University Of Alabama At Birmingham

NIH Research Projects · FY 2025 · 2021-01

Abstract Research shows widening health disparities among midlife women since the mid-1980s. However, the mechanisms through which these health gradients operate are not fully known. Although about 85 percent of midlife (ages 40-50) women today are mothers, the pathways to and contexts of motherhood—what we call motherhood biographies—have become increasingly diverse across many dimensions relevant to health, including age at first birth, parity, spacing of children, and relationship status. Despite evidence that each of these individual dimensions of the motherhood biography shape maternal health early in the life course, their longer- term consequences for maternal health at midlife have been largely ignored. Additionally, research to date has failed to examine whether midlife mother-child relationship characteristics (e.g., coresidence, relationship quality) either explain or condition the impact of motherhood biographies on midlife women's health. What is unknown in the scientific literature is how motherhood biographies and midlife motherhood contexts are related to health and health disparities among midlife women and how these effects vary by education and race-ethnicity. The proposed R01 study, Motherhood Biographies and Midlife Women's Health, will be the first to comprehensively determine how motherhood biographies and midlife motherhood contexts matter for midlife women's health by education and race-ethnicity. We use nationally-representative data from the 1979-2016 waves of the National Longitudinal Study of Youth (NLSY79; N=4,271 women). The data are unmatched in their ability to address our research aims as they include nationally representative longitudinal data—the gold standard in research on family and health—and allow us to follow women from adolescence to their 50s, tracking key moments in motherhood and health. We examine a comprehensive collection of health variables in order to capture the critical heath disparities found at midlife including related to a) health behaviors, b) physical health, and c) mental and cognitive health. This project is innovative in that it presents new solutions to the perplexing puzzle of the midlife health gradient by theorizing and examining motherhood biographies and contexts as key pathways though which health outcomes are stratified at midlife. This proposal will have a significant impact in demonstrating risk factors and mechanisms for midlife health disparities. Additionally, given that education and race-ethnicity are also associated with health disparities and motherhood, this study is significant in testing how diversifying motherhood biographies by education and race- ethnicity play a role in the widening of midlife health disparities. Examining motherhood biographies at this life course juncture helps us to better understand health disparities as this generation ages into later-life. Because health disparities widen with age, it is both possible and imperative to identify the social causes of what may be small health issues in midlife in order to ameliorate larger health issues in later life.

NIH Research Projects · FY 2025 · 2021-01

Sepsis accounts for nearly 50% of acute kidney injury (AKI) in the intensive care unit and significantly impacts mortality. However, therapy for sepsis-associated AKI (SA-AKI) has remained elusive because the pathophysiology of injury is not well understood. Evidence emphasizes the pathogenic role of systemic cytokine storm and proximal tubular damage (oxidative stress and mitochondrial dysfunction) in SA-AKI. The cytokine response, mediated by NFkB and HIF-1α signaling in myeloid cells (particularly, macrophages) is a dominant pathogenic mechanism in sepsis. In this context, treatment of macrophages with ferritin light chain (FtL) reduces lipopolysaccharide (LPS)-induced activation of NFkB and HIF-1α and subsequent pro-inflammatory gene expression (IL-6, TNFα). Additionally, administration of FtL to wildtype mice mitigates cecal ligation and puncture (CLP) induced hyperinflammation. Single cell RNA sequencing on renal cell populations from mice administered FtL (or saline) and then subjected to LPS endotoxemia identified cystatin A (CSTA) as the most significantly upregulated gene in the myeloid populations of FtL administered mice. CSTA is an intracellular inhibitor of cathepsins. While the role of CSTA in sepsis is unknown, cathepsins augment the inflammatory response via activation of NFκB. Therefore, we propose that FtL prevents the hyperinflammatory response via CSTA- mediated inhibition of cathepsin and NFκB/HIF-1α signaling during sepsis. Pertinent to the kidney, while CLP led to marked expression of kidney injury markers (NGAL and KIM-1), FtL administration prevented such induction and preserved expression of peroxisome proliferator-activated receptor gamma coactivator 1- alpha (PGC-1α), a regulator of mitochondrial biogenesis and metabolism. Proximal tubules (PT) are the sites of maximal injury during sepsis and FtL is expressed in this tubular segment. Thus, we propose to determine the disparate roles of macrophage- and PT-derived FtL in the protective response during sepsis. Our findings are clinically relevant because serum ferritin levels (predominantly FtL) are often elevated during inflammation but its role in inflammation is unknown. We propose that an increase in FtL is an adaptive physiological response to control inflammation and promote survival. In Aim 1, using two models of sepsis (CLP and LPS) combined with novel tools to delete or overexpress FtL, we will determine whether FtL induces CSTA expression and inhibits macrophage HIF-1α signaling, thereby preventing mitochondrial dysfunction, glycolysis and subsequently mitigating overproduction of cytokines. In Aim 2, we will determine the distinct functional roles of macrophage vs. PT-specific FtL expression in mitigating loss of kidney function, renal inflammation, oxidative stress and mitochondrial dysfunction. Using an integrative approach of in vitro and in vivo models, we will determine the function of FtL during sepsis. If our hypothesis is validated, the results will justify the development of a new treatment for SA-AKI that could alleviate the significant burden of sepsis induced morbidity, mortality and substantial health care expenditures.

NIH Research Projects · FY 2025 · 2020-12

Project Summary: This project proposes to study the role of Smad8 and muscle-enriched microRNAs, known as myomiRs, in Duchenne muscular dystrophy. Duchenne muscular dystrophy is a skeletal muscle wasting disease that is at least in part mediated by secondary effects from membrane fragility due to loss of dystrophin. These secondary effects include impairments in muscle proliferation, differentiation, and regeneration that are propagated by inflammation. This project has identified the TGF-associated transcription factor, Smad8, as markedly elevated and associated with the repression of myomiRs in Duchenne muscular dystrophy skeletal muscles. As such, the proposal will use cell culture and mouse models of Duchenne muscular dystrophy to molecularly map the role of Smad8 in skeletal muscle function and disease. The short-term goal is to identify the mechanisms by which TGF / Smad8 signaling might promote dystrophic processes by understanding its connection to myomiRs repression with a goal of identifying novel pathways for potential therapeutic intervention. For example, we will study the effects of over-expression and knockdown of Smad8 on key pathways like muscle proliferation, differentiation, and skeletal muscle regeneration. We will also study impact of Smad8 modulation on myomiRs and their downstream mRNA pathways. The long-term goal is to expand our understanding of TGF / Smad8 cell signaling and microRNA biology in skeletal muscle function in health and disease.

