University Of Alabama At Birmingham

NSF Awards · FY 2026 · 2026-03

The University of Alabama at Birmingham (UAB) will host the 59th Annual Spring Topology and Dynamical Systems Conference (STDC), March 11-13, 2026, in Birmingham, Alabama. The STDC is one of the longest standing regular conferences in general topology, having started in 1967 and continuing as an annual conference. It attracts participants nationally and internationally. There are 7 plenary talks and 12 semi-plenary talks in most areas of topology and its applications by established researchers. Talks bridging two or more research areas are encouraged. In a highly technological society like the USA, a high level science research, and in particular mathematics research, is crucial for further progress. Conferences are an essential part for developing successful and competitive research programs in mathematics and for the education of young researchers. The STDC has played an essential part in the success and education of many of its participants. The conference will include contributed talks by PhD students, post-doctoral students, as well as junior mathematicians. There are six special sessions in subareas of topology including a new session in Applied Topology and Topological Data. The 59th Spring Topology and Dynamical Systems Conference will run six special sessions: Continuum Theory, Dynamical Systems, Geometric Topology, Geometric Group Theory, General and Set Theoretic Topology, and Applied Topology and Topological Data that will include most topics of contemporary research in topology as well as highlighting connections between topology and other mathematical subjects. The winner of the Mary Ellen Rudin Award for beginning mathematician will be announced at this meeting and will be invited to give a plenary address. The conference has succeeded in strengthening major connections between areas which normally do not interact. Particularly effective have been interactions between dynamical systems and continuum theory, between geometric topology and continuum theory, between geometric topology and geometric group theory, and between set theoretic topology and continuum theory. The interaction between these areas and graph theory is being encouraged by particularly inviting speakers who can bridge between the former areas and graph theory. The STDC encourages these interactions by providing travel support to students, post-docs, and junior mathematicians. More information and an invitation to participate may be found at the conference website: https://scholarlattice.org/collections/ddc12896-b56a-4419-872b-1a0a0a161829. 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 2026 · 2026-03

In this UG3/UH3 Exploratory Clinical Trial, we will test low-dose naltrexone (LDN) as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). ME/CFS affects approximately 1 million people in the United States, with incidence rates increasing with the SARS-CoV-2 pandemic. ME/CFS is characterized by profound fatigue, cognitive issues, pain sensitivity, and post-exertional malaise (PEM). Several studies support the hypothesis that ME/CFS involves chronic inflammatory activity in the central nervous system (CNS) that is driven by hyperactive microglia. More than 35 years since recognizing ME/CFS as a distinct medical condition, there is still no FDA-approved medications and no consensus on optimal treatment of the disorder. There is an urgent need to identify treatments that are safe and effective in reducing the severity of ME/CFS. Low dose naltrexone (LDN) involves daily doses of naltrexone in the 0.5mg to 6.0mg range. LDN crosses the blood-brain barrier, pushes microglia from an inflammatory to a resting state, and reduces the production of pro-inflammatory chemicals in the brain. LDN reduces fatigue severity in conditions such as ME/CFS, fibromyalgia, and Long-COVID. LDN is an ideal first treatment for ME/CFS because it is generically available, inexpensive, safe, and well-tolerated. LDN also has no abuse potential. In this Phase II trial, several questions will be answered to optimize a future Phase III efficacy trial of LDN for ME/CFS. This trial uses a remote design where individuals can enroll from anywhere in the United States and can complete all study tasks from their home. This approach allows individuals who are homebound or bedbound to participate in the clinical trial. Study 1 is a dose-finding study where 75 ME/CFS participants will receive LDN at 1.5mg/day, 3.0mg/day, 4.5mg/day, and 6.0mg/day for 2 months each, in blinded order. This study will be used to determine the best dose of LDN to be used in future trials. Study 2 is a randomized controlled trial (RCT) in 150 individuals with ME/CFS. Participants will be randomized to receive LDN or placebo. This study will be used to test safety and tolerability, determine the likely side-effects, determine the best measure to use as a primary outcome, identify predictors of a positive LDN response, and preliminarily measure the strength of the LDN effect. A subgroup of participants (25 LDN and 25 placebo) will be recruited close to the University of Alabama at Birmingham (UAB) to complete advanced neuroimaging and blood tests of neuroinflammation, neurodegeneration, and oxidate stress. These tests may yield biomarkers of LDN response for predicting who is a good LDN candidate, or for tracking improvement with the treatment. Neuroimaging will focus on brain lactate and temperature, two measures of brain inflammation. Study 3 is an extended-duration study where participants may be switched between placebo and LDN, in order to collect additional safety, tolerability, efficacy, and durability information. Ultimately, we hope this study will lead to the first widely accepted pharmaceutical treatment for ME/CFS.

NIH Research Projects · FY 2026 · 2026-03

In the U.S., more than 1 in 5 children have obesity, and 1 in 5 adolescents have prediabetes, with rapidly rising rates of youth-onset type 2 diabetes (T2D) and significant impacts on long-term health and mortality. One of the key risk factors for development of childhood obesity and diabetes is exposure to maternal T2D in pregnancy. The effectiveness of metformin in treating T2D in pregnancy and reducing neonatal morbidity was recently tested in the “Medical Optimization and Management of Pregnancies with Overt T2D” (MOMPOD) randomized, double-blind, placebo-controlled trial. Compared with placebo, addition of metformin to insulin therapy failed to reduce the incidence of composite neonatal morbidity. Although metformin reduced the rate of large-for-gestational-age (LGA) neonates and birthweight, it did so at the expense of fat free (lean muscle) mass, questioning whether the reduction in birthweight was actually beneficial. Critical knowledge gaps remain concerning long-term effects of metformin on childhood outcomes. Small follow-up studies of 5-10 year-old children exposed to metformin in utero for treatment of other maternal conditions (GDM and PCOS) have shown paradoxically higher rates of childhood obesity and abnormal cardiometabolic health. Given that metformin readily crosses the placenta and continues to be used in >1 in 4 pregnant women with T2D, it is crucial to define the long-term impact on childhood outcomes. MOMPOD, the largest T2D treatment trial in pregnancy, provides a unique opportunity to address this critical knowledge gap, and thereby improve lifelong health of children born to women with T2D in pregnancy. We plan to enroll 462 (~65% of all eligible) children born to MOMPOD participants and conduct a single in-person visit at 9-11 years of age to address: Aim 1: To evaluate the association between in utero metformin exposure and childhood obesity at age 10 (9-11) years. Hypothesis 1a: Among children born to pregnant women with insulin-treated T2D, metformin exposure is associated with higher prevalence of obesity (BMI >95th percentile for age/sex), compared to placebo. 1b: Metformin exposure is also associated with greater central adiposity and fat mass, measured by skinfold thicknesses, waist circumference and DXA imaging, compared to placebo. Aim 2: To quantify the association between in utero metformin exposure and childhood cardiometabolic health at age 10 (9-11) years. Hypothesis 2a: Compared to placebo, in utero metformin exposure is associated with poorer cardiometabolic health measured with an NHANES-validated continuous metabolic syndrome risk score calculated using BMI Z-score, systolic blood pressure, glucose, triglycerides, and HDL cholesterol, which is predictive of adult metabolic syndrome from 5 years old. 2b: Metformin exposure is also associated with lower time in tight range on continuous glucose monitoring, increased insulin resistance and decreased β-cell function calculated using fasting and oral glucose tolerance test results. Successful completion of this study will generate high-quality, practice-changing results to inform treatment of diabetes in pregnancy and break this vicious cycle of intergenerational transmission of obesity and diabetes.

