University Of Alabama At Birmingham

NIH Research Projects · FY 2025 · 2023-09

The Chronic Hypertension and Pregnancy (CHAP) randomized trial recently led to new national recommendations regarding antihypertensive treatment for chronic hypertension (CHTN) during pregnancy. CHAP tested treatment (vs. none) initiated before 23 weeks for mild CHTN (BP <160/105 mmHg) at 61 US sites (N=2408). Treatment improved maternal and perinatal outcomes including preeclampsia, preterm birth and low birth weight. CHAP is the largest CHTN treatment trial in pregnancy. However, critical knowledge gaps remain concerning long-term effects of a) routine prenatal antihypertensive therapy and b) superimposed preeclampsia in women with CHTN on exposed offspring. Preeclampsia complicates >30% of patients with CHTN, is associated with impaired fetal growth, and emerging data suggest preeclampsia may impair neurodevelopment (ND) and childhood growth/cardio-metabolic outcomes– including elevated BMI and blood pressure (BP). Small for gestational age is an independent risk factor for impaired childhood ND and altered growth. Therefore, it is crucial to define the long-term effects of prenatal antihypertensive therapy on offspring (as well as mothers in our funded CHAP Maternal Follow-up study R01HL120338). CHAP has randomized treatment and adjudicated preeclampsia data to enhance rigor to address: Aim 1: Define the long-term safety of routine prenatal pharmacologic treatment of mild CHTN on childhood ND and growth. Hypothesis 1a: Antihypertensive therapy for mild CHTN to a BP goal <140/90 mmHg compared with no treatment is not associated with worse ND including cognitive functioning determined by General Conceptual Ability (GCA, primary outcome). If we demonstrate non-inferiority, we will also test whether therapy improves ND - given salutary neonatal results in CHAP. Hypothesis 1b: Antihypertensive therapy (goal <140/90 mmHg) vs. no treatment for mild CHTN is not associated with worse childhood growth and other cardio-metabolic outcomes including BMI ≥85th percentile (primary outcome), obesity, underweight, and BP. Aim 2: Determine whether preeclampsia superimposed on mild CHTN is associated with childhood outcomes including ND, growth and other cardio-metabolic outcomes. Hypothesis 2a: Preeclampsia (vs. no preeclampsia) is independently associated with adverse ND in children including impaired cognitive functioning by GCA (primary outcome). Hypothesis 2b: Preeclampsia is independently associated with altered childhood growth (including a primary outcome of BMI ≥85th percentile), obesity, underweight, serial growth and BP. We will also explore mechanisms of childhood ND and abnormal growth by evaluating pre-specified perinatal and postnatal characteristics as risk and predictive factors for abnormal ND and growth. The landmark CHAP findings and the NHLBI-funded CHAP maternal follow-up study offer a truly unique opportunity and synergy for this proposed child follow-up study in order to glean the complete picture of long- term effects of prenatal antihypertensive therapy and preeclampsia on offspring.