NIH Research Projects · FY 2025 · 2020-12

Stroke remains a leading cause of death and morbidity in the USA and lacks effective therapeutic interventions. Redox imbalance and mitochondrial dysfunction are considered as leading causes of cell death in stroke. Identification of novel therapeutic targets that restore redox homeostasis, mitochondrial function, and cell survival is a critical need. Deregulation in peroxiredoxins (PRDXs) is one of the mechanisms leading to redox imbalance and mitochondrial dysfunction. PRDXs act as double-edged swards that the highly neuroprotective when inside the cells in reduced forms. However, when oxidized and released from damaged/dead cells, PRDXs can lead to secondary cell death signaling via inflammatory responses. Therefore, the regulation of PRDXs in stroke is a vital neuroprotective strategy. We identified that regulation of PRDXs by SULT4a1 (relatively less studies neuronal protein) is a critical neuroprotective function of SULT4a1 and may have a vital neuroprotective role in stroke. Loss of SULT4a1 in mouse neurons leads to the accumulation of oxidized PRDXs with subsequent redox imbalance, mitochondrial dysfunction, and cell death. SULT4a1 can interact with PRDX1, PRDX2, PRDX3, and PRDX5. These PRDXS (cytosolic-PRDX1 and PRDX2, and mitochondrial-PRDX3 and PRDX5) are crucial for cytosolic and mitochondrial redox homeostasis via detoxification of peroxides. During this process, PRDXs are oxidized and must be recycled back to reduced forms. Expression of SULT4a1 increases the levels of reduced PRDXs in peroxide-treated cells. SULT4a1 protein levels decrease in stroke via the ubiquitin proteasomal system. However, the role of SULT4a1 in stroke or the mediators that lead to loss of SULT4a1 in stroke are not known. We will use oxygen- glucose deprivation in mouse cortical neurons and a middle cerebral artery occlusion (MCAO) model of stroke in mice to identify the neuroprotective roles of SULT4a1 in stroke. We propose the following four aims to study the role of SULT4a1 in stroke: Specific Aim #1: Can SULT4a1 maintain redox homeostasis via PRDXs in stroke? Specific Aim #2: Can SULT4a1 rescue mitochondrial function in stroke? Specific Aim #3: Is SULT4a1 neuroprotective in stroke? Specific Aim #4: Identify the mechanisms leading to loss of SULT4a1 in stroke Our supporting data strongly favor our hypothesis and the proposed aims. Combining viral-mediated expression of SULT4a1 with Seahorse Flux analysis, electron microscope imaging, proximity ligation assays, proximity-dependent biotin identification, live-cell imaging, and MRI imaging in experimental models of stroke represents a novel approaches to identify the neuroprotection by SULT4a1 in stroke. These studies will reveal essential knowledge about the role of the novel SULT4a1-dependent pathways in stroke, and determine whether SULT4a1 can represent a credible target for therapeutic intervention in stroke.

NIH Research Projects · FY 2025 · 2020-12

The increasing availability of “big data” has transformed the training required to advance our understanding of the pathophysiology of cardiovascular disease (CVD), the identification of patient-level and public health approaches to prevent its occurrence and aspects of quality of care for patients with CVD and its risk factors. The goal of the proposed pre-doctoral National Heart, Lung, and Blood Institute T32 CVD training grant is to engage and empower biostatistics and epidemiology students with a strong foundation in both disciplines so they will be positioned to lead the design, conduct and analysis of the big data that are being collected in the 21st century. Located in the Southeastern US, an area with the highest heart disease death rates, the University of Alabama at Birmingham (UAB) has been at the forefront of CVD biostatistics and epidemiology research for over 25 years. The Departments of Biostatistics and Epidemiology are internationally recognized for leading randomized trial coordinating centers, serving as the coordinating center and field sites for epidemiology studies, conducting analyses of health insurance claims and electronic medical record data, and developing new methods for statistical genetics/genomics. For this T32 program, we are requesting funding for a total of 12 pre-doctoral trainees over the course of 5 years including 2 new trainees in each of years 1 through 3 and 3 new trainees in each of years 4 and 5. Trainees enrolled in the T32 program will receive a strong foundation in the pathophysiology and epidemiology of CVD, skills to design and conduct observational research, training on rigor and reproducibility in CVD research, familiarity with how real-world data are collected and analyzed, experience conducting big data analytics including omics data, grant writing experience, and networking opportunities within UAB and the larger scientific community of CVD researchers. Pre-doctoral trainees will complete activities that provide added value to their doctoral programs in biostatistics and epidemiology including didactic cross-training courses, a grant writing class and workshop, research immersions in three areas of big data, professional development workshops, and CVD seminars and a journal club. We have designed three workshops for this T32 grant including an 8-week summer training program on CVD, a high performance computing boot camp and a workshop on team science and communication. The training program’s capstone experience is a mentored research project resulting in a peer-reviewed manuscript. The program will be led by Drs. Hemant Tiwari and Paul Muntner, full professors in Biostatistics and Epidemiology, respectively, with strong mentoring records and program development experience. We have received the commitment from 14 primary mentors and 11 secondary mentors from the Departments of Biostatistics and Epidemiology. An additional 21 faculty members from across UAB have committed to serve as content mentors. The proposed pre-doctoral T32 Training Program will produce a cadre of biostatisticians and epidemiologists prepared to lead CVD research studies that address the priorities of NHLBI.

NIH Research Projects · FY 2025 · 2020-12

ABSTRACT There is a fundamental gap in understanding the maternal and neonatal effects of antenatal corticosteroid (ACS) administration in women with threatened preterm birth (PTB) who have type 2 diabetes mellitus (T2DM). Since the initial discovery of ACS for neonatal benefit in 1972, more than 40 randomized controlled trials have been performed evaluating its efficacy. However, none of these trials have included women with T2DM. While ACS have been shown to reduce neonatal morbidity associated with PTB in non-diabetic women, the side effects of ACS (maternal hyperglycemia and fetal hyperinsulinemia) may mitigate the neonatal benefit of ACS in women with T2DM. Before we are able to evaluate the neonatal benefit of ACS in this population, the first step is to optimize maternal glycemic control after ACS. Previous studies evaluating maternal hyperglycemia after ACS have been limited by small sample size, retrospective study design, or insufficient glucose data. Use of continuous glucose monitoring (CGM) in a randomized clinical trial provides a unique opportunity to overcome these challenges. My long-term goal is to improve maternal and child health among women with T2DM as an independently funded clinical researcher. The research objectives of this proposal are to test the efficacy of three treatment strategies at achieving maternal glycemic control after ACS and evaluate the association between maternal glycemic control and neonatal outcomes. My central hypothesis is that treatment with a continuous insulin infusion will improve maternal glycemic control, which is key to improving neonatal outcomes, but at the cost of less patient satisfaction and more health resource utilization. This hypothesis will be tested by pursuing the following specific aims: 1) Test the efficacy of three treatment strategies (addition of sliding scale insulin, up-titration of home insulin, and continuous insulin infusion) at achieving maternal glycemic control after ACS and 2) Quantify the association between maternal glycemic control after ACS and neonatal morbidity. Completion of these aims in this K23 proposal will determine the optimal strategy to achieve maternal glycemic control after ACS and inform a larger, multicenter trial to improve neonatal outcomes among women with T2DM and threatened PTB. The research plan will be augmented by intensive mentoring from a multidisciplinary team of experts, formal training at the University of Alabama at Birmingham, and participation in premier national training programs. The training plan was carefully crafted to ensure Dr. Battarbee achieves her specified career development goals: 1) Expand skills in CGM data acquisition, management and analysis of repeated measures, 2) Understand behavioral science theory and develop skills in implementation science, 3) Develop skills for leading a multidisciplinary research team, and 4) Refine grant writing skills to ensure ability to secure funding for future research. Completion of this proposal will transform care of pregnant women with T2DM receiving ACS and uniquely position Dr. Battarbee to achieve independence with R01 funding to improve neonatal outcomes of women with T2DM on a larger scale.