NIH Research Projects · FY 2026 · 2026-03

Integrating genomic medicine into routine healthcare holds immense promise for improving patient outcomes through more timely testing, diagnosis, and precision therapeutics. Although the importance of genomic testing is recognized, its use in patient care remains scant due to a lack of training (literacy), confidence, and access to specialists and resources. These barriers are especially pronounced among the Southeast region of the US. To catalyze significant advances in genomic medicine and make it an integral part of healthcare for clinical populations, we propose to create the Southeast Regional Genomic Medicine eConsult Service (SEGEMS), led by the University of Alabama at Birmingham (UAB) and Vanderbilt University Medical Center (VUMC). This clinical and research collaborative will build on separate well-established eConsult services to conduct outreach, promotion and education and provide comprehensive genomic medicine eConsults (GM-eConsults) to all communities. We have identified community partners providing care to clinical populations across the region. This effort aims to reach beyond the 5 million patients receiving care at our institutions, to over 12 million residents in Alabama and Tennessee, and surrounding regions to create a sustainable service scalable to over 1,000 GM- eConsults per year. We will evaluate the implementation of SEGEMS using the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) Framework, assessing the technology usability, reach, adoption, sustainability, and clinical impact of the eConsult service using mixed methods across the two major EHR vendor platforms, Epic (VUMC) and Cerner (UAB).  We will develop, test, refine, and share a transferable and sustainable implementation toolkit to support subsequent dissemination of the genomic eConsult service to other organizations. Guided by an integrated Consolidated Framework for Implementation Research (CFIR), we will identify barriers and facilitators to implementation of genomic eConsult services and develop a transferable set of best practices to assist with future implementations. We will use mixed methods to gather data on key components of success for implementation. We will use and share the toolkit to widely disseminate genomic eConsult services for use by other organizations. We bring together an experienced investigative team with established history of collaboration and leadership in national genomic medicine efforts. We leverage our expertise in genomics (including clinical genetics, cardio-genomics, cancer genetics (germline and somatic), pharmacogenomics, maternal-fetal medicine, genetic counseling, nephrology, neurology, and primary care), informatics, implementation science and telehealth and eConsults to create, implement, expand, and evaluate a region-wide genomic medicine eConsult service.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY B lineage cells are responsible for greater than 85% of non-Hodgkin’s lymphomas (NHL), including the most prevalent leukemia in Western countries, chronic lymphocytic leukemia (CLL). Recent studies of lymphoprolifer- ative disorders and CLL have highlighted their dependence on the B cell receptor (BCR) and its signaling com- plex. Numerous co-receptors are integrated with and are capable of modulating BCR responses. Immunothera- peutic targeting of discrete B cell surface regulatory proteins (e.g., CD19, CD20) and selective inhibition of critical signaling pathways is dramatically shifting our approach to the care of individuals with this class of malignancies. However, emerging resistance to antibody and cellular immunotherapies as well as small molecule inhibitors in patients over time limits these therapies. The development of strategies to address these issues is impeded by gaps in knowledge concerning how B cells differentially regulate BCR signals at homeostasis versus activation, what factors become proximally dysregulated to drive disease pathology and progression, and the mechanisms underlying maintenance of transformed B cells. Members of the Fc receptor-like gene family (FCRL1-5) encode cell surface receptors with complex tyrosine-based regulation that are preferentially expressed by B cells. Their significance as mediators of B cell pathology, and thus as potential therapeutic targets, is indicated by their asso- ciations with human lymphoproliferative, autoimmune, infectious, and immunodeficiency disorders. The long- term objective of our studies is to determine the mechanistic roles of FCRL molecules in B cell pathology and reveal their therapeutic potential. Importantly, FCRL1 is a pan B cell marker overexpressed by CLL and many other mature B cell malignancies and correlates with disease aggression in NHL. While it is uniquely positioned among human and mouse FCRL members in terms of enhancing BCR activation, new findings indicate FCRL1 exhibits context-dependent regulation. Our hypothesis is that FCRL1 harbors tyrosine-based properties that differentially regulate B cell responses, but when dysregulated influence the pathogenesis of lymphoproliferative and autoimmune disorders. Based on supportive preliminary data, in Aim 1, we will determine the influence of FCRL1 on B cell responses in human and mouse disease models of CLL and tolerance. In Aim 2, we will dissect the mechanisms underlying FCRL1 signaling and its B cell regulation. In Aim 3, we will investigate conserved in vivo roles for FCRL1 by employing new physiologic models. The proposed studies are anticipated to have broad implications that advance the understanding of B cell signaling by focusing on a remarkably understudied surface receptor and a novel regulatory axis. Our findings will be translationally relevant by providing insights into control mechanisms influencing B cell malignancy and tolerance with the promise of advancing novel therapeutic strategies capable of modulating or targeting this axis.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY This proposal aims to (i) identify immunoregulatory metabolic signals induced by IL-4 that suppress TLR7 stimulation of lupus pathogenic B cells including T-bet+ B cells, and (ii) develop safer SLE therapeutics using immune-regulatory metabolites to inhibit TLR7-induced lupus pathogenic B cell development. Our recent findings show that in SLE, reduced IL-4R expression and defective maintenance of naïve B cells contribute to increased T-bet+CD11c+ B cells and autoantibody development. Co-culture with IL-4 blocked interferon- promoted development of T-bet+CD11c+ B cells and preserved a T-bet−CD11c− phenotype. IL-4 treatment in vivo suppressed a TLR7 ligand R848-promoted development of T-bet+ age-related B cells (ABCs), germinal center (GC) dark zone B cells, CD138+ plasma B cells (PBs), and autoantibody in BXD2 mice. Preliminary data from lupus BXD2 mouse B cells treated with IL-4 revealed upregulation of IL4i1, which generates indole- 3-pyruvic acid (IPyA) from tryptophan (Trp), and metabolites including kynurenine (Kyn) that activate the aryl hydrocarbon receptor (AhR) pathway. In the absence of IL-4, AhR agonists including Kyn and 6- Formylindolo[3,2-b]carbazole (FICZ) suppressed T-bet+CD11c+ B cell development and preserved naïve B cells. A deficiency of AhR in B cells enhanced TLR7 ligand-induced T-bet+ B cell development in vivo and nullified FICZ suppression of T-bet+ B cells in vitro. We hypothesize that IL-4 stimulates IL4i1-mediated IPyA and Kyn to inhibit ABC, GC, and PB development via AhR activation. Aim 1 will determine the Trp metabolic signals induced by IL-4 to inhibit TLR7-induced lupus autoantibody precursor B cells including ABCs and GC B cells in vivo. The induction and essential role of B-cell endogenous IL4i1, Ido1, and AhR for IL-4 suppression of lupus pathogenic B cell development will be determined in wild-type (Aim 1A) and knock-out mice (Aim 1B). Aim 2 will determine what IL-4-induced Trp metabolites can effectively suppress TLR7-mediated ABCs and GC B cell development in vivo. The primary metabolites that activate the AhR program and can be induced by IL-4 in vivo in B cells will be determined (Aim 2A). Whether these metabolites can suppress TLR7-induced development of ABCs, GC B cells, and autoantibodies will be determined (Aim 2B). Significance: This research shifts focus from pro-inflammatory factors to strategies that restore immune cell homeostasis, potentially offering safer SLE treatments. Innovation: The proposed project aims to discover metabolites that regulate B-cell homeostasis, offering novel, druggable targets for SLE therapy. Team and Environment: Dr. Mountz specializes in cytokine-mediated B-cell transcriptomics in SLE, while Dr. Barnes, Director of UAB's TMPL, will provide metabolomics expertise. Dr. Corinne Augelli-Szafran who specializes in small molecule drug discovery will be a collaborator to assist in developing the hit-to-candidate pipeline of Trp metabolite prioritization and screening.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT The objective of this proposal is to define the molecular mechanisms and identify new therapeutic strategies for of an understudied class of myopathies, specifically X-linked myopathy with excessive autophagy (XMEA). XMEA is characterized by elevated levels of autophagy due to disruptions in the autolysosome function. One MEA of interest is X-linked myopathy with excessive autophagy (XMEA), a rare autophagic vacuolar myopathy that characterized by progressive proximal muscle weakness, high levels of serum creatine kinase and accumulation of autophagic vacuoles. XMEA is caused by pathogenic mutations in the VMA21 gene in which N- terminal loss-of-function variants result in early death by 10 years and milder pathogenic VMA21 splicing variants result in a slower disease progression. Patients with VMA21 pathogenic mutations have a defective autophagy and an impaired ability to form the autophagosomes. VMA21 is a subunit of the V-ATPase protein pump and its disruption results in a failure to properly acidify the autolysosome resulting in the formation of vacuolar inclusions in XMEA. No extensive biomarker studies have been performed in the XMEA population resulting in a dearth of knowledge and the lack of suitable XMEA models is a significant barrier towards any effective treatment. We have generated a Vma21 knock-in (Vma21 KI) mouse model based on an RNA-splice mutation identified in a set of XMEA patients observed at our Children’s of Alabama muscular dystrophy clinic. Vma21 KI mice have a progressive muscle weakness, impaired muscle function, and have vacuolar inclusions that form as they age, which phenocopies the XMEA patient symptoms. In parallel, we generated vma21 mutant zebrafish that have a severe loss-of-function (LoF) pathology resulting in muscle paralysis, vacuolar inclusion bodies, and early lethality by 10 days post fertilization (dpf). An autophagy drug library screen of our vma21 mutant zebrafish identified edaravone, an FDA-approved autophagy and oxidative stress inhibitor for ALS, as the most corrective compound out of 29 leads for XMEA zebrafish pathologies. This proposal seeks to establish molecular and therapeutic biomarkers for XMEA based on our analysis of XMEA patient cells, and VMA21-defective zebrafish and mouse models, with an emphasis on the Vma21 KI mice. Proteomic evaluation of the muscles from Vma21 KI mice will allow us to identify VMA21-dependent factors that progress with XMEA disease status. We also seek to evaluate the therapeutic mechanism of action for edaravone in a 6 month treatment of our Vma21 KI mice. These studies seek to establish the XMEA/VMA21 disease processes while advancing a promising autophagy inhibitor compound to eventually treat these XMEA patients suffering from this devastating neuromuscular disorder.