NIH Research Projects · FY 2025 · 2023-09

Abstract. The Origin Recognition Complex (ORC), a heteromeric six-subunit protein complex, is essential for DNA replication. ORC's functions also extend beyond DNA replication. The smallest of ORC subunits, Orc6 protein, is important for DNA replication in all eukaryotes. We have shown that in Drosophila Orc6 has an additional role in cytokinesis through interaction with the septin complex, a highly conserved polymerizing protein assembly that is critical for cytokinesis in many species and is recognized as important component of the cytoskeleton. In preliminary studies we solved the structure of human Orc6 and identified its structural features that contribute directly to the functions of the protein in replication and cytokinesis. We characterized the mutations in different domains of Orc6 leading to Meier-Gorlin syndrome (MGS) in humans, an autosomal recessive disorder characterized by primordial dwarfism and developmental abnormalities. We showed that despite different underlying molecular mechanisms these mutations resulted in similar phenotypes, defects in pre-RC formation and impaired DNA replication. Thus, the diverse molecular functions of Orc6 can be experimentally dissected to obtain a complete understanding of its discrete roles in the cell. The overall goal of this proposal is to define the distinct mechanisms of metazoan Orc6 function in DNA replication and in cytokinesis using Drosophila as a model system. We established a humanized Orc6-based Drosophila model system which will be used to analyze the effects of naturally occurring and structure-guided targeted mutations of human Orc6 in protein functions. Regulatory insights into replicative and non-replicative functions of ORC in metazoans are limited, despite decades of research. Our completion of this project will help to fill this gap in our understanding of diverse ORC's functions in metazoans and provide clues as to how a specific mutation or mis-regulation would lead to growth and developmental defects.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Opioid use disorder (OUD) is often comorbid with other drug use, and alcohol is one of the most commonly co- used drugs. Yet most of the basic research on OUD has been conducted in single-drug use models. Current FDA-approved treatments for OUD target the endogenous opioid system directly, either as substitution therapies (e.g. buprenorphine, methadone) or antagonists that oppose opioid effects (e.g. naltrexone, naloxone). These treatments establish the mu opioid receptor (MOR) as a major therapeutic target for OUD. Similarly, opioids have been implicated in the pathophysiology of alcohol use disorder (AUD), and naltrexone is used to treat both OUD and AUD, further underscoring the overlapping mechanisms between these disorders. As the seat of executive function, the prefrontal cortex plays an integral role in the inhibitory control over drug craving and relapse. Humans with substance use disorders (SUDs) exhibit structural and functional changes in the prefrontal cortex, accompanied by deficits in cognitive function. Thus, the prefrontal cortex may be a key locus for opioid-induced adaptations that impact SUD severity. My lab has identified the rodent infralimbic (IL) prefrontal cortex projection to the nucleus accumbens shell (ILNAshell) as an important limiter of heroin seeking. Within the IL cortex, interneurons express MORs, and layer 5 pyramidal neurons (which give rise to the NAshell projection) express 5-HT2A receptors. Furthermore, we have recently demonstrated the ability of a 5-HT2A agonist to reduce opioid and alcohol seeking (in single-drug use models), and these effects were long-lasting after a single treatment. Thus, 5-HT2A agonists are an emerging class of therapeutics for OUD and AUD, and they may act upon prefrontal cortex microcircuits to elicit these effects. This proposal aims to examine these two receptor systems, with a focus on the prefrontal cortex, in a preclinical model of polydrug heroin and alcohol use. This model incorporates chronic comorbid alcohol exposure, initiated prior to heroin self-administration and continuing throughout the period of opioid exposure. The overarching objectives of this project are to identify the role of 5- HT2A receptors in drug seeking after comorbid heroin and alcohol self-administration, to define the role of the ILNAshell circuit in drug seeking after polydrug use, and to determine how polydrug exposure alters intrinsic excitability of different neuronal populations in the infralimbic cortex and the regulation of neuronal excitability by 5-HT2A and MOR. These receptors are positioned to regulate excitability of cortical sub-circuits, with each predicted to culminate in increased ILNAshell output, and therefore increased inhibitory control over drug seeking. Information gained from this project will provide insight into whether heroin and alcohol polydrug use elicits neuroadaptations in cortical sub-circuits that are oppositional, additive, or otherwise distinct. It will also shed light onto how these circuits are regulated by 5-HT2A and MOR, both of which are druggable targets with known or emerging therapeutic applications for SUDs. Collectively, this will provide the groundwork for understanding how treatments can best be tailored to individuals with comorbid opioid and alcohol use.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT The overall goal of this 5-year K23 proposal is to support Melissa Mannion, MD, MSPH to become an independent investigator using medical decision methodology to evaluate and improve personalized treatment decisions for each patient with juvenile idiopathic arthritis (JIA). JIA is the most common rheumatic disease of childhood and is a life-long chronic disease that requires long-term treatment to prevent pain, loss of physical function, and permanent impairment. While there are recommendations regarding initial therapy, when that is ineffective, the next best option is less clear and can be affected by patient, parent, and provider preferences. Due to this uncertainty and the various attributes of treatment options, shared decision making (SDM) is recommended for treatment decisions and can reduce decisional conflict, improve satisfaction with care, and improve quality of life. Incorporation of SDM in routine clinical care is poor and, in pediatrics, is often reliant on parents sharing medical information and making decisions. Parent-adolescent dyads with JIA report different acceptable symptom state thresholds and different treatment experiences including adherence rates and negative treatment effects, but it is unknown how this discordance affects subsequent preferences, decisions, and outcomes. There is a critical need to identify and incorporate both adolescent and parent preferences into decisions related to JIA medication and treatment targets. Therefore, the specific aims of this project include Aim 1: identify optimal characteristics of a treatment escalation SDM tool in JIA according to patients, parents, and providers, Aim 2: compare patient and parent preferences for treatment and goal priorities of JIA, and Aim 3: develop and pilot test decision aid in a pediatric rheumatology clinic among parent and adolescent patients with JIA at the time of treatment change. I will use nominal group technique to identify characteristics of the decision aid that will favorable impact care and promote adoption by patients, parents, and providers in routine clinical workflow. I will use discrete choice experiment and latent class analysis to identify and quantify preferences and tradeoffs related to medication choices and treatment goals for both adolescents with JIA and their parents. I will develop a decision aid based on previously conducted qualitative research to facilitate triadic (adolescent, parent, and provider) SDM for treatment escalation in JIA and pilot test the tool in a clinical setting. The results of each aim will contribute to iterative revisions of the tool so that it will be optimized for a subsequent larger trial. My expert multidisciplinary mentoring team will provide guidance and training in stated preference methods and SDM, specifically related to pediatric triadic decisions. At the conclusion of this project, I will be uniquely positioned for an independent research career using medical decision methodology to improve the quality of life and disease outcomes for patients with JIA by improving SDM between patients, parents, and providers.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT CANDIDATE: The candidate is a postdoctoral fellow in the laboratory of Dr. Zeglis at Hunter College of CUNY. Her proposed research will provide a strong foundation for independent research career following the K99 phase of this grant. Her long-term career goal is to establish a robust program in environmental pollution research utilizing molecular imaging. To achieve this, she has developed a career plan that will (1) broaden her technical and scientific skills (2) strengthen her presentation and communication skills, and cultivate her professional relationships, (3) enrich her mentoring skills, and (4) prepare her for the transition to independence. RESEARCH: The proliferation of micro- and nanoplastics in the environment is increasing at an alarming rate. Micro- and nanoplastics have been found to be persistent and ubiquitous pollutants in a variety of environments, including sea water, fresh water, soil, sewage, and air. In light of this harrowing phenomenon, the evaluation of the possible health effects of microplastic (<5 mm) and nanoplastic (<100 nm) pollutants has emerged as an unmet scientific need. The over-arching goal of this investigation is to study the biodistribution and health effects of micro- and nanoplastics in mammals using a sensitive and quantitative molecular imaging technique: positron emission tomography (PET). The exquisite sensitivity of PET is major advantage of this strategy, as it will facilitate the non-invasive tracking of micro- and nanoplastics at environmentally relevant concentrations. The specific aims are: 1) To determine the bioaccumulation and bioretention of radioplastics in mice after pulmonary and oral exposure, 2) To quantify the bioaccumulation and bioretention of radioplastics in pregnant mice after oral and pulmonary exposure, and 3) To quantify the pro-inflammatory effects of micro- and nanoplastic exposure via non-invasive approaches. ENVIRONMENT: Hunter College is known for its highly collaborative environment to facilitate interdisciplinary research efforts such as those proposed in this application. The candidate is mentored by Dr. Zeglis, a recognized inorganic radiochemist with groundbreaking work in preclinical investigations of radiopharmaceuticals. In addition, she is co-mentored by Dr. Stapleton, an environmental toxicologist who has done pioneering and innovative contributions to the plastic research. Hunter College provides a rich set of collaborative, technical and scientific resources to execute the research and career development proposed here.

NIH Research Projects · FY 2025 · 2023-09

Daily oral PrEP has been scaled up in Kenya for numerous populations, including young women with substantial risk for HIV. For many young women who start oral PrEP, numerous studies have demonstrated that discontinuation rates are high and they unlikely benefit from long-term HIV protection. Newer PrEP products that are longer acting, including dapivirine-eluting vaginal rings and intramuscular injections of cabotegravir, offer 1-2 months of protection and less dependence on the user to remember to take a daily pill. Following normative guidelines, these products are being integrated into clinical guidelines in Kenya and other countries. For daily oral PrEP, a key strategy for efficient scale up was integration into existing programs, such as those for reproductive health care (e.g., family planning, antenatal care) and we have been studying ways to optimize integration of PrEP into these settings. Through implementation science research protocols, we have been working with public clinic staff to introduce PrEP, train providers to deliver PrEP, develop linkages between clinics and national supply chain mechanisms for PrEP, and support providers and programs to overcome challenges. Despite documented high levels of interest in PrEP yielding high frequency of PrEP initiation – 13-35% of eligible women ages 15-30 years in our reproductive health clinic partners – we have continued to see high levels of program drop out, non-adherence, and only moderate ability to track whether PrEP is re-started in alignment with fluctuating sexual behavior and potential exposure to HIV. These barriers to PrEP continuation are driven by young women’s needs for PrEP products that afford discretion, convenience, and safety. It is yet unknown whether the availability of multiple HIV PrEP products in a PrEP program will yield a degree of choice, support longer term use of PrEP, and ultimately, greater HIV prevention coverage. Through a multi-step process invoking formative work and a stepped-wedge cluster randomized trial, the research team proposes to determine whether the availability of a suite of PrEP options yields greater HIV protection coverage over a 3- and 6- month period relative to periods when only daily oral PrEP is available. The proposed study aims to: 1) develop a pathway to add injectable cabotegravir and dapivirine ring into existing PrEP services offered through in reproductive health clinics in Kenya leveraging qualitative and community-based research methods, 2) determine whether integration of injectable cabotegravir and dapivirine ring into existing PrEP programs improves PrEP uptake and persistence among young women accessing reproductive health services via a stepped-wedge cluster randomized trial in 12 facilities, and 3) interrogate potential weak points in the PrEP choice intervention including: a) provider hesitancy and client experiences, b) quality of choice-based HIV prevention counseling.