NIH Research Projects · FY 2025 · 2020-11

SUMMARY. Loss of B cell tolerance and production of auto-antibodies (Ab) by plasma cells (PCs) play a major role in Systemic Lupus Erythematosus (SLE) pathology. Though Ab-dependent pathogenesis can be partially controlled with immunosuppression, there is no cure for Ab-mediated disorders. One of the main limitations when developing therapeutic strategies aimed to prevent Ab-dependent pathology is the lack of a precise understanding of how auto-reactive PCs are generated and maintained. In this regard, T follicular helper (Tfh) cells, a subset of CD4+ T cells that provides help to B cells, play a critical role in promoting auto-reactive PCs. As such, the expansion of self-reactive Tfh cells correlates with auto-Ab production and disease severity in murine and human lupus. Similar to Tfh cells, Double-negative (DN) T cells, a particular population of T cells that characteristically lack CD4 and CD8 expression, are also expanded in lupus. Importantly, the frequency of DN T cells also correlates with disease activity and auto-Ab production. Thus, it is generally believed that these cells play a role in autoimmune disease pathogenesis. Despite their putative role in disease development, we do not know what signals control DN T cell formation, and their exact origin and pathogenic function remain largely elusive. Furthermore, the mechanisms that regulate DN T cell homeostasis are entirely unknown, and there are currently no therapies to selectively deplete DN T cells in vivo. The main goal of this proposal is to define the cellular and molecular mechanisms that control pathogenic DN T cell development and function. In this regard, our preliminary data demonstrate that DN T cells and Tfh cells share phenotypic, transcriptional, and developmental requirements. As such, we have identified a population of Bcl6+ DN T cells that phenotypically resemble Tfh cells. The central hypothesis that will be tested in this proposal is that Tfh cells are the precursors of Bcl6+ DN T cells and that, similar to Tfh cells, these cells are efficient B cell helpers. Importantly, our preliminary data also suggest that Bcl6+ DN T cells are more plastic than Tfh cells, which allows them to acquire a “hybrid” Tfh/Th17 signature that we believe is critical for supporting auto-reactive PC responses. In Aim 1, we will test the hypothesis that Tfh cells are precursors of Bcl6+ DN T cells and examine the capacity of these cells to help self-reactive B cell responses. In Aim 2.1, we will test the hypothesis that IL- 17 production by DN T cells is critical for supporting PC responses and Ab-mediated pathology. In Aim 2.2, we will determine the molecular mechanisms controlling the acquisition of a “hybrid” Tfh/Th17 signature. Finally, in Aim 3, we will develop a new synergistic IL-2-based immunotherapy aimed to selectively target Tfh and prevent the differentiation of IL-17+Bcl6+DN T cells by combining “ultra-low” doses of rIL-2 with STAT3- signaling blockade. We believe that our studies will provide a new paradigm for how pathogenic DN T cells are generated, will reveal new pathways implicated in autoimmune disease pathogenesis, and will be crucial for designing new therapeutic interventions to target Tfh and DN T cells and prevent Ab-mediated pathology.

NIH Research Projects · FY 2024 · 2020-09

Influenza A virus (IAV) profoundly enhances the susceptibility of lung epithelial cells for pneumolysin-mediated necroptosis. Briefly, pneumolysin is the pore-forming toxin produced by Streptococcus pneumoniae (Spn), whereas necroptosis is a caspase-independent form of programmed cell death that results in cell lysis. Herein, we will determine the molecular basis and full biological consequence of a new key observation: Spn binds to necroptotic respiratory epithelial cells via Pneumococcal surface protein A (PspA). Briefly, our preliminary results show that PspA binds to host-derived (h)GAPDH on dying cells and this property directly contributes to IAV/Spn disease severity. Furthermore, Spn/sloughed epithelial cell aggregates formed in the nasopharynx likely promote Spn transmission to a naive host. Herein we test the hypothesis that during IAV/Spn superinfection a high level of epithelial cell necroptosis occurs that promotes PspA-mediated binding to cells. This property directly enhances Spn outgrowth and promotes Spn transmission. AIM 1: Determine the molecular basis for PspA-mediated adhesion to necroptotic lung epithelial cells (LEC). Spn adhesion to LEC is PspA-dependent, enhanced when cells undergo necroptosis, and mediated by PspA binding to hGAPDH found on the surface of dying cells. We will identify the domain of PspA responsible for hGAPDH binding, how conserved this domain is across sequenced strains of Spn, and the affinity of representative PspA variants to hGAPDH. We will create and test the ability of isogenic mutants in the PspA hGAPDH binding motif to bind dying LEC. We will identify the region of hGAPDH that is bound by PspA. AIM 2: Determine the biological impact of PspA-mediated adhesion on IAV/Spn pneumonia severity. PspA is required for the enhanced disease severity that occurs during IAV superinfection. We will determine if hGAPDH binding alters the canonical role of PspA, which is inhibiting lactoferricin-mediated killing. We will determine how PspA-binding influences the localization of Spn within the airway and how this is impacted by co-infection with IAV, neutralization of pneumolysin, or blocking of necroptosis. We will determine if PspA- mediated binding of Spn to dying LEC promotes their outgrowth in otherwise nutrient restricted conditions. We will determine how antibody against the hGAPDH-binding motif of PspA alters overall disease progression. AIM 3: Determine the requirement of PspA mediated adhesion to colonization and transmission. Spn binds to dying mucosal epithelial cells during colonization and they are together expelled in nasal secretions. Sloughed Spn/host cell aggregates are infectious and thought to promote Spn survival on fomites. We will determine the requirement for PspA on the formation of Spn/host cell aggregates, moreover, how pneumolysin, IAV superinfection, and necroptosis inhibition influences their number in secretions. We will determine the requirement of PspA hGAPDH binding for transmission to a naive host. We will determine if antibody against PspA and/or pneumolysin reduces transmission rates and shortens the length of colonization.

NIH Research Projects · FY 2024 · 2020-09

Modified Project Summary/Abstract Section PROJECT SUMMARY/ABSTRACT Childhood cancer survivors are at high risk for developing new cancers (such as cervical and anal cancer) caused by persistent infection with the human papillomavirus (HPV). An effective vaccine exists that can prevent these cancers, but uptake of the HPV vaccine is low among young cancer survivors (fewer than 1 in 4 have received the vaccine). Lack of a healthcare provider recommendation for the HPV vaccine is the most common reason that cancer survivors fail to get the HPV vaccine. Strategies that are most successful in increasing HPV vaccine uptake in the general population focus on improving healthcare provider knowledge about the HPV vaccine, enhancing the skills that healthcare providers need to effectively recommend the vaccine to young people and their parents, and reducing barriers to receiving the vaccine. This proposed research will evaluate the effectiveness and implementation of an evidence-based intervention, adapted for use by healthcare providers in pediatric oncology clinics, to increase the uptake of HPV vaccine among young cancer survivors (9 to 17 years of age and at least one year off-therapy). If the intervention is effective in improving and sustaining increased uptake of the HPV vaccine in young cancer survivors, this study will contribute important information needed to move forward with testing the widespread use of the intervention in pediatric oncology practices. This proposed research addresses improving healthcare delivery and clinical outcomes for cancer survivors through prevention of HPV-associated cancers, which are high-priority research areas for the National Cancer Institute.