NIH Research Projects · FY 2025 · 2026-02

Adults who smoke, especially those who smoke menthol cigarettes, suffer excess tobacco-caused morbidity and death, including cancer and cardiovascular disease. Compared to adults who smoke non-menthol cigarettes, adults who smoke menthol cigarettes have a greater dependence on nicotine and are less likely to quit smoking. This may be partly due to greater abstinence-induced declines in positive mood/affect and nicotine cravings and high risk situational/contextual factors. However, there are limited data on the underlying mechanisms that explain smoking lapses among adults who smoke menthol cigarettes, whom experience limited success with cessation interventions. Few studies that have used ecological momentary assessment (EMA) to examine how negative affect (i.e., poor mood), nicotine craving (i.e., smoking urge), and contextual factors, like stress, predict cigarette smoking lapse in real-time have considered cigarette flavor. Understanding these momentary precipitants to smoking lapse will help us to inform effective smoking cessation interventions for adults who smoke menthol cigarettes. To fill these critical research gaps, this study will use EMA to 1) define the within-subject associations between momentary negative affect, nicotine craving, and smoking lapse (aim 1); and 2) determine whether momentary perceived stress is a moderator of the momentary affect, nicotine craving, and smoking lapse relationship (aim 2) among adults who smoke menthol cigarettes. Our central hypothesis is that, at the within-subjects level, higher levels of negative affect than usual and exposure to situational/contextual factors (i.e., perceived stress) will be associated with stronger nicotine cravings, and in turn predict momentary smoking lapse (any v. no smoking) during a planned quit attempt among adults who smoke menthol cigarettes. We will recruit up to 150 adults in Arkansas between the ages of 21-75 years who smoke menthol cigarettes and plan to quit smoking in the next 30 days to test our hypothesis on the primary outcome, momentary of smoking lapse (any v no smoking). Secondary outcomes include time to smoking lapse, time to smoking relapse, and cigarette consumption. Participants will complete 7-day pre-quit and 7-day post-quit EMA waves, as well as baseline, 1 month, and 3-month follow-up online surveys. Smoking status will be verified using exhaled carbon monoxide. This study will fill literary gaps on momentary predictors of smoking lapses among adults who smoke menthol cigarettes and provide preliminary data for an R01 application. The PI has assembled an outstanding mentorship team who will guide her rigorous training and career development plans. Through formal coursework, summer institutes, hands-on training, and external trainings the PI will increase her competency in EMA/mHealth, randomized behavioral trials, advanced statistics, and tobacco research. Receipt of this K award will strengthen the PI's likelihood of achieving her career goal to become an independent researcher and conduct technology-supported observational studies and interventions that aim to increase successful smoking cessation among people who smoke.

NIH Research Projects · FY 2026 · 2026-01

AMPA receptors (AMPARs) mediate the majority of excitatory glutamatergic synaptic transmission in the brain. Most AMPARs are impermeable to Ca2+ whereas receptors that lack the GluR2 subunit allow Ca2+ flux. Ca2+- permeable (CP) AMPARs are highly expressed in GABAergic interneurons where they contribute to synaptic plasticity that allows the brain to constantly adjust to changing conditions. A biophysical characteristic known as rectification is commonly used to differentiate CP-AMPARs from the more common Ca2+-impermeable (CI) AMPARs . Inward rectification of CP-AMPARs results from intracellular polyamines that act as open channel blockers to prevent outward current flux at positive membrane potentials. Thus, rectification and sensitivity to antagonists that bind at the polyamine site provide biophysical signatures of AMPAR subunit composition and hence Ca2+ permeability. These properties have been widely used to establish rules of postsynaptic AMPAR localization, especially at interneuron synapses where AMPAR subunit-switching is a widely recognized mechanism of synaptic plasticity. However, our preliminary data suggest that CP-AMPAR rectification and pharmacology are sensitive to presynaptic factors that potentially complicate the use of these biophysical properties as sole proxies of postsynaptic subunit composition. We hypothesize that presynaptic mechanisms contribute to AMPAR biophysical properties at mossy fiber to interneuron synapses in the hippocampus, where a continuum of rectifying and non-rectifying AMPARs are expressed with established rules for plasticity based on rectification and pharmacology. We will test this idea by recording from interneuron subtypes with high CP-AMPAR content and use selective optogenetic activation of mossy fibers to minimize confounding variability of synapse specificity. Using slice electrophysiology and high-resolution Ca2+ imaging, we will determine the contribution of presynaptic properties to AMPAR biophysical properties. AMPAR subunit composition has important functional consequences ranging from regulating the ability of postsynaptic cells to precisely follow high-frequency synaptic activity and mediating Ca2+ influx that can trigger plasticity or pathology. Successful completion of the proposed studies will reveal novel properties of AMPARs that are essential for understanding their function within synapses and intact circuits.

