristics and geographic location serve as proxies for multiple, potentially modifiable factors along the cancer care continuum, that threaten delivery and receipt of care. Identifying these factors is critical to improve the delivery of high quality cancer care. Accurate identification of patients at risk for non-GCT is a vital first step to intervene. However, there is no screening tool to identify patients at risk for non-GCT. This project aims to use mixed methods research to develop a clinic-based risk prediction tool that utilizes modifiable risk factors to identify patients at risk for non-receipt of GCT. Together, this clinically applicable and statistically valid model and the high-yield screening instrument will inform an emerging model that identifies patients at risk for non-receipt of care, and facilitates the administration of personalized, solution-focused interventions that can redirect the course of care. My long-term objective is to become an independent researcher focused on understanding and developing systems-based approaches to improve the delivery of cancer care. This career development award will help achieve my objective by filling gaps in knowledge and skills through a personalized training program that will include didactics, mini-sabbaticals, experiential training and mentorship in three areas: (1) mixed methods with a focus on patient-oriented research (2) statistical modeling and measure development and (3) implementation science. This training plan will support my proposed project and enable my transition to an independent surgeon-scientist. The specific aims are (1) to identify challenges in access to GCT in patients with foregut cancers through a patient-centric and stakeholder-informed approach (2) to examine the extent to which modifiable factors predict risk for non-GCT using quantitative modeling and (3) to develop and pilot test a clinic-based screening tool to prospectively identify patients at risk for non-GCT. This proposal is novel in its exploration of underlying modifiable determinants to inform the development of a model and clinic-based screening tool that predicts risk for non-GCT. While there are currently a range of successful interventions such as patient navigation that have shown promise in improving the delivery of cancer care, there is no streamlined way for clinicians to identify patients at risk for non-GCT. This proposal will allow for the identification of patients at risk for non-GCT in a consistent way across providers and embedded in health systems. The results of this study will be used to apply for an R01 to prospectively evaluate