NIH Research Projects · FY 2025 · 2023-09

Junior scientists often face barriers to academic career success that can limit their ability to thrive as independent investigators. Academic units with strengths in nutrition, obesity, and diabetes research have an opportunity and a responsibility to develop programs that address these challenges and enhance the careers of early-stage researchers. This need is particularly relevant in Alabama and surrounding Deep South states, where obesity-related chronic diseases remain a major public health concern. We propose to develop, implement, and evaluate an innovative program to help junior scientists identify and overcome barriers to academic success, while enhancing their research, mentoring, and leadership skills. We have a strong pipeline of T32 training grants at pre- and postdoctoral levels to bring talented scientists to UAB, along with commitments from units within UAB to create faculty positions (and/or retention packages) for those who complete the program. The specific aims are: (1) To engage the participation of at least three cohorts of 3–4 junior scientists (postdoctoral fellows, assistant professors) to spend three years in a program aimed at developing skills for success as independent researchers/principal investigators in academia, (2) To provide a three-year educational and mentoring program focusing on the development of intrapersonal, interpersonal, and team-development skills, (3) To establish mentoring teams for each participant that include scientific mentors, academic/institutional navigators, and a wellness coach, and (4) To develop a comprehensive plan for evaluating and potentially expanding the program. UAB provides an ideal environment for supporting the career development of scientists. The Department of Nutrition Sciences houses three NIH-funded centers – the Nutrition Obesity Research Center (NORC), the Nutrition for Precision Health Clinical Center (NPHCC), and the Diabetes Research Center (DRC). The School of Health Professions also houses a CDC-funded National Center on Health, Physical Activity, and Disability (NCHPAD). This application is supported by the institution and includes consideration for hiring scholars who successfully complete the program. Innovative aspects of this proposal include the use of dedicated mentoring teams to facilitate research productivity and to help participants develop the professional skills needed for advancement and long-term success within academic institutions

NIH Research Projects · FY 2024 · 2023-09

Neurofibrillary tangles (NFTs) of the microtubule-associated protein tau are a universal feature of the aging brain. The extent of tau pathology throughout the brain correlates with both synapse loss and severity of cognitive impairment in age-related tauopathies. The ability to maintain cognitive function with a brain accumulating NFTs relies on the preservation and maintenance of synaptic networks. Therefore, understanding the mechanism by which tau contributes to network and synapse vulnerability is critical for developing preventative therapeutics. The goal of this proposal is to determine the cellular mechanism(s) by which pathologic tau drives neuronal network dysfunction. The experiments proposed in this application will uncover these mechanisms and provide intellectual and technical training for a successful transition into a postdoctoral position. The F99 phase (Aim 1) will test mechanistic cell biological hypotheses to better define how abnormal tau accumulation induces synaptic dysfunction, while providing opportunity to develop intricate experimental design and execution skills through cutting-edge biochemistry, microscopy, and electrophysiology techniques. The K00 phase (Aim 2) will build upon the F99 studies with computational strategies to integrate proteomics data from humans and experimental models to identify co-existing molecular changes that are highly relevant to age-related tauopathies.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a fatal progressive fibrotic disease characterized with excessively deposited extracellular matrix (ECM) proteins. Persistent myofibroblast activation is considered as one of driving forces that lead to excessive ECM protein production and fibrosis in IPF. The molecular mechanisms that perpetuate persistent myofibroblast activation and pro-fibrotic responses in IPF have not been fully understood. KH-Type Splicing Regulatory Protein (KSRP) is a mRNA destabilizing protein involved in post-transcriptional regulation of gene expression. Preliminary data demonstrate that KSRP expression is significantly decreased in IPF lung fibroblasts and tissues when compared to that in normal human lung fibroblasts and tissues. However, the role of KSRP in lung fibrosis, and the functional consequences of pathologic KSRP downregulation in pro-fibrotic responses in IPF, are completely unknown. This proposal aims to reveal the novel restrictive role of KSRP in lung fibrosis and the molecular mechanisms involved. Preliminary data demonstrate that KSRP deficient mice have increased lung fibrosis when compared to wild-type mice in response to Bleomycin, and that KSRP deficiency promotes, while gain of KSRP inhibits, myofibroblast differentiation and ECM protein production. These data indicate that KSRP functions as a restricting factor of fibrotic reactions, and impaired KSRP function promotes fibrotic reactions and lung fibrosis. Furthermore, KSRP negatively regulates Migfilin mRNA stability and expression and KSRP deficiency results in increased Migfilin expression. Our preliminary data demonstrate that Migfilin functions as a “pro-fibrotic switch”, promoting pro-fibrotic reactions. Migfilin is required for myofibroblast differentiation and survival. Based on preliminary data, we hypothesize that KSRP functions as a restrictive regulator of lung fibrosis, and that impaired KSRP function fosters a “pro-fibrotic niche” fueling persistent myofibroblast differentiation and pro-fibrotic responses mediated by Migfilin and Migfilin mediated signaling. To test the hypothesis, three specific AIMs are proposed. Specific AIM 1 will determine the mechanisms by which KSRP regulates myofibroblast differentiation and survival. Specific AIM 2 will determine the restrictive role of KSRP in controlling ECM expression and matrix assembly. Specific AIM 3 will examine the in vivo cell-specific role of KSRP in fibrogenesis and functional consequences. The findings will help to understand the mechanisms that perpetuate persistent myofibroblast activation and pro-fibrotic responses in IPF and serve my long-term goal to develop effective therapy for IPF.

NIH Research Projects · FY 2025 · 2023-09

Astroviruses are small, non-enveloped, positive-sense single-stranded RNA viruses (+ssRNA) that are prevalent in bird and animal populations. Human astrovirus (HAstV) infection has historically been known as a leading cause of non-bacterial gastroenteritis. However, in recent years, divergent HAstVs have been found in cases of encephalitis. Despite their prevalence, there is limited information regarding the mechanisms of virus infection. The virus is known to produce two nonstructural polyproteins required for infection, which are cleaved into functional subunits by host signal peptidase and the virus-encoded serine protease (Pro). However, the specific sites of Pro cleavage in the polyprotein have not been discovered. Thus, we do not know the specific sequences of viral proteins, which has made it difficult to assign functions to these proteins. Similarly, lack of information and tools has made studying virus-host interactions challenging. Thus, few host proteins that regulate HAstV infection have been identified. Furthermore, like all +ssRNA viruses, HAstV infection leads to dramatic remodeling of intracellular membranes to form replication organelles (ROs), which concentrate viral host factors required for infection. However, the source of the membranes for these critical structures is not well understood. Overall, there are major gaps in our knowledge of all aspects of HAstV biology and there is a need for tools that will allow us to build a foundation to expand our research on fundamental mechanisms that regulate HAstV infection. The goal of this proposal is to utilize tools we have developed for +ssRNA viruses and HAstV to understand the mechanisms of (1) viral nonstructural polyprotein processing and Pro activity, (2) host protein regulation of virus infection, and (3) viral protein manipulation of host organelles. We have made significant progress to be well-suited to accomplish these proposed projects. We have developed a library of polyprotein expression constructs and a cDNA infectious clone to investigate Pro-dependent cleavage. Additionally, we have successfully developed a versatile viral protease activity reporter that has been shown to work for enteroviruses and flaviviruses, which we will adapt for HAstV to study intracellular Pro activity. We have generated tools to study the microenvironment of the viral nonstructural proteins in living cells and to perform a CRISPR screen for pro- and anti-viral proteins. Lastly, we have innovative tools and strategies to visualize the manipulation of host organelles upon viral protein expression or infection using long-term, time-lapse imaging of living cells. Overall, the proposed projects are designed to significantly advance the field of cell biology of HAstV infection through investigation of the molecular virology and virus-host interactions.