NIH Research Projects · FY 2024 · 2020-09

Abstract Nearly all pediatric and young adult (PYA) kidney transplants fail within 10-15 years, significantly reducing life expectancy for young people with end-stage renal disease (ESRD). Pediatric kidney transplant recipients face distinct barriers to allograft survival, including diagnostic and prognostic tools that are inadequate and not tailored for children. Consequently, kidney transplant injury regularly escapes detection until substantial damage has occurred that hastens allograft failure. Surveillance biopsies allow for earlier detection of subclinical injury prior to transplant dysfunction, but we have shown that the presence of subclinical phenotypes are still predictive of transplant failure. Improved methods of detecting clinical and subclinical kidney transplant endpoints are needed to increase longevity of youth with ESRD. Recent studies have validated patterns of gene expression (e.g., molecular biomarkers) in adult kidney transplant biopsies with greater diagnostic precision than conventional histology. Similar advances with molecular biomarkers have not been translated to children. The objective of this proposal is address this unmet clinical need by identifying and validating molecular biomarkers of key outcomes in young kidney transplant recipients. We will integrate clinical features, traditional histology, and molecular biomarkers to create powerful tools for precision diagnosis and prediction of long-term outcomes that are tailored for PYA kidney transplants. Our central hypothesis is that distinctive gene expression patterns in kidney biopsies will predict clinical and subclinical events in young transplant recipients and expand the capabilities of traditional histology. The central hypothesis was formulated by our preliminary data in which we identified molecular biomarkers of WNT pathway activation as novel predictors of kidney transplant injury and subsequent allograft failure, even in individuals with reassuring clinical features and normal traditional histology. We will test the central hypothesis by using the NanoString platform to interrogate archived PYA kidney transplant biopsies in pursuit of three specific aims. In aim 1, we will identify molecular biomarkers of clinical endpoints in PYA kidney transplantation. We expect that PYA-specific molecular biomarkers will: a) have excellent diagnostic performance for clinical endpoints, b) help discriminate cases with diagnostic uncertainty by traditional histology, and c) outperform conventional clinical features and histology for predicting long-term outcomes in youth. In aim 2, we will discern the role of subclinical molecular phenotypes in PYA kidney transplantation. We expect to find unique molecular biomarkers of subclinical endpoints that will outperform conventional histology in predicting future rejection episodes and allograft failure. In aim 3, we will validate clinical and molecular biomarkers as predictors of kidney transplant outcomes in a prospective biorepository cohort of PYA kidney transplants. Collectively, this project will externally validate PYA-specific covariate-adjusted molecular biomarkers as comprehensive clinical prediction tools that are ready for use in future studies of PYA kidney transplants.

NIH Research Projects · FY 2024 · 2020-09

Project Summary The overall goal of this 5-year K76 resubmission is to support Anand S. Iyer, MD, MSPH to become a leader in geriatrics-palliative care with the skills to improve the health and well-being of older adults with chronic obstructive pulmonary disease (COPD). Dr. Iyer is a pulmonologist and AHRQ-K12 COPD outcomes researcher. COPD is the third leading cause of death for older Americans and accelerates loss of quality of life and functional independence. Research priorities of the NIA identify a critical need for innovative geriatrics-palliative care models to address unmet care needs for older adults, especially those from rural and underserved areas where COPD is prevalent and palliative care access is limited. However, no geriatrics- palliative care interventions have been systematically developed and tested for community-dwelling older adults with COPD. Through this K76, Dr. Iyer will gain advanced training in: 1) gerontology and geriatrics-palliative care; 2) clinical trials and implementation science; and 3) leadership development in aging. To support his career development, Dr. Iyer and his primary mentor, Cynthia Brown, MD, MSPH, have assembled a mentor team of experts in geriatrics (Seth Landefeld, MD), palliative care-implementation science (Marie Bakitas, DNSc, APRN), and COPD clinical trials (Mark Dransfield, MD). Dr. Iyer will seek advisement from international leaders in aging biology (Steven Austad, PhD), lung aging (Victor Thannickal, MD), geriatrics-palliative care (Christine Ritchie, MD, MSPH), and the aging brain in COPD (Karin Hoth, PhD). Supported by an AHRQ-K12, Dr. Iyer developed, “EPIC: Early Palliative Care In COPD”, a 6-month telehealth, palliative-nurse coach-led intervention for COPD patients and their family caregivers. Preliminary feasibility results in middle-aged COPD patients and their family caregivers are promising; however, it is not known how EPIC needs to be refined to meet the needs of older COPD patients, especially the old-old. Guided by Baltes’ Theory of Successful Aging, this K76 will: 1) Refine the geriatrics content of EPIC by engaging diverse stakeholder groups of older COPD patients, family caregivers, clinicians, staff, and policy leaders; and, 2) Conduct a hybrid type-1 effectiveness-implementation pilot randomized controlled trial of Geri-EPIC plus usual COPD care versus usual COPD care alone to determine feasibility and acceptability, to refine trial procedures, and to collect preliminary data on Life- Space mobility to inform a fully-powered trial at the R01 level. Ultimately, this K76 will position Dr. Iyer to be a leader in geriatrics-palliative care and patient-oriented aging research.

NIH Research Projects · FY 2025 · 2020-09

The BIGDATA CCCR encompasses three distinct and synergistic cores – the Methodologic and Health Informatics Core, a newly proposed Dissemination, Implementation and Community Engagement (DICE) Resource core, and an Administrative Core. All three are aligned around the theme of patient-centered research using real-world evidence, mobile and digital health (e.g. apps, virtual reality), informatics, and advanced analytics. The DICE Core will facilitate our important subtheme of community engagement. In this renewal application, we will continue to foster our goal to bring innovative tools and methods to the research community to effectively advance the NIAMS mission for rheumatic and musculoskeletal disease (RMD) research. We will support innovative approaches, methods and technologies necessary to transform healthcare in the 21st century through achieving these Specific Aims: Specific Aim 1: To harness the outstanding, innovative, and synergistic RMD research expertise at UAB to expedite clinical, translational, and informatics-related science through the utilization of our Methodologic and Health Informatics (MHI) Core. The MHI core is composed of a multidisciplinary team with expertise in biostatistics, informatics (e.g., natural language processing, machine learning, artificial intelligence, data visualization), epidemiology, and implementation science. Specific Aim 2: To strengthen community engagement through our newly proposed Dissemination and Implementation and Community Engagement (DICE) Resource core. DICE will focus on three main capacities: 1) study recruitment and community engagement; 2) Dissemination and implementation (D&I) research, translating research into practice in academic and community settings; and 3) incorporating the patient voice in all aspects of clinical research, starting with the study question, extending to representing patients’ input in the data acquisition process to ensure that data collected is relevant to patients, and bridging to implementation so that RMD patient views are well represented. Engagement with the DICE Core will be facilitated in part by our Patient Advisory Committee and through tested structures to engage patients in pre- and post-award roles. Specific Aim 3: To comprehensively coordinate our CCCR’s activities, effectively leverage institutional resources (e.g. the UAB CCTS) and promote training for both early and established investigators in state-of- the-art methods applicable to the NIAMS mission through a broad range of enrichment activities, all overseen by our Admin Core.

NIH Research Projects · FY 2025 · 2020-09

ABSTRACT (OVERALL SECTION) The identification of genetic variants associated with human diseases is accelerating, thanks to advances in technology and reduced costs of next-generation sequencing. Distinguishing between pathogenic and benign variants poses a significant challenge, necessitating robust informatics tools complemented with experimental validation. These tools must analyze extensive amounts of data and present it in a comprehensive and accessible format for expert evaluation and prioritization of the variants based on likely clinical significance. These tools must help select optimal model systems in which to engineer the variant to mimic human disease, to study disease mechanisms, identify and test therapeutics, and to develop diagnostic tools and clinical care strategies. To tackle this complex set of issues, we established the Center for Precision Animal Modeling (CPAM1.0) in 2020. CPAM’s multidisciplinary team encompasses expertise in clinical care, disease diagnostics, genetics, computational and data sciences, artificial intelligence and machine learning, genome engineering, disease modeling, and therapeutic screening. This network of expertise forms a well-integrated and efficient CPAM analysis platform through which community-based nominations undergo systematic evaluation using established criteria, ensuring that selected variants represent both scientific merit and potential patient benefit. CPAM’s Preclinical/Co-clinical Section (PCS) serves as the liaison for incoming nominations and manages comprehensive patient clinical data collection, ensuring secure integration of medical records, genomic information, and treatment histories along with robust patient protection policies. The PCS received 169 submissions over the past four years, highlighting the demand. Each nominated variant undergoes thorough analysis by our Bioinformatics Section (BIS), with reports presented to the Steering Committee (SC) for evaluation, selection and prioritization of variants for further modeling. For projects that CPAM accepts for disease modeling, the Coordination Section (CS) initiates collaborations and the BIS employs AI approaches to identify therapeutic strategies. The Disease Modeling Unit (DMU) develops patient variant human cell and animal models across multiple species. These models are analyzed in parallel with clinical investigation enabling direct comparisons to help ensure that CPAM animal models effectively predict treatment outcomes and accelerate therapeutic development. Concurrently, the Resource and Service Section (RSS) and the BIS develop functional assays to assess variant pathogenicity and test prioritized drugs. After establishing the animal model, the RSS conducts quality control, cryopreserves the line, and distributes it to collaborators and repositories. The DMU evaluates phenotypes, and interfaces with the BIS, PCS and a Phenotype Validation and Clinical Curation Committee to assess human disease relevance. Finally, the BIS compiles all data into a final Patient Variant Report and the PCS returns results to the nominator. Ultimately, CPAM has a pivotal role in driving the translation of genomic discoveries into tailored therapies that can significantly improve patient outcomes.