NIH Research Projects · FY 2025 · 2023-05

PROJECT SUMMARY Substance use disorder is a multidimensional neuropsychiatric disease increasing in prevalence across the United States despite increased awareness and substantial leaps in treatment approaches. Unfortunately, these treatments commonly fail due to strongly encoded drug-associations, often resulting in relapse. Drugs of abuse, such as cocaine, act on the mesolimbic dopamine system to increase dopaminergic transmission in the nucleus accumbens (NAc), a key brain region important for reward processing. Medium spiny neurons (MSNs) within the NAc are responsive to increases in dopamine transmission. Importantly, MSNs do not generate spontaneous action potentials so changes in excitability are dependent on dopaminergic input, in addition to input from other projecting areas. When studying MSNs in relation to substance abuse, there is substantial evidence demonstrating MSNs increase their excitability following cocaine exposure or dopamine stimulation. However, very little research has examined why this happens and how voltage-gated ion channels in the NAc are implicated in cocaine-induced physiological and behavioral plasticity. My preliminary data suggests a role for KCNQ2/3, m-current, potassium channels in MSN excitability and the rewarding effects of cocaine. Although pharmacological manipulation of KCNQ2/3 channels decreases drug seeking behaviors and KCNQ2/3 channels are important for several intrinsic properties, the role of KCNQ2/3 channels in MSN excitability and cocaine- related molecular and behavioral adaptations has never been studied. In this Proposal, I will test the overarching hypothesis that KCNQ2/3 channels in the NAc are involved in functional and behavioral plasticity associated with cocaine-seeking behaviors. Specific Aim 1 of this proposal will use multiple approaches to determine how KCNQ2/3 channels influence baseline MSN excitability and establish gene-to-function relationships between KCNQ expression and MSN physiology. Specific Aim 2 will will combine CRISPR/dCas9 tools and cocaine self- administration to target specific KCNQ2/3-mediated aspects of drug related learning and compulsive drug seeking. Together, these experiments will define how KCNQ2/3 channels regulate MSN physiology, identify the relationship between KCNQ subunits and MSN excitability, and determine if KCNQ2/3 channels in the NAc modulates cocaine-related behavioral plasticity. These studies with reveal previously unknown mechanisms by which KCNQ2/3 channels contribute to psychostimulant response, and will provide a foundation for future experiments to explore how KCNQ2/3 channels contribute to motivated behavior.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Rationale: Low health literacy affects over a third of surgical populations and is associated with significantly worse outcomes in surgery. Interventions that reduce disparities in this large population are urgently needed. Our team has previously shown that enhanced recovery programs (ERPs) mitigate racial disparities in surgical outcomes and offer a pragmatic way to address surgical disparities. Existing ERPs, however, work poorly for patients with low health literacy who still experience worse outcomes. This gap arises from the lack of fit between current ERPs and the needs of low health literacy patients. Through a K23, our team assessed these needs and developed a novel multilevel strategy to improve fit: engage patients with VISuAl aids, Coach providers in communication, and Train organizations in health literacy (VISACT). An opportunity now exists to deliver and test the VISACT using a theory-based adaptation framework. Successful adaptations would transform existing ERPs and broaden its disparity-reducing impact to low health literacy populations. Objectives: Our long-term objective is to eliminate disparities and improve outcomes for low health literacy populations in surgery through context-driven adaptations of existing ERPs. We hypothesize that VISACT will improve fidelity to ERP’s components for low health literacy patients and thereby surgical outcomes. To achieve our objective, we aim to: (SA1) identify the health literacy-sensitive components of ERPs to augment with VISACT, (SA2) assess the health literacy needs of providers and organizational units on ERP teams, and (SA3) deliver and pilot test the VISACT implementation strategy on existing ERPs. Methods: Guided by the Dynamics Adaptation Process framework, we will first use machine learning on a large ERP database (n>7,000) to identify the health literacy- sensitive components of ERPs to augment with VISACT (SA1). Second, we will use a convergent mixed- methods integrative approach to identify gaps in health literacy knowledge, best practices, and preparedness to adapt on ERP implementation teams through three interrelated methods: in vivo observations of ERPs in-action at 4 Alabama facilities, extended semi-structured interviews of 120 stakeholders, and surveys measuring health literacy knowledge and organizational preparedness to adapt. Third, we will deliver the VISACT to two sites in Alabama (urban and rural) through a novel interactive response platform in a pilot study and assess for feasibility/acceptability through a RE-AIM framework of reach, efficacy, adoption, implementation, and maintenance measures. Acquired data will inform design of a multi-institutional stepped-wedge trial of the VISACT in the Deep South. Significance: This study will advance the NIH/NIMHD mission to eliminate surgical disparities and responds directly to the NIMHD Science Visioning Research Strategies by removing health literacy barriers (#24) and building the science of adapting interventions to different contexts (#30). Our team will furthermore (i) deliver the first health literate intervention in surgery, (ii) establish a novel implementation strategy (VISACT) to address surgical disparities and (iii) advance the science of interventions through adaptations.