NIH Research Projects · FY 2025 · 2026-01

PROJECT SUMMARY This NIH F30 application describes a three-year plan for mentored research and career development for the PI, Jana Badrani. The scientific premise of this proposal is focused on the role of GR-1+ non-microglial myeloid cells (NMCs) on brain development and adulthood behaviors under normal conditions and following maternal immune activation (MIA). MIA encompasses any pro-inflammatory response within the mother during pregnancy and can be caused by infectious and non-infectious stimuli. MIA is a known risk factor for psychiatric and neurodevelopmental disorders, like schizophrenia and autism, in offspring. MIA is also implicated in hematopoietic changes and disruptions in immune cell development and differentiation. Here, we will elucidate the cellular and molecular mechanisms of meningeal and brain non-microglial immune cell interactions with neurons during normal brain development and following a representative MIA model of maternal systemic challenge with polyI:C (PIC). Our preliminary flow cytometric data identifies a prominent GR- 1+ NMC population that increases within the brains of male MIA offspring. scRNA-seq analysis identified GR-1+ neutrophil populations in the brain, with significant gene expression changes in PIC offspring compared to vehicle offspring. Male MIA offspring also demonstrated behavioral deficits in the elevated plus maze (EPM). Systemic depletion of GR-1+ cells improved the EPM behavioral deficits in PIC male offspring. Thus, our central hypothesis is that GR-1+ neutrophils in the brain impair neuronal function and behaviors via MMP in male PIC offspring. We will test this hypothesis through immunohistochemistry, flow cytometry, single-cell transcriptomics, and a variety of in vivo experiments, including the use of anti-GR1 depleting antibodies and MMP inhibitors. Understanding the involvement of GR-1+ non-microglial myeloid cells in brain development and following MIA will have a significant impact on our understanding of immune-brain interactions underlying brain homeostasis. The proposed training plan for the PI is sponsored by Dr. Shin-ichi Kano, MD, PhD, and Dr. Farah Lubin, PhD. Included in the training plan are experiences that will help Jana develop in three major areas: (1) rigorous neuroimmunological research in neuro-immune interactions, which includes developing familiarity with existing literature, critical evaluation of data, and training in responsible conduct of research; (2) rigorous training in advanced bioinformatics, high dimensional data analysis, and scRNA-sequencing analysis; and (3) career and professional development, including grant and manuscript writing, scientific communications, and the translation of research findings to clinical applications. This proposal drives the development of skills required for rigorous scientific research in immunology, neuroscience, and bioinformatics necessary for the PI’s future career as a clinician-scientist focused on neuropsychiatry and immunotherapy.

NIH Research Projects · FY 2026 · 2026-01

Abstract Diminished mitochondrial function, excessive production of reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) damage are key contributors to age-related physical capacity and muscle strength decline. Adaptation to aerobic and strength exercise training is currently one of the most effective ways to preserve physical performance and muscle strength in older adults. Aerobic and resistance exercise training improves mitochondrial function and stabilizes production of ROS, which contribute to aerobic capacity as well as strength improvements. However, obtaining optimal effects of exercise training may be limited by heterogeneity in the responsiveness due to biological barriers in skeletal muscle energy production, regardless of the adherence. Therefore, there is an unmet need for combining non-pharmacologic therapies with exercise training to “unlock” its full energetic potential to more effectively improve physical performance and muscle strength in older adults at risk of mobility disability. (-)-Epicatechin, a flavanol and a major ingredient present in cocoa, improved survival, muscle mitochondrial function and reduced excess ROS in mice. Supplementation with (-)-epicatechin-rich cocoa improved walking performance and muscle strength in older adults. Combination of (-)-epicatechin with exercise further improved mitochondrial function and reduced muscle fatigue in mice. We hypothesize that the combination of (-)-epicatechin-rich cocoa with structured aerobic and resistance exercise training will be more effective than exercise alone in improving physical performance and muscle strength by improved mitochondrial function and reduced ROS production in moderately functioning older adults. Our proposed pilot trial will test a 6-month exercise training intervention to collect preliminary data on walking performance, muscle strength and muscle size in 36 moderately functioning (slow walking speed <1m/s) older adults (>65 years old) without major comorbidities, preceded by pre-randomization 1-month lead-in cocoa supplementation. The participants will be randomized to 6 months of daily (-)-epicatechin-rich cocoa (2 capsules/d containing 450 mg cocoa flavanols/day, including 80 mg of (-)-epicatechin) combined with aerobic (30min of moderate-intensity walking) and resistance (25 min of whole-body workout) exercise training 3 times a week (Epi-Ex, n=18) or the same exercise training regimen combined with cellulose-based placebo (PL-Ex, n=18). Our primary outcome is walking distance measured by the 6-minute walk test. The lower-limb muscle strength and size measured by the Biodex test and ultrasound will be our secondary outcomes. We will explore the potential mechanism of the hypothesized effect of Epi-Ex on walking performance and muscle strength by measuring mitochondrial function in permeabilized muscle fibers, mtDNA damage, ROS production and antioxidant enzyme activity in the vastus lateralis biopsies at baseline and 6-month follow-up. The objective of this exploratory/developmental R21 proposal is to gather preliminary data on the efficacy and explore the mechanism of the Epi-Ex intervention to support the future Phase III clinical trial testing (-)-epicatechin-rich cocoa flavanols for exercise training optimization in older adults.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Traditional genome-wide association studies (GWAS) have typically overlooked the heterogeneity in coronary heart disease (CHD), which could be one of the reasons for the gap between current risk assessment models and a personalized approach for CHD prevention and treatment. To bridge this gap, I will focus on the development of CHD without prior elevated traditional risk factors in diverse populations. The pooled cohort equations (PCE) are recommended by the American College of Cardiology and the American Heart Association to guide primary CHD prevention in clinical practice. However, the PCE’s limited portability to other ancestries, small sample sizes, and a limited set of variables available contribute to its imprecise nature in risk assessment. Patients who develop CHD without prior elevated traditional risk factors, thus having low PCE scores (defined as CHDlowPCE), may have different underlying mechanisms not captured by traditional risk factors in the PCE, and therefore require a more in-depth investigation for accurate CHD prediction. To address the knowledge gaps, I propose to leverage advanced statistical methods, including polygenic risk scores (PRSs) and machine learning (ML) algorithms, in diverse populations to better understand the physiological mechanisms underlying CHDlowPCE. I aim to identify novel genetic variants that are associated with incident CHD risk without prior elevated traditional risk factors (CHDlowPCE), prioritize potentially causal variants, and optimize multi-ancestry PRSs for CHD (Aim 1). I will create a novel score representing increased incident CVD risk and decreased traditional risk factors and perform multi-ancestry GWAS on it. I will also prioritize potentially causal variants and genes in identified loci and prioritize relevant biological system. In addition, I will build genome-wide PRSs that combine common and rare variants from summary statistics and evaluate their performance in assessing CHDlowPCE. In parallel, I aim to identify non-traditional risk factors for incident CHDlowPCE using EHR data and ML methods (Aim 2). This involves conducting a risk factor search using clinical features in the EHR data and a random forest-based ML framework, and evaluating the causal effect of novel risk factors on CHD using Mendelian Randomization approaches. Lastly, I will utilize these findings to subtype CHD patients based on genetic and phenotypic risk factors (Aim 3). I hypothesize that subsets of genetic loci that group based on their association signatures and pathway-based PRSs will shed lights on different disease mechanism and define subgroups for CHD patients in diverse populations. In summary, this project will enhance the CHD risk assessment by systematically evaluating the genetic and non-genetic risk factors underlying the misclassified CHD risk in diverse populations, and subtype patients based on CHD pathophysiology.