NIH Research Projects · FY 2024 · 2020-09

Arsenicals such as lewisite, diethylchloroarsine, diphenylchlorarsine, and diphenylcyanoarsine are extremely toxic chemicals that have been used in chemical warfare since World War I and continue to remain a threat to humans, who may be exposed through accidental or intentional mass population exposure. Topical exposure to these agents results in severe cutaneous blistering, inflammation and pain, and therapeutic strategies that safely and effectively attenuate this damage remain urgently needed. Such a strategy has long remained elusive in large part because the molecular mechanisms that underlie the cutaneous damage caused by arsenicals had not been identified. With our previous award, we developed murine and porcine models that, upon topical arsenical exposure, develop cutaneous lesions nearly identical to those that occur in humans. Employing these animal models, we identified a master regulatory signaling cascade underpinning the complex pathobiology of arsenicals. Mechanistically, the inflammatory responses, cell death, tissue disruption, and pain pathways induced by cutaneous arsenicals exposure are mediated by the induction of endoplasmic reticulum (ER) stress and reactive oxygen species generation and subsequent activation of unfolded protein response (UPR) signaling, particularly that involving the ATF4-eIF2α axis. Phosphorylated eIF2α, which we found to be upregulated after arsenicals exposure, blocks translation of most nascent proteins but upregulates the translation of the ATF4 transcription factor. RNA-Seq and CHIP-Seq data confirmed an unbiased role of ATF4 in the pathogenesis of the skin lesions and identified a unified role of ATF4-regulated proteins in this injury. Therefore, we investigated the therapeutic potential of the chemical chaperone 4-phenylbutyric acid (4-PBA), which has been shown to enhance protein folding and reduce ER stress; the antioxidant N-acetyl cysteine (NAC); and the inhibitor of eIF2α phosphorylation ISRIB. Each of these drugs was highly effective in restoring protein translation and diminishing inflammation, tissue disruption, and pain in our mouse model. Thus, we have validated the mechanism-based efficacy of these small molecule agents against cutaneous toxicity induced by arsenicals. 4-BPA and NAC are FDA approved, thus we propose to advance these findings through the lead optimization of 4-PBA and NAC delivered by topical administration after arsenicals exposure in our murine and porcine models. Specifically, we propose to determine the efficacy of the maximum tolerated dose, the window of efficacy, and the durability of response for these drugs, alone and in combination, in treating arsenicals-mediated cutaneous injury in mice (Aim 1); to develop various topical formulations of these drugs and assess the efficacy thereof against arsenicals-mediated cutaneous injury in mice (Aim 2); and to confirm the efficacy of the identified novel outstanding formulation in our porcine model of arsenicals-mediated cutaneous injury (Aim 3). These studies will drive the clinical translation of an antidote for the cutaneous toxicity of arsenicals, which may be further expedited as these drugs are already FDA approved.