NIH Research Projects · FY 2025 · 2023-09

For over 30 years, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has funded the O’Brien Kidney Center program to advance kidney-related research. To expand the breadth and impact of these centers, NIDDK has modified this program by establishing the O’Brien Kidney Consortium. This consortium includes 7 theme-based National Resource Centers (NRCs) tasked with developing and sharing specialized resources, tools, technologies, services, and expertise and a National Coordinating Center (NCC) to lead, manage, and harmonize all aspects of the Consortium. The University of Alabama at Birmingham (UAB) serves as the NCC for the O’Brien Kidney Consortium. Led by an epidemiologist (Dr. Amanda Anderson) and nephrologist (Dr. Orlando Gutiérrez) and supported by nephrologists, data scientists, kidney physiologists, health behaviorists, and strong research mentors, the NCC investigator team is interdisciplinary with experience participating in NIDDK-sponsored consortia. UAB has the infrastructure to lead the NCC and support a central website and web-based data portal, committees and working groups, a comprehensive set of training and outreach activities, a robust Opportunity Pool Program, and patient engagement. Additionally, the UAB investigators have implemented and administered competitive pilot grant programs that have nurtured the development of numerous early career researchers and supported high-impact research ideas with a substantial return on investment. The UAB NCC has five aims including (1) Providing administrative support and coordination to the O’Brien consortium by implementing standard operating procedures and consortium-wide committees; (2) Creating a centralized website and intake portal to facilitate and track all requests for O’Brien Kidney Consortium resources from the NRCs; (3) Developing and implementing an outreach and training plan to engage researchers in collaboration with the O’Brien NRCs; (4) Engaging patient viewpoints, priorities and preferences through feedback on the NRCs’ scientific aims and activities to inform the O’Brien Kidney Consortium; and (5) Administering a national pilot program with high impact to support early-stage investigators, investigators new to kidney research and collaborations with the broader kidney community. The UAB NCC will support NIDDK and the O’Brien Kidney Consortium to advance kidney research nationwide maximizing the impact on improving kidney health.

NIH Research Projects · FY 2025 · 2023-09

African Americans (AA) are more likely to receive ineffective and burdensome interventions at end-of-life (EoL) and are less likely to receive palliative care or enroll in hospice. For example, goals of care conversations, which are critical discussions between clinicians, patients and families near the EoL, are less likely to occur for AAs than for Whites. EoL decisions for many AA persons are informed by their prior experiences with healthcare. Efforts to improve EoL care need to address patient-level needs and EoL care values, interpersonal- and community-level norms for EoL communication and treatment, and healthcare institutional- contexts for delivering EoL care. Our research group began to address this need with ‘African American Community Speaks’, a proof-of-concept prototype of a community-developed training program for clinicians caring for AA older adults with serious illness. The program originally focused on rural Southern older AAs and is not broadly generalizable across the US due to geographic differences in experiences, attitudes, and communication preferences among AA persons in the US. Thus, we propose to adapt our prototype program to urban-dwelling Southern and Northern older AA adults using our established platform of Community-Based Participatory Research (CBPR) in two geographically diverse regions: Birmingham, Alabama and the Bronx, New York. To create the new training program called ‘Caring for Older African Americans’, our team of experts in CBPR, medical sociology, and clinical trials will work with local Community Advisory Boards to: 1. Conduct a comparative ethnographic study of urban- dwelling AAs in the North and South to describe AA community values and preferences related to EoL care; 2. Adapt of our prior community-developed training program by integrating community-developed storytelling videos for empathizing with experiences of healthcare, guidelines for EoL care delivery that meets AAs needs, and understanding how clinicians’ assumptions and perceptions shape communication; and 3. Conduct a cluster randomized trial in which we will randomize training times to 1 of 4 start dates using a stepped wedge design to accommodate training of all clinicians and to mitigate the effect of secular trends. Patients’ trust of the healthcare system will be measured using the Group Based Mistrust Scale. The primary outcome will be patient/family’s perception of therapeutic alliance using The Human Connection Scale. Secondary outcomes will be family-reported goal- concordant care, and clinicians’ knowledge of values, awareness of assumptions and perceptions, and confidence to change practice. This innovative effort will be the first training program that: 1. addresses care tailored to the needs of AAs, management of assumptions and preferences, the key elements in enhancing the provision of high quality care; and 2. is designed and implemented in full partnership with two distinct communities in the South and the North of the US.

NIH Research Projects · FY 2025 · 2023-09

Arsenicals cause rapid, severe and painful inflammatory and blistering responses in the skin. The available medical countermeasures against arsenical-induced toxicity are not effective due to toxicity and a low therapeutic index. Hence, there is a demand for the development of more effective and less toxic antidotes for arsenicals. Developing hybrid inhibitors of bromodomain-containing protein 4 (BRD4) which are responsible for the regulation of inflammatory genes, receptor-interacting protein kinase-3 (RIP3, or RIPK3), a central player in necroptosis, and interleukin-6 (IL-6) would be an effective and efficient treatment to attenuate arsenical-induced inflammation. We have identified three potent inhibitors, SRI-43887, SRI-47362 and SRI-47561 of BRD4, RIPK3 and IL6. For example, SRI-43887 exhibited significant activity in vivo against phenylarsine oxide (PAO) and arsenicals (Lewisite)-induced mice. Continued optimization of these compounds will lead to the identification of a potential preclinical candidate(s) for the treatment of cutaneous injuries associated with arsenicals. To achieve this goal, we will (i) utilize molecular modeling to design and synthesize analogs of these three lead compounds and test in vitro for BRD4, RIPK3 and IL6 inhibitory activity; (ii) evaluate select compounds for cytotoxicity and in vitro drug-like properties (solubility, metabolic stability, log D, permeability); (iii) determine the in vivo pharmacokinetic profile (bioavailability and half-life); and (iv) perform in vivo studies on select compounds against PAO and Lewisite to determine the efficacy of these compounds. These goals will be accomplished through a collaborative effort involving a team with extensive experience in drug design, medicinal chemistry, computational chemistry, biological assays, pharmacokinetics, molecular biology and drug development.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY / ABSTRACT Adults aged 65 and older represent ~23 million (18%) annual Emergency Department (ED) visits. Delirium, an acute, fluctuating change in cognition with numerous modifiable and nonmodifiable risk factors, is prevalent in up to 35% of older adults in the ED. However, the incidence and time course of ED delirium is currently unknown. Prevention is the only effective treatment, yet only 40% of delirium cases in hospitalized older adults can be prevented, making prediction and early recognition of patients at-risk of incident delirium – such as in the ED – vital. Unfortunately, ED providers fail to recognize up to 83% of delirium cases, which can lead to significant downstream consequences, such as ED revisits, falls, and hospitalizations. Thus, there is a critical need to identify older adults at highest-risk of delirium in the ED to facilitate early interventions. The overall objective of this proposal is to establish the incidence, time course, and risk factors of delirium during the ED stay, which is a critical prerequisite for implementing effective delirium prevention and management interventions. We will achieve this objective with the following three aims: (1) Determine the incidence and time course of ED delirium with validated detection tools, (2) Identify modifiable and nonmodifiable risk factors of incident ED delirium, and (3) Examine existing risk stratification screening instruments for incident ED delirium. We propose a prospective cohort study of older adults ≥65yo in a Level 1 accredited Geriatric ED. We will collect delirium and other cognitive impairment screenings on all patients ≥65yo at ED admission to establish baseline cognitive status. During the ED stay, patients will be screened for delirium at regular intervals to determine the incidence and time course of ED delirium. For admitted patients, delirium will continue to be assessed once per nursing shift during inpatient hospitalization. Using electronic health record data, we will examine modifiable and nonmodifiable risk factors for delirium in the ED and within 24- and 48- hrs of admission. Further, we will assess if recommended geriatric risk stratification instruments can predict incident ED delirium. Consistent with the goals of the “National Institute on Aging: Strategic Directions for Research, 2020-2025”, findings from this proposal will improve our understanding of the aging brain and its impact on the prevention, progression, and prognosis of ED delirium. Specifically, this work will have a positive impact on Geriatric ED care by identifying a subset of older adults at-risk for delirium. We will also establish the rate and risk factors for incident ED delirium, which will be the first steps in preventive strategies. During the award period, the candidate will acquire specific skills in aging research and benefit from interdisciplinary mentorship by accomplished geriatrics clinician-investigators. This study will serve as the basis for a K-award application by providing the groundwork and infrastructure for evaluating future delirium prevention and management strategies.