NIH Research Projects · FY 2025 · 2023-05

PROJECT SUMMARY The composition of the gut microbiome has been shown to determine responsiveness or resistance to immune checkpoint inhibitors (ICI), such as anti-PD-1, in patients with melanoma and other cancers. Unfortunately, although immunotherapy works well in glioblastoma (GBM) pre-clinical mouse models, the therapy has not demonstrated efficacy in humans. Most pre-clinical cancer studies have been done in mouse models using mouse gut microbiomes, but there are significant differences between mouse and human microbial gut compositions. To address this anomaly, we developed a novel humanized microbiome (HuM) model to study the response to immunotherapy in a pre-clinical mouse model of GBM. We have recently published that various human microbiome compositions can dictate the efficacy of T-cell ICIs (anti-PD-1) in a pre-clinical GBM model. We are the first to report that human microbiota affects T-cell ICI response in mouse models of GBM, indicating that for patients with GBM, there may be beneficial microbes that can increase efficacy of ICIs. Furthermore, the largest portion of immune cells in GBM are tumor associated macrophages and microglia (TAMs). To date, no studies have examined the role of the microbiome in response to TAM targeted therapies, such as CSF1R inhibition or anti-CD47, in GBM. In addition, the question still remains of whether the “responsive” microbial communities in can be therapeutically exploited to rescue resistance to therapies, or if the “resistant” microbial communities in can be depleted and/or replaced. We have identified “responder” or optimal human microbiome compositions, as well as “non-responder” or resistant human microbiome compositions in our pre-clinical GBM models, which have also been confirmed in a melanoma model. We hypothesize that responder microbiome communities promote a heightened baseline level of anti-tumor inflammation, which helps stimulate the efficacy of immunotherapy in GBM. Using our novel humanized microbiome mouse model, this proposal seeks to uncover the human microbial- immune mechanisms of response to immunotherapies in GBM pre-clinical models, including T-cell (Aim 1) and TAM (Aim 2) mediated effects, and assess if responder microbiomes can be exploited and used therapeutically. Overall, we seek to enhance our understanding of the role of human microbiota in innate and adaptive immune-microbial interactions, and to demonstrate the translational potential of responder “optimal” microbiomes.

NIH Research Projects · FY 2026 · 2023-05

Environmental pollutants can contribute to the unresolved or impaired resolution of inflammation which is one of the critical mechanisms for developing chronic diseases. Cadmium (Cd), an environmental pollutant, is one of the top ten hazardous chemical pollutants that negatively impacts human health and increases the burden of disease. One real-life example of environmental Cd pollution-related negative health impacts is the North Birmingham Superfund site. It is established that Superfund Site at N. Birmingham has high environmental Cd contamination due to being near coke and steel plants in the area. Our laboratory is associated with the Superfund Research Center at UAB and works closely with the community at the Birmingham Superfund Site. In our research with the biological samples from the superfund site community, we have found that residents from Superfund Site (Affected Area) have two times more incidence of chronic airway diseases. Environmental exposure to Cd can induce dysregulated resolution pathways related to persistent inflammation which can be one of the reasons for the increased incidences of airway diseases. The lung tissue and AMs from these residents demonstrate higher levels of Cd than normal levels. The macrophages also demonstrated decreased efferocytosis ability, presence of increased PAD4 and citrullinated CaMKII. We will be investigating Cd toxicity mediated effects of PAD4 related downstream pathways for the impaired efferocytosis and airway remodeling. We have 3 specific aims to test our hypothesis that Cd inhibits efferocytosis by AMs through PAD4 which leads to continued inflammation and airway remodeling. Our specific aims are: (1) determine the mechanisms of Cd induced PAD4 activity on efferocytosis by AMs in vitro and determine the impact of AMs with dysfunctional efferocytosis previously described 3D ex-vivo pulmospheres model. (2) Determine if Cd exposure mediated PAD4 dependent dysfunctional efferocytosis is associated with airway disease in vivo. (3) Determine if association of environmental exposure of Cd and decreased efferocytosis, and lung function in the residents from North Birmingham Superfund Site.