NIH Research Projects · FY 2024 · 2020-09

Roadmap for America’s Cancer Explorers for the 21st Century (RACE21) is an interdisciplinary program to develop a pipeline to a diverse 21st century cancer research workforce. Cancer is a primary cause of adult mortalities in the US, despite excellent advances in understanding cancer biology and innovative treatments. In Alabama, cancer is the 2nd highest cause of mortality, and cancer death rates are almost double in Alabama’s African-American (compared to White) males. One of the underlying causes of this anomaly is the lack of communication about cancer among Africa-Americans, especially within families. Also, relatively few African-American youth are seeking careers in cancer research, largely due to very little exposure to cancer biology in most of their secondary schools and their teachers’ lack of cancer biology training. Further, few informal programs excite students about careers in cancer biology. RACE21 will build an innovative and effective pipeline to cancer research careers, especially for students underrepresented in cancer research (URM) by building on 5-basic foundations: 1) The University of Alabama at Birmingham’s (UAB) outstanding O’Neal Comprehensive Cancer Center, 2) Over 200 cancer researchers, eager to mentor high school and college students to become the next generation of cancer researchers, 3) development of an innovative Undergraduate Cancer Biology Major, 4) the Center for Community OutReach Development (CORD), which will train high school biology teachers in cancer research and introduce advanced high school students to cancer research in both formal and informal settings and 5) training in communication about cancer. RACE21 employs successful methods developed at UAB, and uses them to advance cancer biology education. The pipeline starts with high school students being introduced to cancer biology through state-of-the-art experiences in the Summer Science Institute (10 URM rising seniors will be Summer Research Interns) and experiences at the GENEius lab. RACE21 will also provide intense cancer biology training to high school teachers via an annual 3-week BioTeach-Cancer training. RACE21 students (>80% URM) entering UAB’s new Cancer Biology Major will complete a paid summer internship in cancer research in their rising year 1 and 2, and in year 3 and 4 they will receive fellowships as cancer researchers. Each year 10 RACE21 students will complete the undergraduate major, with most continuing to graduate school in cancer research related areas. The Intellectual Merit of RACE21 will be in testing a pipeline that leads to increased minorities in cancer biology careers. The Broader Impacts will annually educate about 6,000 minority students, families and the public about cancer biology and launch the cancer research careers of >40 minority students.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY The goal of the proposed research is to identify the best predictive biomarkers of dementia in Parkinson’s disease (PDD) through a multimodal and multivariate statistical model utilizing both neuroimaging derived measures (diffusion-weighted MRI (dMRI), resting-state functional MRI (rsfMRI), and T1-weighted MRI measures) and non- imaging measures such as demographics (age, sex, years of education), clinical (disease duration and severity), genetics (LRRK2), and CSF-measures (Total Tau, β-Amyloid, α-synuclein). It is critical to identify biomarkers that can predict dementia in Parkinson’s disease (PD) as approximately 50-80% of PD patients develop PDD within twelve years of diagnosis. Identifying pathophysiology-based biomarkers that could identify PD patients at high risk for PDD reliably is critical for better prognostication, correct identification of PDD in its prodromal stage to recruit in new disease-modifying clinical trials, and better understanding the pathophysiological processes underlining PDD. The proposed project has two important components. The first component of the project is to understand the pathophysiological mechanism underlying PDD through sophisticated voxelwise dMRI-derived measures estimated using a multi-shell high angular and spatial resolution dMRI data acquisition, and understanding network-level white matter (WM)-derived structural connectivity and rsfMRI-derived functional connectivity in PDD. The second component of the project is to identify the biomarkers that predict PDD through multivariate statistical modelling by combining these sophisticated pathologically relevant neuroimaging measures with non-imaging measures (such as clinical, demographics, genetics, and CSF-measures). We will recruit demographically matched healthy controls (HC) along with demographically, disease duration, and disease severity matched PD patients with mild cognitive impairment (PD-MCI), PD-non-MCI (PD-nMCI), and PDD for this project. We will acquire multi-shell dMRI data at three b-values, namely 500s/mm2, 1000s/mm2, and 2500s/mm2 with a high angular and spatial resolution and estimate various unbiased free-water (fiso) corrected Gaussian dMRI-derived measures along with non-Gaussian dMRI-derived measures such as diffusion kurtosis measures, and neurite orientation dispersion and density imaging measures. We will further compare these measures between the groups to identify significant dMRI-derived measures separating the groups, and understanding the neuroanatomical correlates of these measures with various neuropsychological scores. Furthermore, we will estimate dMRI-derived structural connectivity and rsfMRI-derived functional connectivity to understand network-level discrepancies predicting PDD. These pathologically relevant neuroimaging measures will be further combined with various non-imaging measures through a novel machine learning algorithm to identify the comprehensive and best predictors of PDD. The tools developed in our proposal also has great potential for significantly advancing the understanding of other neurodegenerative disorders such as Alzheimer’s disease (AD) thereby helping to understand AD- and PD-specific neuroanatomical changes predicting dementia.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY/ABSTRACT The aim of this R35 application is to develop a high quality, translational research program in inflammation- induced endothelial damage and organ dysfunction. Dysregulation of microvascular function contributes to the pathophysiology of indirect organ injury after trauma. In particular, damage to the endothelial glycocalyx occurs within minutes of traumatic injury and is associated with increased microvascular permeability resulting in multi- organ failure and increased mortality. Strategies that attenuate glycocalyx disintegrity by preventing its cleavage and/or facilitating its repair hold significant promise for minimizing microvascular dysfunction and post-traumatic organ injury. The long-term objective of our research program is to establish basic science and translational studies that focus on the identification of novel therapeutic targets that will (1) prevent glycocalyx damage, (2) repair glycocalyx integrity or (3) inhibit dysregulation of endothelial cell permeability that occurs as a result of glycocalyx disintegrity. The specific programmatic areas of focus will include studies to identify the role of heparanase in regulating glycocalyx (dis)integrity after trauma-hemorrhage and on mechanisms that mediate glycocalyx synthesis. Additionally, our proposed studies will identify signaling pathways that regulate endothelial barrier function that are effected by loss of cell surface glycosaminoglycans, heparan sulfate and hyaluronic acid, which are primary constituents of the glycocalyx layer. Our research program will focus on the endothelial cell- specific response to trauma-hemorrhage in organ systems that are most susceptible to secondary injury (e.g., kidney, lung and intestines) with the over-arching goal of determining how resuscitation strategies mediate glycocalyx-dependent mechanisms in each organ. These programmatic areas of research hold promise for significantly impacting the current resuscitation paradigm for patients in hemorrhagic shock by aiding in the discovery of novel therapeutic targets that can be used to inhibit glycocalyx dysfunction, facilitate its repair or reverse the downstream consequences of glycocalyx disintegrity.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY Patient-reported Outcomes (PROs) have been integrated into routine care at the UAB HIV Clinic to monitor depression and substance use disorders (SUD) that, when untreated, threaten progress along the HIV care continuum. PROs more accurately identify these comorbid conditions relative to provider documentation. Thus, PROs enable clinics to allocate scarce mental health (MH) and SUD services to those in greatest need. Additional treatment barriers remain even for patients with prompt diagnoses, especially in rural and Southern states with limited access to MH and addiction treatment providers. Telemedicine has been effectively used to expand medical care to rural and impoverished areas. Yet, there remains a knowledge gap about optimal implementation strategies for and effectiveness of innovative technologies (PROs, telemedicine) in real-world settings. To address this gap, investigators will leverage the Alabama Quality Management Group (AQMG), a consortium of Ryan White HIV/AIDS Program (RWHAP)-funded clinics in Alabama, founded in 2006. We propose a multicomponent intervention, HIV+ Service delivery and Telemedicine through Effective PROs (+STEP), to increase screening and treatment of depression and SUD in AQMG sites. According to Gelberg’s Behavioral Model for Vulnerable Populations, health outcomes are optimized by addressing (1) predisposing factors like MH and substance use disorders; (2) enabling factors such as personal and community resources; and (3) health behaviors like use of medical services. The +STEP intervention will address these domains using PROs to more accurately diagnose depression and SUD (predisposing), targeted knowledge to frontline clinicians (enabling), and use of telemedicine to expand MH and SUD resources (health behavior). We propose a hybrid type 1-design study to evaluate the implementation and effectiveness of this multicomponent intervention (PROs, training, and telemedicine). We will use the Consolidated Framework for Implementation Research (CFIR) to identify implementation strategies and guide implementation, scale up, and maintenance of +STEP. Our principle objectives are to characterize patient and clinic uptake; create an implementation blueprint of barriers, facilitators and implementation strategies; and evaluate effectiveness through the following aims: Aim 1. Conduct a needs assessment and implement +STEP to improve diagnosis and treatment of MH and SUD at 6 RWHAP clinics in Alabama. Aim 2. Describe implementation strategies addressing barriers to uptake of +STEP in six RWHAP clinics using CFIR. AIM 3. Measure the impact of implementing +STEP on diagnoses, referrals, and healthcare utilization related to depression, SUD, and HIV by comparing clinical outcomes from patients receiving +STEP with historical controls. The expected outcomes are an implementation blueprint and real-world outcomes to inform broad implementation of +STEP to accelerate progress along the HIV continuum towards ending the HIV Epidemic.

NIH Research Projects · FY 2025 · 2020-09

Many studies implicate mitochondrial dysfunction as a key contributor to age-related neurodegenerative diseases, including Parkinson’s disease (PD). Previously published gene expression analyses from laser-captured dopaminergic (DA) neurons from the substantia nigra of preclinical patients found a decrease in genes associated with mitochondrial respiration. However, the implications of this decrease in mitochondrial genes and its link to disease progression and pathology are still unknown. A decrease in a large number of nuclearly-encoded mitochondrial genes suggests that a central regulator of gene expression is impaired; in fact, most affected genes are putative targets for the transcription factor estrogen-related receptor gamma (ERRg), a transcription factor that has not been well-characterized in neurons. Here, we determine the dependence of DA neurons on ERRg for gene expression, survival, and regulation of motor function and explore whether cell type-specific deletion of ERRg predisposes DA neurons to alpha-synuclein-mediated neurotoxicity. Preliminary experiments determined that removal of ERRg from DA neurons influenced gene expression and motor function and rendered DA neuron processes more vulnerable to loss with alpha-synuclein pre-formed fibril (PFF) exposure. This led to the hypothesis that ERRg has a role in promoting synaptic viability in the presence of alpha-synuclein. Experiments in the predoctoral portion will use bioinformatics, transcriptional assays and novel, cell type-specific proteomic techniques to reveal the ERRg-dependent pathways by which nigral neurons regulate mitochondrial and synaptic function and whether these pathways can be leveraged to prevent or delay disease-related synaptic loss. Synaptic abnormalities also occur in the cortical-hippocampal circuit with age, contributing to cognitive decline; however, the transcriptional and proteomic changes which contribute to this decline have not been delineated in a cell type-specific way. In the postdoctoral phase of this award, the applicant will apply the technical knowledge acquired during the predoctoral stage to understand the aging circuits in the hippocampus and cortex using bioinformatics and novel cell type-specific proteomic techniques. This work has the potential to reveal how synapses change with age, with the long-term goal of developing strategies to counteract cognitive decline. In addition to a rigorously designed and innovative research strategy, this application involves a strong training plan specifically designed to promote the future success of the applicant as an independent research scientist in neuroscience and aging. The plan includes exposure to emerging themes and techniques in aging research, opportunities for development in presentation skills and manuscript preparation, co-sponsorship from principal investigators with strong training records and commitment to graduate training, a unique combination of academic and drug discovery expertise, and training in the responsible conduct of research. Altogether, the combined research and training plans position the trainee to become an independent and productive member of the neuroscience aging research community.