NIH Research Projects · FY 2025 · 2025-09

We propose the inaugural University of Alabama at Birmingham (UAB) School of Nursing (SON) T32 training program, Improving HEalth Across the Lifespan (iHEAL), which will be one of the few Deep South nurse scientist training programs addressing comprehensive healthy living from a life-course lens. Aligned with the NINR Strategic Plan, we will prepare a nurse scientist workforce of pre- and postdoctoral trainees who can address a wide variety of health challenges through lenses of health disparities, social determinants of health, population and community health, prevention and health promotion, and systems and models of care. In collaboration with a transdisciplinary cadre of faculty mentors (including, Core, Content, and Mentors-in- Training) and through guidance from our esteemed Internal and External Advisory Boards, we will accomplish the following specific aims: 1) RECRUIT well-qualified pre- and postdoctoral trainees, who aspire to become independent researchers to address the complex healthcare challenges in the Deep South and improve outcomes across the lifespan; 2) TRAIN pre- and postdoctoral trainees by providing 1) mentoring, 2) experiential learning opportunities, and 3) required coursework that fosters knowledge acquisition regarding transdisciplinary health research, research ethics, professional development, and leadership skills; 3) LEVERAGE UAB’s rich training environment to provide pre- and postdoctoral trainees with training and collaboration opportunities across UAB (including the Comprehensive Healthy Living Research Center, Social Determinants of Health [SDoH] Institutional Core, and other relevant Centers); 4) EVALUATE and ENHANCE how effectively our training program is meeting our T32 trainees’ needs and expanding the next generation of future nurse scientists. Our training program has three components: expert mentoring, experiential learning, and required coursework. Trainees will receive individualized support from a mentorship team drawn from 39 Core, 7 Content, and 5 Mentors-in-Training, selected for their prior successful mentoring experience and strong research track records. Experiential learning activities will center primarily on mentored research and Health Engagement Research Observerships (HERO). Trainees will also write a grant proposal, design and conduct their own research study, and disseminate their work via peer-reviewed publications and presentations at scientific conferences. Five required courses cover transdisciplinary comprehensive healthy living research, research ethics, grant writing, and one elective topic. The iHEAL T32 training program will equip trainees with skills that can be applied across the region and the nation wherever populations are exposed to the challenges of rural location, poverty, or other sources of disadvantage that threaten the opportunities for healthy living across the lifespan.

NIH Research Projects · FY 2026 · 2025-09

HIV disproportionately affects the Southern United States. Development of effective interventions to scale up and sustain HIV pre-exposure prophylaxis (PrEP) utilization is essential to change the face of the epidemic. Defining the PrEP Care Continuum in geographic “hot spots” throughout the South will expedite deployment of evidence-based practices, developed in response to gaps coverage and tailored for priority populations, by clearly defining gaps in care. It is for this exact reason that the Alabama Department of Public Health and Alabama Quality Management Group (AQMG), Ryan White Clinics across the state, have prioritized expansion of PrEP services in high HIV incidence areas as a strategic goal for the state. A needs assessment to determine desired implementation strategies to utilize data in defining the state’s PrEP Care Continuum (preliminary work funded through Ending the HIV Epidemic CFAR Supplements) resulted in our research proposal to develop PrOTECT AL (PrEP Optimization Through Enhanced Continuum Tracking) with the following aims: (1) Sub-aim1a – Refine the PrOTECT AL dashboard with clinic performance metrics, including PrEP coverage scores (i.e., number of persons prescribed PrEP compared to those with an indication) AND Sub-aim 1b – Assess on-site readiness assessments to improve adoption of the dashboard by collaborating sites, (2) Evaluate implementation outcomes associated with deployment of PrOTECT AL, grounded in RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance implementation framework) AND (3) Evaluate the public health impact of PrOTECT AL by conducting an interrupted time-series study of local PrEP to Need Ratio (i.e. PNR – the number of PrEP users divided by new HIV diagnoses) and PrEP coverage. This multi-phase mixed methods implementation study will engage key-informants from the seven collaborating AQMG sites (5 key-informants per site, n = 35) and is guided by a unified implementation logic research model grounded in the Consolidated Framework for Implementation Research and RE-AIM. This phase will focus on improving Adoption and Implementation of PrOTECT AL, by engaging community partners in refining and evaluating our data platform and dashboard, as well as its Reach in improving PrEP coverage in prescriptions. The study will be able to assess whether implementing the PrOTECT AL platform is associated with improvements in PNR over time, above and beyond recent secular trends. The proposed grant is responsive to the “Prevent Pillar” of the National EHE and reflects high priority research topics for the National Institute of Health. This research will lay the groundwork for understanding how to improve the effectiveness of data dashboards in changing clinical practice and improving health outcomes. Future work will focus on how to engage community and populations facing disparities in accessing data dashboards to inform HIV prevention behavior as well as expansion of partnerships to other Southern states.