NIH Research Projects · FY 2026 · 2023-04

Project Summary We propose experiments to rigorously investigate whether lncRNAs influence gene transcription programs in the hippocampus in response to Alzheimer’s disease (AD) pathology, and the potential of lncRNAs to be therapeutically leveraged to promote memory resiliency in AD. AD progression involves profound disruptions in gene transcriptional programs in the hippocampus, the brain region necessary for learning and memory. Epigenetic interventions to enhance memory resilience in AD are possible. However, it is not well-understood how abnormal epigenetic control of gene transcription contributes to AD-related memory deficits. We and others have demonstrated that epigenetic chromatin remodeling mechanisms, like posttranslational modifications of histones, DNA methylation, and non-coding RNAs are crucial for the regulation of memory-permissive genes in the hippocampus during memory formation. Currently, a significant gap in knowledge exists regarding the role of long non-coding RNAs (lncRNAs) in memory formation in the healthy brain and how it is altered in AD-related memory dysfunction. Our long-term goal is to study the role of lncRNAs in a cell-type specific manner and to identify how these powerful epigenetic regulators impact memory formation in AD. Our pilot data demonstrate that Neat1 is overexpressed in area CA1 of the hippocampus from the hAPP-J20 AD model. Furthermore, we demonstrate that inhibiting Neat1 expression in area CA1 of the hippocampus of the hAPP-J20 AD model reverses memory impairments. Pilot studies also suggest a strong relationship between histone methylation mechanisms with Neat1 overexpression in the hAPP- J20 AD model. Based on these preliminary results, we plan to examine the effects of manipulating Neat1 in the hippocampus and determine effects on AD-related memory decline. To gain further mechanistic insight into Neat1 mediated gene transcription in the hippocampus of AD mouse models, we will use state-of-the-art approaches such as single nuclei RNA isolation followed by sequencing and Chromatin Isolation by RNA Purification to elucidate the cell-type specific epigenetic mechanisms coupled to lncRNAs in our AD animal models. Our overarching hypothesis is that Neat1 contributes to AD-associated transcriptional changes in hippocampal cells, hippocampal function, and vulnerability to memory dysfunction. Our Specific Aims are as follows: Specific Aim 1: Test the hypothesis that Neat1 impacts AD pathology in the hippocampus; Specific Aim 2: To determine the necessity of Neat1 on AD responsive gene transcription programs in the hippocampus; Specific Aim 3: To identify the mechanisms by which Neat1 contributes to chromatin restructuring in AD; and Specific Aim 4: To test whether hippocampal Neat1 dysregulation contributes to AD-related memory dysfunction. Collectively, these studies will have broad implications for treatment options for AD associated cognitive decline.

NIH Research Projects · FY 2023 · 2023-04

Contact PD/PI: BHAT, KRISHNA MOORTHI This proposal examines the functional role of Sec20, a BH3 and Secretory (Sec) domain protein, in neurons and its relevance to a motor neuron disease using Drosophila. It also examines the interaction between sec20 and GGGGCC (G4C2) repeats of the gene C9orf72 (Chromosome9 open reading frame), a well- known mutation that causes Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD) in humans. ALS-FTD are two progressive, adult-onset neurodegenerative diseases, often occurring together. The particular focus of this proposal is neuronal loss and mitochondrial and autophagy defects in the brain. Dysfunctional mitochondria and autophagic failures have emerged as important factors in neurodegenerative diseases. They may actively mediate these diseases or exacerbate them. sec20 is the ortholog of vertebrate Bnip1 gene, which is a member of the Bcl2 interacting protein family. Bnip1 has been tentatively identified as a risk factor for ALS and FTD in humans. We found that loss of function for sec20 in the CNS in Drosophila caused severe motor neuron disease and death. There was neuronal loss, mitochondrial dysfunction and autophagic failures in these flies. The disease and these molecular features had similarities to the motor deficits disease caused by the expression of G4C2 repeats. The phenotypes caused by the G4C2 repeats were upstream of sec20 in flies as well as in humans. Thus, our specific aims are: 1) Determine the molecular basis for the loss of motor neurons in sec20 mutant flies, 2) Determine if defective mitophagy and autophagy in sec20 mutants contribute to the disease, and 3) Delineate the interaction between sec20 and the c9orf72-G4C2-R in the CNS. In Drosophila, we go from phenotypes to genes and then molecular underpinnings. There is always a bottom line with this system. Our aims investigate the basics of the phenotypes caused by these genes/mutations. These studies will help understand the function of Sec20 in the CNS and how it relates to G4C2 repeats in the biology and in the diseases of the brain. Project Summary/Abstract Page 6