NIH Research Projects · FY 2026 · 2023-09

PROJECT SUMMARY In primates, including humans, the macula and especially the fovea, is critical for high-acuity vision. The metabolic needs of the fovea and macula are primarily met by the choriocapillaris, the capillary network of the choroid located immediately behind Bruch’s membrane. There is considerable evidence that compromised choroidal perfusion contributes to many eye diseases, such as age-related macular degeneration and diabetic retinopathy, that affect these retinal regions. Importantly, choroidal blood flow is substantially controlled by inputs from the parasympathetic nervous system. However, the parasympathetic circuitry controlling the choroidal vasculature in primates is very poorly understood. The precise locations of the pre- and postganglionic parasympathetic motoneurons supplying the choroid, as well as their premotor inputs have not been established, nor have the functional roles of these neurons been fully defined. Therefore, the overall goal of this proposal is to determine the location and function of the parasympathetic circuits controlling the choroidal vasculature in non-human primates. We propose to perform neuroanatomical, electrophysiological, and pharmacological experiments to address these questions. Specifically, in Aim 1, we will use retrograde tracers, both conventional and trans-synaptic, to identify the motor and premotor circuitry controlling the parasympathetic innervation of the choroid. In the functional part of the study, we will use infrared (IR) laser doppler flowmetry, IR laser speckle flowgraphy (LSFG), and optical coherence tomography (OCT)/OCT angiography (OCTA) to measure the choroidal vasculature. Specifically, in Aim 2, we will study the effects on the choroidal vasculature of modulating preganglionic motoneuron activity by electrical microstimulation and of modulating retinal activity by light. In Aim 3A, we hypothesize that pharmacological inactivation of preganglionic motoneurons reduces overall choroidal blood flow and thickness in darkness, reduces choroidal blood flow compensation for changes in blood pressure, and eliminates luminance induced changes in the choroidal vasculature. In Aim 3B, we hypothesize that electrolytic or chemical lesions of preganglionic motoneurons will result in reduced choroidal blood flow. In the long term, we hypothesize that the retina will show evidence of outer segment loss and inflammatory markers. We will non-invasively assess retina, retinal pigment epithelium, and choroid health in life by OCT/OCTA, LSFG, and electroretinogram (ERG)/multifocal ERG. We will further assess retinal health postmortem by retinal histology. The proposed experiments will constitute the first extensive and systematic investigation of the circuitry and role of the parasympathetic, preganglionic neurons controlling blood flow in the choroidal vasculature of a primate. These results will set the stage for future studies in which this circuitry is modulated in order to improve the survival of central vision in human macular degeneration.

NIH Research Projects · FY 2025 · 2023-09

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The overall mission of the Deep South KUH PRIME TL1 Training Core is to provide training in interdisciplinary and translational research that ensures pre- and post-doctoral trainees will learn the skills and knowledge to successfully transition to the next steps of their careers in KUH research. To overcome the challenge presented by a lack of researchers adequately trained in basic, clinical and population sciences, we will develop an integrated training program that focuses on interdisciplinary and translational research with support from experienced mentors and enhanced collaboration. The impact of our program will be felt across the Deep South through established strong partnerships between Augusta University, Tulane University and UAB. The TL1 Core is designed to support highly talented trainees from a wide range of scientific backgrounds. This includes trainees from nephrology, urology, urogynecology, and non-malignant hematology as well as relevant disciplines in pediatrics, surgery, medicine, epidemiology, and biomedical engineering among others. There will be no specific restrictions to joining the TL1 program across disciplines provided the research is relevant to the KUH goals. While we will leverage successful approaches developed for current T32 and related programs and other institutional resources, this new program will broaden the spectrum of research training to include those not directly funded by the TL1. We will work closely and collaboratively with the U2C Administrative, Professional Development and Networking Cores to assume a seamless process for developing skills that will be critical for achieving success in the modern workforce. The TL1 Core will work with each trainee on an individual basis to ensure appropriate mentoring, research opportunities and educational experiences to meet their personal and professional goals. Further training will include developing skills in managing and leading research teams critical for future success in KUH research. This effort will encompass the spectrum of trainees supported by the TL1, institutional trainees supported by extramural awards (R25s, Fs, Ks, CDAs etc.) or other mechanisms (graduate, medical, and public health schools, residency programs, and basic & clinical fellowship programs). The TL1 Core has three specific aims: 1: Establish didactic training and instructional programs to expand the knowledge base and interest in scientific discovery of pre- and post-doctoral trainees in the areas related to kidney and non-malignant diseases of the upper and lower urologic and hematologic systems, 2: Develop individual training plans that include instilling a culture of discovery supported by interdisciplinary, translational activities designed to meet individual interests, needs, and goals, and 3: Collaborate with the Administrative, Professional Development, and Network Cores to achieve the following mission-oriented objectives. These include programs to recruit and retain individuals from various disciplines, evaluate and support the training program, personalize research training with writing, presentation and leadership skills, and foster a larger network of mentors, collaborators and peers to engage the broader scientific community.