NIH Research Projects · FY 2024 · 2020-08

SUMMARY The purpose of this Mentored Patient-Oriented Research Career Development Award (K23) is to provide Ariel A. Salas, MD, MSPH, with the mentorship, training, and research experience needed to become an independent clinician scientist and leader in neonatal nutrition research. His long-term career goal is to reduce the burden of postnatal growth failure through novel translational studies and large scale, multi-center clinical trials of promising dietary interventions that optimize growth, reduce dysbiosis of the gut microbiome, and ultimately improve neurodevelopment. His immediate goal is to acquire the skills needed to conduct a clinical research program to study the effects of the protein intake and gut microbiome on growth and body composition of extremely preterm infants (28 weeks of gestation or less). To achieve these goals and transition to independence, Dr. Salas and his mentors have developed a comprehensive research and career development plan that includes mentorship from an exceptional team of scientists with proven track records of successful mentorship; intensive didactic training; and a research plan that is purposefully designed to provide experiential learning in advanced research methods to study postnatal growth failure and the gut microbiome of extremely preterm infants. Postnatal growth failure occurs in approximately 60% of the nearly 26,000 extremely preterm infants born every year in the United States. Postnatal growth failure is associated with a higher risk of adverse health outcomes, particularly when fat mass (FM) gains are higher than fat-free mass (FFM) gains. Recent work by Dr. Salas suggests that extremely preterm infants unable to tolerate early progression of enteral feeding volumes during the first 2 weeks after birth have an increased risk of disrupted maturation of the gut microbiome and an increased risk of postnatal growth failure. In the research plan outlined in this K23 proposal, Dr. Salas will expand upon this work by 1) investigating the effects of early postnatal life protein-enriched diets on FFM accretion in extremely preterm infants and 2) identifying maturation patterns of the gut microbiome that differentiate preterm infants with postnatal growth failure and reduced FFM accretion from preterm infants with appropriate postnatal growth and normal FFM accretion. This work will produce novel insights into the pathogenesis of postnatal growth failure in preterm infants and will serve as the foundation for Dr. Salas to inform his future R01 proposals and discover new, evidence-based approaches to prevent postnatal growth failure. His career development plan outlines a clear path to gain the knowledge, skills, and experience needed to become an independent clinician scientist, leader, and innovator in neonatal nutrition research.

NIH Research Projects · FY 2024 · 2020-08

Seasonal influenza (flu) infections kill hundreds of thousands of people throughout the world each year and morbidity and mortality rates increase even further when a new pandemic virus emerges. The annual flu vaccine provides an important line of defense against influenza infections but there are many documented examples of poor vaccine efficacy, even in healthy individuals. Thus, there is an unmet public health need to improve influenza vaccination. However, before we can improve the vaccine, we must first better understand the immune cells that respond to the vaccine. One cell type of particular importance is the memory B cell, which is rapidly recalled following infection and vaccination and can contribute to anti-viral immunity by differentiating into short-lived antibody secreting cells (ASCs) that produce antibodies (Ab) that can either neutralize the virus or facilitate its rapid clearance. Memory B cells also seed the vaccine-driven humoral immune response and can give rise to new cohorts of long-lived ASCs and memory B cells that will protect against future exposures to the circulating flu virus. Despite the fact that memory B cells are the direct targets of vaccination in adults, we know remarkably little about these cells. This substantial knowledge gap is due, at least in part, to an inability to isolate and characterize these cells. Studies of memory B cells in humans have been even more difficult as we can typically only look at the cells in the blood and many immune cells, including the memory B cells, reside in tissues that are usually inaccessible in humans. We developed new tools to track flu-specific memory B cells in both mice and humans and have now identified and characterized distinct populations in the tissues of mice that we believe are likely to contribute to long-lasting vaccine induced immune responses. The central hypothesis of this application is that a flu-specific memory B cell subset that expresses the transcription factor T-bet is maintained long-term in tissues like the lung and is preferentially recalled by vaccination. The specific goals for this proposal are to identify the vaccine-elicited signals required to establish lung-resident T-bet expressing memory B cells, to determine whether vaccination and infection induce distinct populations of memory B cell with differing functions and life- spans, to identify which memory B cell subsets are preferentially recalled following antigen exposure, and to evaluate whether the repertoire of the T-bet expressing memory B cells found in human tissues are enriched for reactivity to older “historic” flu antigens that the individual likely encountered early in life. The long term goal of this proposal is to fill our gap in our knowledge by developing the tools and animal model systems that will allow us to systematically and comprehensively study the heterogeneous populations of flu-specific memory B cells that persist in lymphoid and non-lymphoid tissues and are the direct targets of vaccination in adults. We believe that this contribution is significant as we expect to provide new insight into the complex and heterogeneous memory B compartment that is critical for vaccine-induced responses to flu.

NIH Research Projects · FY 2024 · 2020-08

Project Summary This application is for an Independent Scientist Award (K02) from the National Institute on Aging. The candidate, Dr. Thomas W. Buford, is an Associate Professor in the Department of Medicine at the University of Alabama at Birmingham. Dr. Buford has to date established a strong scientific track record in aging and the preservation of physical function. His long-term goal is to establish a sustainable research program focused on identifying and developing therapeutic strategies for the preserving physical independence among older adults. The objective of this application is to provide the candidate with the protected time necessary to acquire knowledge and skills needed to incorporate two inter-related areas, cognitive health and pain management, into his existing research program. These areas represent two major epidemics in aging including chronic opioid abuse and cognitive disorders including mild cognitive impairment, Alzheimer’s, and other dementias. While these areas are recognized as high-priorities for older adults and are associated with declining physical function, few investigators to date have routinely incorporated these factors into prospective studies concerning the preservation of physical function among older adults. Acquiring expertise in these areas will provide the candidate with a more nuanced view of the key issues surrounding the preservation of physical independence. Award activities will also lead to and expanded skillset, ultimately contributing to an improved ability to design and execute research studies capable of making meaningful impacts on the health and quality of life of older adults. The training plan includes three primary objectives which are to: 1) Acquire new knowledge and skills to the assessment and maintenance of cognition in aging, 2) acquire new knowledge and skills in the assessment and treatment of pain in older adults, and 3) advance mentoring and leadership skills necessary to support a sustainable research program. The research plan is designed to integrate with the training plan to provide the candidate with opportunities to 1) utilize established data sources to explore novel relationships between cognition/pain and indices of physical function, and 2) participate in prospective data collection to learn laboratory methods in these areas and generate novel data in these areas. His advisory team includes established, well-funded experts in both cognition (Ronald Lazar, PhD; Virginia Wadley, PhD) and pain (Roger Fillingim, PhD, Burel Goodin, PhD) in aging as well in biostatistics (Gerald McGwin, PhD) and research leadership (Marcas Bamman, PhD). This outstanding team will facilitate the candidate’s success in integrating these new concepts with his existing research. This K02 award will provide the candidate with protected time to expand his research program which will enhance the overall creativity and sustainability of his research. Ultimately this progress is expected to enhance his potential to make significant contributions to the field of healthy aging and to improve the training of future mentees by creating a more interdisciplinary approach incorporating principles from physical, cognitive, and pain sciences.