NIH Research Projects · FY 2025 · 2025-09

The influenza virus (IAV) is a serious public health concern causing seasonal epidemics and sporadic pandemics with significant mortality and morbidity worldwide. Yet, there are several basic aspects of the viral lifecycle that remain under-investigated from a mechanistic and structural perspective. Filling these gaps in knowledge would not only yield fundamental knowledge of influenza biology, but it would also identify novel targets for the development of critically needed antivirals against influenza. Considering their critical roles in the influenza lifecycle, the influenza non-structural protein 1 (NS1) and nuclear export protein (NEP) are the focus of this proposal as they have been highlighted in numerous studies as viable targets for the development of antiviral therapeutics. NS1 is a virulence factor that suppresses the innate immune response to infection by interacting with both nuclear and cytoplasmic proteins, while NEP facilitates nuclear export of the vRNP complex by serving as an adaptor between the host nuclear exportin CRM1 and the vRNP complex. Furthermore, NS1 and NEP functions are predicated on their ability to translocate between the nucleus and cytoplasm of the host cell And since NS1 and NEP are encoded by the same segment of the influenza genome, mutations in NS1 are frequently accompanied by concomitant mutations in NEP and vice versa. Despite their obvious connection, most of the previous work does not focus on differentiating how individual NS1 and NEP mutations govern specific steps of the influenza lifecycle. Despite our knowledge of the functions that NS1 and NEP have during the viral lifecycle, a mechanistic and structural understanding of how they accomplish their functions remain largely unknown. To fill this gap in knowledge, the objective of this application is to define the structure-function relationships that regulate both NS1 and NEP function. The rationale that underlies the proposed research is that elucidating the mechanisms by which NS1 and NEP govern the influenza lifecycle. Furthermore, defining these structure- function relationships will provide detailed structural analysis for the development of novel influenza antivirals that target NS1 and/or NEP function. We will achieve our objective by pursuing three specific aims: 1) structurally characterize the multiple interactions between NS1 and host proteins previously implicated in the regulation of NS1 intracellular transport, 2) solve the high-resolution structure of NEP in complex with the CRM1 export machinery, and 3) determine how these interactions affect various aspects of the viral lifecycle such as replication kinetics and pathogenicity. Our innovative approach will combine several state-of-the-art techniques to perform studies that span from protein structural studies to live cell imaging of NS1 intracellular distribution to in vivo pathogenesis. The proposed research is significant because it will define the molecular mechanisms that govern processes that touch on a number of fundamental aspects of influenza biology. By defining these molecular mechanisms, this proposal will inform efforts in developing influenza antiviral drugs that target NS1, thereby supporting the overall mission of the NIH.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT In opioid use disorder (OUD), sleep and circadian disruptions are highly prevalent, interfere with opioid mainte- nance treatment (OMT) outcomes and increase the risk of relapse. So far, the neurobiological mechanisms linking sleep/circadian disruptions and relapse remain unclear and commonly used pharmacological sleep treat- ments fail to improve sleep or decrease illicit drug use in OUD. Thus, there is an urgent need to fill this research gap. The overall objective for this proposal is to determine 1) (Aim1/K99) whether dopaminergic dysfunction underlies sleep and circadian disruptions in OUD and 2) (Aim2/R00) whether bright light therapy can reduce sleep and circadian disturbances, normalize dopaminergic transmission, and improve treatment outcomes in OUD. The primary hypotheses are that altered dopaminergic transmission in OUD plays an essential role in observed sleep/circadian disruptions in OUD. While greater sleep disturbances are expected to correlate with lower D2R availability, delayed circadian rhythms are expected to correlate with greater D1R availability. Daily exposure to bright light in the morning is expected to advance circadian rhythms, improve sleep, normalize the D1R:D2R ratio and facilitate recovery processes in OMT OUD patients. To test the hypotheses, a multi-method approach including actigraphy, polysomnography, salivary melatonin and questionnaires will be used to assess sleep and circadian rhythms and PET scans will be performed to assess striatal D1R and D2R availability. A randomized, placebo-controlled trial will be conducted to assess the effect of a home-based bright light therapy on OUD recovery. OUD patients (on OMT >1 month) will be assigned either to bright white light (10000 lux) or to dim-red light placebo (<300 lux) group for 2 weeks. Their sleep, circadian rhythms and dopamine receptor availability will be measured before and after treatment. My long-term goal is to become an independent investigator studying brain mechanisms linking sleep/circadian disturbances and drug use, and thereby facilitating the development of effective sleep and circadian interventions for patients with substance use disorders. To achieve my goal, I propose trainings that will help me 1) gain clinical experiences in addiction research, 2) expand my research toolbox with PET, which will allow me to examine brain correlates at molecular level, 3) expand my expertise and tools in clinical sleep research and interventions and 4) enhance my professional skills critical for an independent research career. I will acquire these knowledge and skills under the guidance of a group of leading experts in the field of addiction, sleep and PET imaging, including my mentors (Dr. Nora Volkow, Dr. Martica Hall and Dr. Richard Carson) and my internal and external consultants (Dr. Dardo Tomasi, Dr. Dante Picchioni, Dr. Christopher Welsh, Dr. Brant Hasler). Additionally, NIH offer me plentiful resources for successfully completing proposed research project and training plans. The pro- posed research and trainings will prepare me well for an independent tenure-track position.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT The rates of pediatric venous thromboembolism (VTE) have risen substantially over the last decade. Although 90% of pediatric VTE are provoked and carry a low risk for VTE recurrence (~1%), some children have a markedly higher risk for recurrence (16-29%) due to the presence of persistent prothrombotic risk factors (PPRF) after primary anticoagulant therapy. Better VTE prevention strategies are desperately needed. Unfortunately, the factors that contribute to VTE recurrence are not fully understood. Importantly, the impact of social determinants of health (SDOH) on pediatric VTE outcomes has been under studied. This proposal aims to address this critical knowledge gap by systematically analyzing VTE data derived from a multicenter prospective cohort study of pediatric VTE patients <21 years old with a first provoked VTE. The specific aims of this study are to characterize the types of PPRF after primary anticoagulant therapy (Aim1); identify risk factors (secondary anticoagulation use and SDOH) on rates of recurrent VTE one year post index VTE (Aim 2); and to identify facilitators and barriers (patient and provider) to secondary anticoagulation use and acceptability of future clinical trial participation (Aim 3). The applicant’s overarching career goal is to develop and apply field-leading expertise in the design, execution, and analysis of pragmatic clinical trials in children with VTE, with a focus on enhancing representation therein. She has designed a personalized career development plan with the overarching goal of acquiring skills to plan and conduct pediatric VTE randomized controlled trials, developing health disparities research skills to identify, and overcome barriers to care. The long-term goal for this research is to establish which children with PPRF have the highest risk of recurrent VTE and improve overall health outcomes by ushering in an era of riskstratified therapeutics in pediatric VTE management.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Type 2 diabetes leads to greater morbidity and mortality of ischemic heart failure (IHF) with incompletely understood mechanisms. Recent studies show that diabetes reduces the effectiveness of treatments that work in nondiabetics, leading to a `universal resistance' condition that worsens IHF. However, advancements in cellular secretome research highlight the crucial role of the local microenvironment in influencing disease progression and treatment efficacy. This proposal aims to leverage these insights to transform treatment strategies for individuals with diabetic IHF. Cardiac secretomes, known as “cardiokines”, are crucial in maintaining a healthy cardiac microenvironment. C1q/tumor necrosis factor-related protein-9 (CTRP9), a new identified cardiokine, is a potent cardioprotective molecule that is significantly downregulated in diabetic animals and patients. Our research indicated that CTRP9 reduction resulted in failed cell therapy interventions for diabetic IHF, while the therapy succeeded in nondiabetic patients. Small extracellular vesicles (sEVs) are key mediators in cardioprotection during cell therapy. However, how diabetic downregulation of CTRP9 may adversely impact sEV properties and hinder its cardioprotection in the diabetic population remains unexplored. Seeking an engineered approach to modify sEV to effectively overcome the challenges of rescuing the compromised microenvironment in diabetic IHF is our goal. Our data showed that adipose-derived stromal cells (ADSC) serves as favarable implantable parent bioresources produces potent sEV. Genetic engineering to overexpress N- cadherin (Ncad), the receptor of CTRP9, in ADSC (termed NOE-ADSC) significantly enhances their cardioprotective effects. Currently there is a lack of efficient methods to increase sEV surface protein. It is worth noting that our approach demonstrated that CTRP9 stimulates the surface adiponectin level on sEV derived from parent NOE-ADSC. Hence, we poisted a novel hypothesis that “Diabetic downregulated CTRP9 and its receptor impairs sEV production and diminishes cardioprotection, while administering CTRP9 to enhance sEV generation from NOE-ADSC, which serve as parent bioresources suprior to sEV alone, represent a novel intervention against diabetic IHF, providing synergistic protection through CTRP9 and adiponectin. To test this novel hypothesis, we will complete 3 specific aims. Aim 1 will provide in vivo evidence that bioengineered sEV is the causative factor responsible for NOE-ADSC cardioprotection against IHF. Aim 2 will prove that cardionyocyte-generated CTRP9 is essential for NOE-ADSC sEV production and cardioprotection, diabetic downregulation of CTRP9 is causatively related to the incapability of sEV production and resistance to the therapy effect in the diabetic heart. Aim 3 will illustrate the underlying mechanisms that sEV surface adiponectin (APN) is responsible for NOE-ADSC-sEV cardioprotection, and the administration of bioengineered sEV parent bioresources NOE-ADSC may be a novel strategy against diabetic IHF. Therefore, this study will reveal a novel mechanism for the diabetic IHF and identify new therapies (sEV bioengineering modification) against post-MI remodeling in diabetic patients.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The nutritional management of very preterm infants (27 to 31 weeks of gestation) is critical due to their increased risk of faltering growth and adverse metabolic outcomes. Current recommendations for human milk intake range widely from 140 to 200 ml/kg/day. This variability reflects a lack of consensus on the optimal volume to support growth while minimizing risks like obesity. Unlike preterm formula, human milk is believed to protect against metabolic diseases due to its unique nutritive and non-nutritive components. Previous randomized clinical trials have not examined the effects of two enteral fluids intakes on very preterm infants fed human milk exclusively. This project aims to address this knowledge gap by exploring how different volumes of human milk affect fat-free mass (FFM) and body fat accumulation, essential for the development of very preterm infants. The primary objectives of this multicenter, unmasked, randomized clinical trial are 1) to assess growth and metabolic outcomes at term-age equivalent of very preterm infants receiving higher volumes of human milk, and 2) to characterize the gut microbiome assembly patterns in response to these human milk volumes. Our central hypothesis is that providing human milk volumes of 180 to 200 ml/kg/day during the first weeks after birth will improve FFM accretion and reduce the risk of adverse metabolic outcomes at term-age equivalent in very preterm infants. To test this hypothesis, we will randomize 486 very preterm infants into two groups: one receiving 180 to 200 ml/kg/day and the other 140 to 160 ml/kg/day. We will measure daily human milk volumes and weekly macronutrient content of human milk diets. We will assess FFM accretion at study entry, study day 14, study completion, and term-age equivalent or discharge. We will also examine how human milk volumes influence the gut microbiome through shotgun metagenome sequencing of serial fecal samples collected during the trial and establish a correlation between specific gut microbiome compositions and untargeted serum metabolomics. This trial aims to generate high-quality clinical and translational data on the interactions between early life diets, the gut microbiome, and growth in very preterm infants. It aligns with the 2020-2030 NIH Nutrition Research Strategic Plan by determining the health benefits of exclusive dietary patterns, investigating host- microbiome interactions, and reducing the burden of disease in clinical settings. If successful, this patient- oriented, comparative-effectiveness trial will provide critical insights into optimal nutrition strategies for very preterm infants, potentially transforming clinical practices worldwide and enhancing the development and long- term health of this vulnerable population.