NIH Research Projects · FY 2025 · 2023-09

: Pre-Clinical Core Small animal models of human disease have provided important insights into renal pathophysiological processes and are an important preclinical resource to test therapeutic and preventive approaches in acute kidney injury (AKI). The specific aims of the Pre-Clinical Core (Core B) are to: Aim 1. Provide the facilities and skills (Animal Models Resource) to study murine models of AKI. Aim 2. Provide unique facilities and requisite skills (Renal Physiology Resource) to determine renal physiological changes in AKI. This Core will specifically share specialized knowledge, tools, technologies and expertise to (i) utilize rodent models of AKI specifically in the setting of ischemia/reperfusion injury, sepsis and kidney transplantation, and (ii) provide expertise and training for studying renal function on the whole kidney and at the single nephron level, including micropuncture techniques and determination of GFR, microanalysis of tubular fluid and tubular reabsorption, renal hemodynamics with assessment of tubuloglomerular feedback, and metabolic assessment of kidney oxygen consumption in rodents. Core B will also provide technical expertise for the isolation of primary tubular and vascular cells from rodents. The mission of Core B is to provide these unique and relevant resources within the O’Brien Kidney Consortium to help investigators overcome barriers to utilization of relevant rodent models for in vivo and in vitro studies (kidney cells and cell lines) to advance understanding of the pathophysiology of AKI. The Core will capitalize on the excellent, established track record of supporting the national kidney research community through provision of state-of-the-art tools to investigate AKI in animal models. Since the inception of the O’Brien Center, Core B has performed more than 20,000 procedures for the community. The hands-on, technically challenging experimental resources, along with the unique expertise of Core B personnel, will integrate into the Consortium to catalyze collaborative activities and advance AKI research for the kidney research community. These resources have been designed to enhance the skills of the workforce by enticing and supporting early-stage investigators as well as encouraging established investigators in other fields of study into AKI-related research.

NIH Research Projects · FY 2025 · 2023-09

In order to fully engage scholars at Augusta University, Tulane University, and the University of Alabama at Birmingham in the Deep South KUH Premier Research and Inter-disciplinary Mentored Education (PRIME) program, it is necessary to provide opportunities for scholars to come together in a supportive environment to cultivate meaningful interactions. The overall goal of the Network Core (NC) is to help scholars develop and maintain their professional networks and in doing so, give them a solid foundation to establish roots in their scientific and healthcare communities. AIM 1: Develop networking activities that connect scholars with their peers, role models, and mentors and provide the opportunity to enhance networking skill development including the optimal use of social media for professional engagement. The NC will host quarterly hybrid format workshops by a networking expert to teach our scholars how to develop their professional brand and build their networks. We will bring together scholars and role models/established faculty at our annual “Building the KUH community” symposium with events such as lunch with assigned seating. The NC will build the KUH novice, graduate student, postdoctoral/fellow, and early career peer groups where scholars will work together to host 1- 2 in-person events and a virtual cross-institutional networking event annually. The NC will leverage current seminars and the new KUH PRIME Crosstalk virtual journal club and works in progress program to include gatherings with invited role models. All TL1 trainees will record a podcast in our Role Model Engagement program that will be included in our quarterly digital newsletter and shared on our website and KUHPRIME social sites. AIM 2: Engage in regional and national outreach and advocacy activities to increase networking opportunities and enhance the participation of a cohort of scholars from all backgrounds. The NC will harness activities supported by our institutes’ advocacy groups and national organizations to develop approaches to increase awareness of the KUH PRIME for all. The NC will establish the Personal Experiences in PRIME (PEP) outreach initiative with visits between PRIME trainees and faculty and scholars in high schools, community colleges, and various smaller colleges and universities in Alabama, Louisiana and Georgia. These in-person gatherings will introduce biomedical research and the benefits of a career in science or medicine to students who lack such exposure on their local campuses. The unifying vision is that the NC works closely with the TL1 and other training programs in our institutions to build and connect the membership of the KUH community, while the Professional Development Core develops the hard and soft skills of the membership to optimally position them for career success and advancement. In doing so, the Deep South KUH Prime will meet our mission to develop a modern workforce of investigators in the Deep South who have the training and skills necessary to advance KUH health through science and medicine.

NIH Research Projects · FY 2025 · 2023-08

ABSTRACT Heart failure affects 6 million people in the US, resulting on 1 million hospitalizations and a cost of over $30 billion per year. Heart failure with preserved election fraction (HFpEF) accounts for half of these cases, and its prevalence is rising by 1% annually. About 20-30% of HFpEF cases remain undiagnosed, contributing to poor health outcomes for these patients. Preliminary data suggest that primary care providers (PCPs) are often unaware of diagnostic and treatment guidelines for HFpEF. At the same time, primary care has an invaluable potential to improve HFpEF health outcomes by facilitating early diagnosis, referral to cardiology, and treating HFpEF comorbidities. The objective of this proposal is to design and test a novel intervention that will educate PCPs about HFpEF and provide them with a clinical diagnostic decision support aide (CDDSA) that is based on a validated diagnostic score for HFpEF. The overall hypothesis of this project is that if PCPs can detect HFpEF earlier, and therefore, refer patients to cardiology, and manage their comorbidities, it can help improve outcomes in HFpEF. Building on established community-academic collaborations, this project will be conducted with the help of the Alabama Practice-Based Research Network (APBRN). This project will include identification of provider barriers to HFpEF diagnosis among PCPs via an interview and a survey that will measure the prevalence of HFpEF knowledge gaps and preferences for an intervention (Aim 1); a stakeholder-engaged process to design an educational session and CDDSA to optimize HFpEF diagnosis in primary care (Aim 2); and a pilot study to test the feasibility and acceptability of the CDDSA (Aim 3). At the completion of the pilot study in Aim 3, the intervention will be ready to be tested at a larger scale (e.g., R-series grant) to evaluate its efficacy. The candidate for this career development award, Yulia Khodneva, MD, PhD, is a general internist with expertise in clinical medicine, epidemiology, and health services research. This award will enable her to gain skills necessary for her transition to independence focusing her research on improving healthcare delivery, and outcomes for HFpEF patients. Specifically, Dr. Khodneva will receive training in intervention development, implementation science, and conducting of pragmatic clinical trials, designed to improve healthcare delivery and outcomes for HFpEF patients. Dr. Khodneva will be mentored by two NHLBI-funded physician- investigators, Andrea Cherrington, MD (primary mentor; expert in intervention development and pragmatic clinical trials), Pankaj Arora, MD, (co-mentor; expert in HFpEF diagnosis and HFpEF echocardiography), and Larry Hearld, PhD (co-mentor; expert in implementation science). The combination of mentorship, formal coursework, and the proposed experiential learning during the project’s 5-year integrated training and research plan will position Dr. Khodneva to become an independent investigator while advancing the field of primary care for HFpEF patients.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY Survival of out-of-hospital cardiac arrest (OHCA) depends on the prompt delivery of bystander cardiopulmonary resuscitation (B-CPR), which is often administered by layperson community members until the arrival of emergency medical services personnel. There is wide variability in both B-CPR participation rates and survival of OHCA throughout the United States, particularly in neighborhoods of low socioeconomic status. Our central hypothesis is that unique modifiable barriers to B-CPR participation exist in high-risk neighborhoods in Birmingham, Alabama, which can be used to inform a targeted community B-CPR intervention to increase B- CPR rates and ultimately improve OHCA survival. We will test our hypothesis through the following specific aims: In Aim 1 we will utilize geospatial mapping of local cardiac arrest and census tract data to identify and characterize high-risk OHCA neighborhoods in Birmingham, AL. For our study, high-risk neighborhoods are defined as those with a high incidence of OHCA and low B-CPR participation rates. In Aim 2 we will utilize qualitative methods to understand barriers to B-CPR participation in high-risk neighborhoods and elicit community feedback on the current American Heart Association CPR Anytimeâ training kit. Focus group interviews with members of the Bystander Support Network will provide critical insights into the real-life bystander experience, which will help inform local focus group discussions. Stakeholder interviews and focus group discussions with community members residing in a high-risk Birmingham neighborhood will identify neighborhood-specific barriers to B-CPR participation and provide feedback regarding the usability of the CPR Anytimeâ training kit. Finally, in Aim 3 we will adapt the CPR Anytimeâ training kit using the feedback received from community focus groups; and then pilot a prototype targeted community intervention specifically designed to overcome modifiable barriers to B-CPR with the goal of increasing layperson OHCA awareness, CPR education, and willingness to perform B-CPR in at-risk neighborhoods. This project is complemented by a structured career development plan that has been designed with the input of an expert multidisciplinary mentorship team that is committed to provide guidance throughout this award. During the 5 years of this award, Dr. Ryan Coute, an early investigator committed to reducing OHCA treatment and outcome disparities, will learn geospatial mapping, multimethod qualitative research, community intervention design, and implementation science. This K23 award will ultimately support Dr. Coute’s transition to lead an independent research portfolio and will provide the training and preliminary data needed for future R-level proposals; such as (1) evaluating the impact of a targeted community-level B-CPR intervention on OHCA survival, (2) a multi-site trial to determine the impact of the intervention on other communities, or (3) exploring the dynamics of neighborhood make-up and social determinants of health on cardiac arrest survivorship for residents of at-risk communities.