NIH Research Projects · FY 2025 · 2020-07

PROJECT SUMMARY/ABSTRACT We propose a large multi-center non-inferiority follow-up cohort study designed to evaluate long-term obesity/growth and neurodevelopment after perinatal exposure to adjunctive azithromycin as compared with placebo (plus standard cephalosporin) to prevent surgical site infections at cesarean delivery. The parent C/SOAP randomized trial of adjunctive azithromycin (4/2011–11/2014) demonstrated a significant reduction in maternal infections (endometritis and wound infection) without any significant effect on short-term neonatal outcomes in the azithromycin group. This reduction in maternal infection (a major cause of death) was so significant that azithromycin use was found to be cost-saving – saving ~$360/unscheduled cesarean and $270 million/year in US healthcare costs. However, enthusiasm for adjunctive azithromycin has been tempered given reports of changes induced by azithromycin on the newborn gut microbiome that may be associated with childhood weight gain/obesity and neurodevelopmental impairment. In September 2018, ACOG suggested “consideration” of adjunctive azithromycin, but emphasized the need for studies of its effect on long-term childhood outcomes. In response to these concerns, we proposed an R01 study evaluating pulmonary and gastrointestinal (GI) health after perinatal azithromycin exposure (6th percentile score). Reviewers emphasized the need to evaluate obesity/growth and neurodevelopment (NIH officers advised a separate application due to cap limitations). Thus, in this proposal, we hypothesize that perinatal exposure to adjunctive azithromycin compared to standard cesarean prophylaxis alone is not associated with increased risk of obesity/weight gain or neurodevelopmental impairment (i.e. is non-inferior). We propose a follow-up study of the offspring of the C/SOAP trial cohort at target age of 7 years (range 6-9) at the 14 sites in the parent trial. We expect at least 1410 of 2013 children (70% follow-up) whose mothers were enrolled in C/SOAP will undergo a single study visit incorporating growth/biometry and neurodevelopment assessments to address the following specific aims: 1) To compare the incidence of obese/overweight children (primary outcome), and other biophysical measurements, between cohort offspring aged 7 (range 6-9 years) after perinatal exposure to adjunctive azithromycin versus placebo (standard prophylaxis alone) 2) To compare neurodevelopmental outcomes including cognitive ability (primary outcome), functional and behavioral impairment, and motor proficiency, between cohorts at age 7 (range 6-9 years) after perinatal exposure to adjunctive azithromycin versus placebo This study, along with the companion study evaluating pulmonary and GI outcomes (award notice pending), is the only opportunity to efficiently provide comprehensive long-term safety data from a large US trial to inform and strengthen the newly recommended use of adjunctive azithromycin for cesarean delivery.

NIH Research Projects · FY 2025 · 2020-07

The Childhood Cystic Kidney Disease Center (CCKDC) is a vital component of the PKD Research Resource Consortium (PKD RRC), dedicated to advancing research in polycystic kidney disease (PKD). Our primary aim is to accelerate breakthroughs in understanding cyst development to devise effective treatments, ultimately enhancing patient care. By closely collaborating with other PKD Centers, the NIDDK, and the Steering Committee, we are committed to realizing the PKD RRC’s mission. The CCKDC’s Childhood Clinical and Translational Resource (CCTR), which has a unique focus on childhood cystic kidney disorders, will collect and integrate new patient data and biomaterials into a harmonized PKD RRC centralized database and biorepository for clinical studies. The CCTR is also developing new methodology to assess patient/caregiver experiences to better design and conduct patient-centered research activities. The Bioengineering Resource (BR) will develop cutting-edge inducible PKD mutant rat models, new in vivo and in vitro resources to detect and analyze the endogenous PKD proteins under their native conditions in live cells and tissues, and a human induced pluripotent stem cells (IPSCs) derived kidney organoid platform for rapid large-scale analysis of cystogenic pathways and high throughput functionality testing PKD proteins and patient variants. The Informatic and Data Analytics Resource (IDAR) is establishing a comprehensive hub for high-quality, large-scale omic datasets. We provide user-friendly, web-based tools designed for rigorous cross-species analyses, aiding in pathway identification and therapeutic predictions. Our consultation services enhance hypothesis generation and drug target prioritization, fostering data-driven discoveries. Moreover, the Resource Development Core (RDC) extends the consortium’s research capabilities by offering advanced genome engineering, disease modeling, and a robust organoid screening platform for pathway and drug prioritization. Through strategic collaborations with other UAB Centers and Divisions, the CCKDC is enriching the PKD research environment by recruiting top faculty, conducting summer research training programs, and organizing renal workshops and symposia. We are leveraging significant institutional support that will expand our suite of research tools, resources, and analytical programs, and enhance our educational initiatives. These efforts are amplifying the CCKDC’s overall impact on PKD research and patient care, driving transformative advancements in the field.

NIH Research Projects · FY 2024 · 2020-07

Autoimmune disease like Rheumatoid Arthritis (RA) or Systemic Lupus Erythematosus (SLE) cause significant suffering and represent a huge financial burden. Since many individuals are refractory to treatment with the available drugs, there is a large unmet need to develop new therapeutics for these patients. Although we know that B cells, antibody (Ab) secreting cells (ASCs), inflammatory cytokines and TLR ligands all play important roles in driving humoral immune responses to pathogens, vaccines and self-antigens, we still lack a fundamental understanding of how the signals provided by cytokines and TLR ligands are integrated by responding B cells to promote the development and expansion of ASCs, which in the case of autoimmunity may produce pathogenic autoAbs. We characterized an unusual subset of B cells (DN2 cells), which are found in healthy donors (HD) and expanded in some SLE and RA patients. We showed that DN2 cells, which correlate with disease severity in SLE, can rapidly differentiate into ASCs, suggesting that these cells are “poised” pre-ASCs. Our data suggest that early signals provided by IFNg control DN2 development in SLE patients and HD. Moreover, ex vivo experiments using SLE patient DN2 cells reveal that differentiation of these IFNg-“primed” pre-ASCs requires additional signals provided by TLR7 ligands and IL-21 and we observed that signals provided by IFNg and IFNa control TLR7-dependent but not TLR9-dependent differentiation of human B cells. We showed that IFNg but not IFNa induces expression of the transcription factor IRF1 in human B cells and that IRF1 promotes TLR7-driven human ASC formation. Therefore, we identified at least 2, and likely 3, independent B cell differentiation pathways that are differentially reliant on IFNs, IFN-induced transcription factors and TLR ligands. To date, no studies have focused on how IFNg regulates B cell differentiation and why B cell differentiation in response to TLR7 and TLR9 are differentially dependent on IFNg. In this proposal, we will test our central hypothesis that IFNg selectively induces IRF1-dependent reprogramming of B cells, thereby licensing these cells to differentiate in response to (auto)antigens that engage the TLR7 signaling network. The immediate objectives of this proposal are to (i) examine the overlapping and distinct roles that IFNg and IFNa play in promoting TLR7-dependent human ASC development; (ii) determine how IRF1 supports B cell differentiation and (iii) evaluate why TLR7- mediated B cell differentiation is reliant on IFN-derived signals. Our long-term goal is to use what we learn about the fundamental mechanisms controlling TLR and cytokine-induced B cell differentiation to identify interventions that can regulate the formation, maintenance or function of ASCs in health and disease. This research is significant because we will, for the first time, define the mechanistic basis for IFNg-dependent TLR7-driven human B cell differentiation. We believe that our studies are important as they will advance our fundamental understanding of the mechanisms controlling human B cell differentiation and may in the future allow selective targeting of TLR7-driven autoAb responses without affecting B cell responses to other types of antigens. !