University Of Alabama At Birmingham

NIH Research Projects · FY 2026 · 2024-06

The overarching goal of this project is to improve our mechanistic understanding of pregnancy complications in organ transplant recipients. By studying a patient population with increased risks of pre-eclampsia and fetal growth restriction, this project fills critical knowledge gaps in reproductive immunology and improves the health of all women. Pregnancy in organ transplant recipients has historically been difficult to study because reproductive age females represent a minority of transplant recipients and pregnancy has been discouraged given concerns around maternal and fetal health. We overcome these prior limitations by leveraging our access to a unique cohort of transplant recipients who receive a uterus transplant for the express purpose of gestation and delivery. Notably, uterus transplant recipients have high rates of pre-eclampsia and other disorders of placentation, which may be due to perturbations in natural killer cell biology as these cells play critical roles in spiral artery remodeling and placentation. Hence, defects in uNK development, homeostasis, and function likely contribute to the pathogenesis of pregnancy complications. Importantly, our prior studies suggest that immunosuppression medications that transplant recipients receive may impact the survival, localization, and function of uterine natural killer cells, thereby providing mechanistic insights into why pregnancy complications in organ transplant recipients are frequent. Notably, the alterations we have observed in uterine NK cells in uterus transplant recipients associate with abnormal placental histology and have had clinical consequences. In this proposal, we thus build upon these findings to better understand the molecular mechanisms underpinning defects in uNK development, homeostasis and function using uterus transplantation as a model system. We accomplish these goals by analyzing endometrial biopsies from uterus transplant recipients as well as healthy controls using state-of-the- art single-cell technologies (i.e., single cell RNA-sequencing, single-nuclear RNA-seq; CITE-seq) alongside high dimensional, multi-parameter flow cytometry and imaging studies (i.e., immunofluorescence microscopy and spatial transcriptomics). These experiments using human samples are complemented by in vivo mouse studies where placentation in the setting of immunosuppression can be better studied across all phases of pregnancy.

NIH Research Projects · FY 2026 · 2024-06

Project Summary Bronchopulmonary dysplasia (BPD), the most common complication in extremely preterm infants, is characterized by impaired lung development. Decreasing oxidant stress which plays a significant role in BPD pathogenesis remains a critical unmet need. Mitochondrial dysfunction, a known mediator of pathological oxidant stress, disrupts alveolar epithelial function and promotes lung fibrosis. Dysfunctional mitochondria generate more oxidants, exhibit impaired mitophagy, and trigger the release of pro- inflammatory mitochondrial DNA-damage associated molecular patterns (mtDNA-DAMPs) and lung injury. Furthermore, mtDNA haplogroups, which are inherited polymorphisms that vary with ethnicity, have been implicated in various lung pathologies. Our group has observed that perinatal mesenchymal stem cells (MSC) and human umbilical venous endothelial cells (HUVEC) mitochondrial dysfunction predicts BPD risk and that decreased MSC mitophagy correlates with increased BPD severity. We have also found that intranasal thyroid hormone-induced mitochondrial biogenesis is associated with decreased hyperoxic lung injury and that mtDNA haplogroups mediate differences in hyperoxia-induced mtDNA damage, inflammatory lung injury, and arrested lung development in newborn mice. In this "MtDNA Haplogroups in BPD" project, we will build on these findings and test the central hypotheses that mtDNA haplogroup variation-mediated differences in postnatal mitochondrial function, mtDNA-DAMPs and mitophagy modulate BPD risk in infants, and that TH-mediated pulmonary mitochondrial biogenesis can mitigate such differences to decrease neonatal hyperoxic lung injury through these specific aims: Specific Aim 1 Hypothesis: mtDNA haplogroups modulate BPD risk through differences in platelet bioenergetics, apoptosis, and plasma mtDNA-DAMPs in infants. Approach Determine infant mtDNA haplogroups, platelet bioenergetics, apoptosis, plasma mtDNA-DAMPs and lung injury severity (Jensen BPD status). Specific Aim 2 will test the Hypothesis that mtDNA haplogroups modulate BPD risk through differences in oxidant stress, mtDNA damage and mitophagy in infants. Approach Determine HUVEC, MSC and platelet oxidant generation, plasma oxidant stress, mtDNA damage, and mitophagy and lung injury severity. Specific Aim 3 will test the Hypothesis that thyroid hormone signaling effects mitigate mtDNA haplogroup-mediated differences in neonatal hyperoxic lung injury in mice. Approach: Expose wildtype and MNX mice to normoxia/hyperoxia and saline/TH and measure lung damage, inflammation, oxidant stress and single-cell genomic transcriptional/methylation differences.