NIH Research Projects · FY 2025 · 2023-08

Project Summary The UAB Southeastern Biocontainment Laboratory (SEBLAB) is one of 12 Regional Biocontainment Laboratories (RBL) established by NIAID to advance BSL-3 research and pandemic preparedness. In continuous operation since 2009, NIAID award 1G20AI167409-01 enabled the repair of natural wear and tear on non- scientific equipment and essential upgrades to air balance, exhaust, energy recovery, and decontamination systems. Subsequently, NIAID award 1G20AI167409-S1 enabled the acquisition of cutting edge scientific equipment. The current proposal outlines a strategic plan to safely and effectively translate these investments into increased research productivity and innovative ground-breaking scientific discoveries. Core-1 outlines facility operations support, personnel support, and replacement of essential basic scientific equipment required for SEBLAB to foster safe and productive high containment research programs. Core-2 seeks to support a solid and effective biosafety workforce, external training opportunities, and development and implementation of high quality internal training programs critical to the safe execution of high containment research. Core-3 outlines a strategic plan to establish integrated core services within containment enabling the safe and efficient use of cutting edge technologies, optimized research productivity, and ground-breaking scientific innovation/s. Upon completion, this project will achieve the following: 1) Support SEBLAB facility operational expenses; 2) Fund the leadership, administrative, and technical staff required to operate this high complexity facility, 3) Replace existing basic scientific equipment, 4) Support high quality BSL-3 biosafety training, 5) Establish integrated research cores within high containment, 6) Optimize and boost SEBLAB scientific research productivity, 7) Foster RBL/NBL network collaboration, and 8) Fund and maintain a highly skilled BSL-3 scientific workforce ready to rapidly respond at the frontline of emerging pandemic threats.

NIH Research Projects · FY 2024 · 2023-08

PROJECT SUMMARY Chlamydia trachomatis (CT) infection remains the most prevalent bacterial sexually transmitted infection (STI) worldwide, with over 120 million new CT infections reported annually. In the US, African Americans and women are disproportionally affected by CT infection. Although over 1.5 million CT cases were recently reported in the US, this is likely an underestimation as the above-mentioned vulnerable population experiences inequities in access to routine healthcare. Women experience a greater burden of CT infection due to many reproductive complications associated with this infection. To date, prevention and control efforts have not significantly reduced CT infection rates. In addition, up to 20% of infected persons are reinfected within a year suggesting either a short lived or suboptimal immunity. In the context of both murine models and human studies, we and others have previously showed a role of IFN-γ-producing CD4+ T cells in chlamydia clearance and protection against reinfection. Recent studies in humans have however shown that CD8 T cells could play a role in CT infection as well. CD8 T cells recognize pathogens in the context of peptides presented by an infected cell via classical MHC- Ia alleles (in humans, HLA-A, B or C) or non-classical MHC-Ib alleles (in case of humans, HLA-E). Prior work has shown that HLA-E restricted CD8 T cells (HLA-E/CD8s) exert an important immune-regulatory role in control of several intracellular bacterial pathogens such as Mycobacterium and Salmonella. The role of HLA-E/CD8s in CT infection as it pertains to clearance of CT infection is unknown. Two previous human studies examining CD8 T cell responses to CT indirectly demonstrated responses restricted by non-classical HLA-I alleles. However, the precise nature of this restriction and the role of such cells in disease pathogenesis as it pertains to clearance of CT infection was not defined. Since HLA-Ia and HLA-Ib (i.e., HLA-E) are ubiquitously co-expressed, appropriate molecular tools and methodologies are needed to dissect the unique contributions of CD8 T cells responding to peptides presented via each of these alleles. We have recently generated HLA-E*01:01 and E*01:03 specific cellular resources that allowed us to identify HLA-E/CD8s and to assess their relevance in the context of CT infection. Specifically, our preliminary data shows that HLA-E/CD8s producing CD107a/IFN-γ/TNF- α are preferentially detected in women who clear CT infection. Our overall hypothesis is that HLA-E restricted CD8 T cells will play an important role in clearance of CT infection in women. In Aim 1, we will determine if CT-specific HLA-E restricted CD8 T cells play a role in the clearance of CT infection in women. In Aim 2, we will determine if CT-specific HLA-E restricted CD8 T cells can be primed from CT naïve female donors with no current or prior CT infection. In summary our completed studies will demonstrate the biological relevance and functionality of HLA-E restricted CD8 T cell response in clearance of CT infection and thus has direct applications for immunogen selection for a preventative CT based vaccine.