NIH Research Projects · FY 2025 · 2025-09

Summary: Social determinants of health (SDOH) are now widely recognized to play a role in many chronic health conditions. With this recognition, there is a growing body of literature suggesting an important role of SDOH in access to transplantation services for end stage liver and kidney disease as well. In our own work, we have demonstrated the presence of unique geographic regions which rank lowest nationally in the rate of kidney transplantation despite having the highest incident end stage kidney disease rates in the country. These severely underserved areas were also found to have significantly less favorable social determinants of health as measured by the Centers for Disease Control (CDC) Social Vulnerability Index (SVI) when compared to areas with better access to kidney transplantation. We have also demonstrated that regions in which patients listed for liver transplant with model for end stage liver disease (MELD) exception points have a significant advantage over patients without exception points are significantly less socially vulnerable as measured by the SVI compared to regions where MELD exceptions appropriately stratify risk. Others have demonstrated an association between various other measures and access to transplant such as urbanization, poverty, and affordable housing. Despite this increasing recognition of the importance of SDOH in transplantation, we still do not have a robust and widely accepted measure of SDOH relevant for transplant. Instead, we have a body of literature which has examined individual factors or adapted composite measures such as the SVI which were designed to capture outcomes other than transplantation. This lack of appropriate measures of SDOH relevant to transplant has been cited by the Organ Procurement and Transplantation Network (OPTN) liver and intestine committee as a reason why SDOH will not be incorporated in the next iteration of liver allocation policy, while at the same time the committee called for development of such measures to allow for data collection to inform later policies. I propose to fill this knowledge gap through the creation of a robust index of social determinants of health specifically designed to correlation with access to liver and kidney transplant services. I will examine a wide variety of measures of SDOH drawn from sources such as the American Communities Survey and existing indices such as the SVI to determine which specific factors are significantly associated with access to the kidney and liver transplant waitlists, respectively on a county level, and then incorporate these factors into indices using multivariable spatial Poisson regression. These measures will in turn form the basis for futures studies into how SDOH can best be incorporated into more equitable transplant policies. More specifically, the results of the research proposed in this R03 will provide important preliminary data on which to base a planned R01 submission aimed at creation of an equitable liver allocation policy which incorporates SDOH as I transition to an independent research career.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Alzheimer’s disease (AD) and related dementias (ADRD) have been characterized as “our top public health crisis” by four US Surgeons General. The Healthy Brain Initiative (HBI) Road Map, developed by the Centers for Dis- ease Control (CDC) and Alzheimer’s Association, outlines a public health agenda for responding to this crisis at a population level. Much of the HBI Road Map would be implemented in the earliest stages of dementia, with a key goal of shortening the period of undiagnosed dementia through early detection and referral for diagnosis, aligning ADRD public health efforts with shifts in patient care towards prevention and early intervention. Implementation would largely occur at the state and local, rather than national, levels to tailor ADRD policies and programs to the needs of each community, in keeping with ‘precision public health’ initiatives. However, although the HBI Road Map provides an action agenda for stakeholders, the evidence base for its implementation is currently too limited to guide concrete action. In this proposal, we will address this need by augmenting claims data from Medicare with regular brief cognitive assessment data from the REasons for Geographic and Racial Differences in Stroke (RE- GARDS) study, a population-based, longitudinal cohort with 30,239 participants from 1,833 counties across the continental United States. The resulting dataset will be a unique resource for studies of ADRD across the lifespan and of geographic disparities in ADRD. In addition, we will utilize this data to uniquely examine the timecourse and consequences of undiagnosed ADRD on a national level, first by applying joint longitudinal-survival models to estimate duration of undiagnosed ADRD and identify county- and hospital referral region (HRR)-level ‘hotspots’ with longer durations. We will also apply large-scale data mining methods to examine associations of healthcare utilization in undiagnosed dementia with a wide range of systems-level health-related resources with time in each stage, providing empirical evidence to guide development of interventions and policies to improve timely diagno- sis of ADRD and to inform best practices for the HBI Road Map agenda. In doing so, this proposal will build on a growing body of work on local variations in disease as a rich information source about health systems influences on population health, and will serve as a critical part of a broader framework addressing the complex public health challenges posed by paradigm shifts in ADRD care towards earlier treatment and prevention.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Bacterial pneumonia leads to harmful clinical manifestations that persist long after resolution of the primary infection, including cognitive decline; also, patients hospitalized for community-acquired or nosocomial pneumonia develop cognitive impairment—including the risk of developing Alzheimer’s disease (AD)-related dementia. Pseudomonas (P.) aeruginosa is a Gram-negative bacterium and common cause of nosocomial pneumonia in intensive care units (ICU) and traumatic brain injury (TBI) is a risk factor for secondary bacterial pneumonia, in addition to being a risk factor for cognitive decline. Our preliminary clinical data demonstrate that TBI patients have increased rates of bacterial pneumonia. In our murine model, mice with P. aeruginosa pneumonia after TBI have significant learning and memory deficits compared to mice with TBI alone. Preliminary data indicate that alveolar epithelial cells release amyloid beta (Aβ) after P. aeruginosa infection, Aβ accumulates in the bronchoalveolar lavage fluid of critically ill patients, and Aβ stimulates expression of tumor necrosis factor alpha (TNF-α) in alveolar macrophages, suggesting a novel link from pulmonary Aβ to inflammatory responses. We have published that P. aeruginosa elicits oligomeric Aβ from pulmonary cells, infection-induced Aβ impairs cognitive function, and that Aβ accumulates in the BALF of pneumonia patients that correlates with end-organ dysfunction. Finally, Aβ and TNFα activate Neuronal Wiskott–Aldrich syndrome protein (NWASP) in brain microvascular endothelial cells, resulting in BBB dysfunction and increased permeability. Data from us and others suggest a novel link between Aβ released from pulmonary epithelial cells and cognitive dysfunction in mice with bacterial pneumonia after TBI, and Aβ-enhanced inflammatory responses as the potential mechanism. Therefore, we hypothesize that bacterial pneumonia after TBI induces Aβ expression and dissemination from alveolar epithelial cells and that Aβ amplifies lung and brain inflammation in an NWASP-dependent manner that worsens lung barrier and cognitive dysfunction. Our strategies aim to test that P. aeruginosa-induced Aβ dissemination enhances NWASP-mediated inflammation, leading to exacerbated cognitive dysfunction in a murine model of bacterial pneumonia after TBI. Aim 1 will determine the molecular mechanism by which bacterial pneumonia after TBI worsens lung barrier and cognitive dysfunction. Aim 2 will define the mechanism(s) of BBB breakdown mediated by NWASP and its role in cognitive dysfunction in a murine model of bacterial pneumonia after TBI. Aim 3 will examine the role of infection-induced amyloids on cognitive dysfunction in mice and determine the level of amyloids in clinically-relevant, archived, de-identified human patient samples. There is little data regarding the impact of bacterial pneumonia on cognitive dysfunction after TBI and this is a significant clinical gap that has yet to be examined; understanding how bacterial pneumonia after TBI impacts cognitive dysfunction would lead to advances in sepsis research and critical care medicine.