NIH Research Projects · FY 2024 · 2023-08

Streptococcus pneumoniae (the “pneumococcus”) is an important human commensal pathogen. A key determinant of pneumococcal fitness and virulence is its ability to produce a protective polysaccharide (PS) capsule which can take the form of >100 biochemically distinct “serotypes”. Pneumococcal capsule PS conjugate vaccines (PCVs) induce protective antibodies that mediate opsonophagocytic killing (OPK) of pneumococci and have effectively reduced the global burden of disease caused by serotypes included in vaccines. Despite this success, immunized people occasionally experience breakthrough infections by PCV serotypes, and the cause for these cases of “vaccine failure” remains unclear. Investigation of vaccine failure has largely focused on host factors and ineffective antibody response, while microbiological aspects have gone largely unaddressed. Furthermore, closely-related serotypes 19A and 19F are the serotypes most commonly implicated in vaccine failure cases, but few studies have evaluated their role in this phenomenon. Appreciating the breadth of capsule malleability and its impact on clinical outcomes, we are examining a potential link between serotype 19A/19F capsule variants, evasion of anti-capsule immune responses, and vaccine failure. Preliminary analyses identified multiple candidate mechanisms through which polymorphisms in the 19A/19F capsule polymerase Wzy can mediate considerable capsule variability while preserving most capsule features. We also found a strain that was serotyped as “19F” by conventional methods, but in fact produces a novel capsule PS structure, herein called 19x. Thus, the full diversity of 19A/19F-like capsule types is yet to be defined. As even small changes in capsule structure can abrogate cross-protective immunity, it is possible that some variants, which are indistinguishable from 19A/19F pneumococci in conventional serotyping methods, can nonetheless evade OPK by anti-19A/19F capsule antibodies in vaccinated individuals and, thus, spur the vaccine failure attributed to these serotypes. In this R21 proposal, we will perform directed mutagenesis to test the impact of Wzy polymorphisms on 19A/19F capsules structure and test the effect of these putative capsule changes on evading anti-capsule antibody-mediated OPK in vitro (Aim 1). We will also structurally/genetically/antigenically characterize the novel 19x capsule type and perform bioinformatics analysis of expansive genomic databases with the goal of identifying other putative capsule variants found among immunized populations (Aim 2). Importantly, tools and concepts developed here will fuel future investigation of the impact capsule PS malleability has in additional pneumococcal serotypes and other medically important bacterial pathogens that employ similar pathways for glycan synthesis. Independent of glycobiological advances, elucidation of the molecular basis of 19A/19F Wzy enzymatic specificity would immediately improve the precision of the molecular typing strategies.

NIH Research Projects · FY 2026 · 2023-08

PROJECT SUMMARY Black and Latinx individuals are at higher risk for certain autoimmune rheumatic diseases (AIRDs) and have experienced worse COVID-19 outcomes compared to their white counterparts. The American College of Rheumatology recommends beyond the initial COVID-19 vaccination, subsequent COVID-19 vaccine doses to complete the primary vaccination series and a booster dose in people with AIRD. Yet, historically, overall vaccine uptake among people with AIRDs has been low, and this vaccine reluctance has extended to COVID- 19 vaccination. This proposal will harness community-engaged methods to develop and test the effectiveness of a multi-modal intervention that combines “storytelling” videos and patient navigation to increase uptake of recommended COVID-19 vaccination among Black and Latinx AIRD patients in two distinct US geographic regions. Aim 1 will develop a multi-modal intervention that includes a) “storytelling” videos we will produce with vaccinated Black or Latinx patients with AIRDs narrating their COVID-19 vaccination experiences, and b) a patient navigation approach to encourage recommended COVID-19 vaccination. Navigators will be trained using virtual case simulation to discuss up-to-date guidance and provide logistical support for vaccination. In Aim 2a we will recruit 1,170 racial and ethnic minority patients from 4 rheumatology clinics in the Southern and Northeastern U.S. to participate in this patient-level, randomized, controlled, parallel group trial. Participants will be randomized to receive at the routine clinic visit either “storytelling” OR an “attention-control” plus usual care. At the clinic visit, coordinators will invite participants to view “storytelling” videos on tablet computers deployed in a private clinic area. At 2 days after the clinic visit, the navigators will contact each participant remotely (phone/video calls) to provide customized assistance for vaccination. A second contact will occur ~2 weeks later. We will examine the differences in rates of COVID-19 vaccine receipt between racial/ethnic minority participants with AIRD exposed to our multi-modal intervention versus an “attention-control” video (focused on the merits of a balanced diet/exercise on health status) plus usual care. We will measure rates of receipt of subsequent COVID-19 vaccination at 3 months after the clinic visit using extant linkages to state vaccination records (primary endpoint). We will measure via surveys COVID-19 vaccine confidence, influenza vaccine uptake (self-report) as a proxy for intervention effect on vaccination behavior for other vaccines, self- efficacy, and social health. We will explore whether insurance status and education moderate COVID-19 vaccine uptake. In Aim 2b, using surveys and semi-structured interviews, we will assess how intervention components achieved their effects to inform future scale-up of our intervention. Beyond our innovative approach and experienced team, a key strength of our study is its generalizability since we are including two geographically distinct regions with substantial ethnic/racial diversity in their populations that deliver care to many uninsured, Medicaid, and other historically marginalized groups.

NIH Research Projects · FY 2026 · 2023-08

Project Summary/Abstract: Amphetamines (AMPHs) are psychostimulants commonly used for the treatment of neuropsychiatric disorders (e.g. attention deficit disorders). They are also abused, with devastating outcomes. The abuse potential of AMPHs is associated with their ability to cause mobilization of cytoplasmic dopamine (DA), which leads to an increase in extracellular DA levels. This increase is mediated by the reversal of the DA transporter (DAT) function, which causes non-vesicular DA release, here defined as DA efflux. Notably, inhibition of DA efflux reduces both the ability of AMPH to increase motor activity and AMPH preference8-10. Imbalances in the gut microbiome (dysbiosis) have been suggested to participate in the pathogenesis of substance use disorders11. In addition, psychostimulant abuse promotes dysbiosis12-15. Therefore, it is possible that changes in the gut microbiome and its metabolites may not only be a consequence of substance use disorders, but may play a role in mediating the behavioral responses to drugs of abuse11. Microbial products, such as short-chain fatty acids (SCFAs), are thought to play a fundamental role in regulating the gut-brain axis16. Among SCFAs, butyrate is known to cross the BBB and directly act on neurons and glial cells17. Fusobacterium nucleatum (F. nucleatum) is an anaerobic, filamentous, gram-negative bacterial species that secretes butyrate18, the growth of which is stimulated by AMPH abuse13-15. Our data demonstrate that in germ-free (gnotobiotic) Drosophila, colonization with F. nucleatum enhances AMPH-induced DA effluxes (recorded in isolated fly brains), as well as AMPH behaviors. This potentiation of AMPH actions by F. nucleatum is paralleled by oral administration of butyrate. To understand, mechanistically, how F. nucleatum promotes AMPH actions, it is important to consider that changes in DAT expression regulate both AMPH-induced DA efflux and psychomotor actions19. Also, butyrate is a potent inhibitor of histone deacetylases (HDACs)20-22; inhibition of HDACs robustly increases expression of both DAT mRNA and proteins21-23. Our hypothesis is that F. nucleatum enhances AMPH actions by elevating DAT expression. This is mediated by secretion of butyrate, HDAC inhibition, and enhanced Drosophila DAT (dDAT) promotor acetylation. We will test this hypothesis through the following specific aims: S.A. #1. To determine how F. nucleatum regulates dDAT expression. S.A. #2. To test, mechanistically, how F. nucleatum increases AMPH-induced DA efflux. The experiments of S.A. #1-2 will be performed in isolated Drosophila brains, a model our laboratory developed to study AMPH actions ex vivo. Furthermore, using adult Drosophila, we will be able to translate the molecular discoveries of S.A. #1-2 to specific AMPH behavioral phenotypes. Thus, S.A. #3 focuses on behavior. S.A. #3. To define how F. nucleatum enhances AMPH behaviors.