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Periconception, pregnant, and postpartum women in HIV-endemic settings are at high risk for acquiring HIV. In Uganda, both fertility rates (4.7 children/woman) and HIV prevalence (8%) are high, and many women conceive with partners with HIV who are not virally suppressed. Oral tenofovir-based PrEP is a highly effective strategy for reducing HIV-acquisition and approved for use during pregnancy and breastfeeding. We designed and pilot tested the 3-session Healthy Families-PrEP intervention in a Ugandan HIV care clinic. Women planning pregnancy were counseled on how to conceive while avoiding HIV acquisition; offered PrEP; and, for those choosing PrEP, provided with quarterly adherence support. Of 131 women enrolled, 90% initiated PrEP and 85% of those initiating PrEP took at least 80% of doses (electronic pill cap) over 9 months; 54% had whole blood tenofovir metabolites consistent with protective dosing at 6 months, and thus 43% of all enrolled used effective PrEP at 6 months. For women with pregnancy, adherence persisted over 9 months. Given compelling pilot data and the importance of HIV prevention for perinatal women, we propose to adapt and test this promising intervention to reduce HIV incidence among periconception, pregnant, and postpartum women accessing community care in Uganda. In Aim 1, qualitative focus group discussions with women, interviews with key stakeholders, and clinic observations guided by the Consolidated Framework for Implementation Research and our client-level conceptual framework will inform adaptation of the intervention to community clinics and postpartum women. We then propose a cluster-randomized control trial with N=10 health centers to evaluate effectiveness (Aim 2) by enrolling N=600 women planning for pregnancy from intervention and control clinics (1:1). Women will be followed for at least 6 months; those who become pregnant will remain enrolled through 18 months to allow for postpartum follow-up. The primary effectiveness outcome will be proportion of women with whole blood PrEP metabolites (TFV-DP) consistent with taking at least 4 weekly doses at 6 months. Tenofovir concentrations in whole blood and plasma (quarterly), questionnaires, and in-depth interviews will provide data to understand factors associated with PrEP use among peripartum women in the community setting. In Aim 3, we will determine the incremental cost-per-person participating in Healthy Families- PrEP and estimate the cost-effectiveness per incident HIV infection averted and per life-year saved among enrolled women and their infants. Adapting this intervention to community clinics and testing effectiveness addresses NIH Office of AIDS Research priorities to reduce HIV incidence and implement research discoveries for public health impact. Moreover, the work aligns with global and Ugandan Ministry of Health goals to reduce HIV incidence among women of reproductive age and eliminate perinatal transmission.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The present proposal aims to develop novel small molecules for epigenetic therapy of medulloblastoma (MB) with the goal of translating them to the clinic. MB is the most common and aggressive malignant brain tumor in children. Current nonspecific cytotoxic therapies cure only a fraction of patients, and cause life-long neurological, intellectual, and physical disabilities, highlighting the urgent need for novel therapeutic approaches. ADGRB1 (BAI1) is an adhesion G protein-coupled receptor (GPCR) specifically expressed in the brain, where it functions as a tumor suppressor. We have recently shown that ADGRB1 expression is significantly reduced in patients with MBs across all 4 main molecular groups because the ADGRB1 gene promoter is epigenetically silenced through CpG island methylation. We showed the involvement of methyl CpG binding protein 2 (MBD2) in the switch to a silent chromatin conformation and demonstrated that we could reactivate the gene through a novel small molecule inhibitor of MBD2 (KCC07). This lead compound significantly extended the survival of mice carrying human MB xenografts in the cerebellum and sensitized them to radiotherapy, providing proof-of-principle for the further development of this chemotype as a new drug for patient treatment. Importantly, KCC07 had excellent brain distribution, was very well tolerated by the mice and no overt toxicity was observed. We propose to perform medicinal chemistry to further optimize this promising chemical scaffold and conduct further IND-directed preclinical studies towards identifying a candidate compound to be evaluated in clinical trials. The proposed study has the potential to generate a new epigenetic therapeutic for children suffering from this disease and improve their survival with reduced side effects.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Diabetes accelerates cardiovascular disease, in part, through hyperglycemia-induced O-linked β-N- acetylglucosamine (O-GlcNAc) modification on proteins in vascular endothelial cells (ECs). Recent advances identified O-GlcNAc modification on histones, which is actively involved in regulating chromatin accessibility and adjacent gene expression. But it remains elusive whether and how hyperglycemia-induced histone O- GlcNAc affect atheroprotecive gene expression and endothelial function, as well as its contribution to diabetes- accelerated atherosclerosis. We recently made the novel discovery that O-GlcNAc modification occurs at the histone H3T32 site (H3T32OG) in ECs under high-glucose. Notably, a loss-of-function mutation (H3T32A) abolished H3 O-GlcNAc while simultaneously increasing H3K27ac enrichment in the promoters of atheroprotective genes. To further investigate the atheroprone effects of H3T32OG, we generated a mouse model with inducible EC-specific replacement of H3T32T with H3T32A, effectively blocking H3 O-GlcNAc. These newly acquired results led to the overarching hypothesis that histone H3T32OG, as a novel histone code in ECs, mediates diabetes-induced EC dysfunction and atherosclerosis. Mechanistically, H3T32OG competes with H3K27ac, restricting chromatin accessibility and downregulating atheroprotective genes in ECs. To test this hypothesis, two specific aims are proposed: Aim 1: To investigate the effect of EC OGT and H3T32OG on diabetes-accelerated atherosclerosis. Using male and female iEC-OGT KO ApoE-/-, iEC-H3T32A ApoE-/-, and H3T32T ApoE-/- mice with low-dose STZ-induced diabetes, the study will compare atherogenesis, lipid deposition, macrophage infiltration, and plaque stability. Mechanistic insights will also be gained through single-nucleus RNA-seq from freshly isolated mouse aortas from these animals. Aim 2: To define the epigenetic features of diabetic condition-induced H3T32OG in ECs and its relation to EC function. Genome- wide H3 O-GlcNAc loci will be mapped via ChIP-seq and integrated with existing datasets. Then, in aortic ECs from H3T32A and H3T32T mice, the interaction between H3T32OG and H3K27ac, as well as histone accessibility and gene expression, will be evaluated in the promoter regions of key atheroprotective and atheroprone genes. Functional differences between these ECs, including nitric oxide bioavailability, monocyte adhesion, and permeability, will also be studied in vitro. In summary, this innovative research, supported by strong preliminary studies and well-established resources, aims to explore the novel histone code involved in diabetes-accelerated atherosclerosis (Aim 1) and endothelial cell dysfunction (Aim 2). The findings are expected to provide a deeper understanding of this epigenetic mechanism and challenge current views on histone codes in diabetic vascular complications.