NIH Research Projects · FY 2026 · 2024-06

This is a career mentoring award to support Dr. Eaton with dedicated time to support a sustainable, structured approach to mentoring for herself, her trainees, and early career faculty mentees. Ellen Eaton, MD, MSPH, is an infectious disease trained clinician-scientist with expertise developing and testing interventions to reduce infectious consequences of substance use disorders (SUD), with an emphasis on HIV in persons who use drugs. Her mentoring portfolio focuses on rural, Southern trainees in science and medicine. Mentees will work alongside Dr. Eaton on newly proposed research in the K24 and ongoing NIH-funded studies in hospitals, clinics and rural communities in Alabama and other rural, Southern states. Dr. Eaton proposes mentoring aims to (1) develop Deep South physician scientists who conduct patient-oriented research at the nexus of SUD and HIV and (2) establish a HIV Education and Addiction Training (HEAT) Program that leverages the complementary expertise of the UAB Center for Addiction and Pain Prevention Intervention and UAB Center for AIDS Research. This proposal will accelerate progress by building Substance Use Disorder research capacity and expertise. Dr. Eaton proposes novel research aims using new skills obtained through this career development award. She has assembled a team of advisors who bring complementary expertise in implementation science, qualitative research, telemedicine, health outcomes, and community engagement. The research will use implementation strategies to identify appropriate use of telemedicine to extend substance use treatment. She proposes a rapid analysis approach to analyze in-depth interviews and focus group discussions conducted with key stakeholders and end-users across Alabama. Research activities will explore feasibility and acceptability of a telemedicine intervention with the goal to inform a future implementation trial. There is a shortage of clinician researchers who study the intersection of infection and addiction, and this shortage is especially pronounced in rural and poor states like AL where substance use has outpaced research on optimal healthcare delivery. This award will contribute to the growth of skilled researchers, while advancing the science of healthcare delivery for persons with substance use disorders in Alabama.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY Frontotemporal Dementia (FTD) is a major cause of early onset dementia and patients can develop a wide range of symptoms including behavioral changes and language impairments. Heterozygous mutations in the progranulin gene (GRN) result in haploinsufficiency of the protein and cause FTD with TDP-43 pathology. TDP- 43 is a RNA binding protein that, in disease states, mislocalizes to the cytoplasm and forms insoluble inclusions. All FTD-GRN patients develop TDP-43 pathology, however it is not understood how partial loss of progranulin promotes TDP-43 mislocalization and aggregation. Progranulin heterozygous mice (Grn+/–) are the genetic model of FTD-GRN and develop age dependent behavioral abnormalities, but do not develop TDP-43 pathology. This project uses Grn+/– mice crossed with human TDP-43 transgenic mice (hTDP+) to investigate whether progranulin insufficiency results in TDP-43 dysregulation. Initial studies of the Grn+/–:hTDP+ mice show a severe impairment of social dominance behavior and an increase in insoluble TDP-43 in the medial prefrontal cortex (mPFC), a region critical for normal social dominance behavior. Additionally, preliminary studies suggest that there may be impairments in TDP-43-dependent splicing and autoregulation in the Grn+/–:hTDP+ mice. My overarching hypothesis is that the synergistic effects of progranulin insufficiency and TDP-43 overexpression on social dominance behaviors are due to TDP-43 dysregulation in the mPFC. This proposal will test two aims: 1) Determine if progranulin insufficiency promotes TDP-43 mislocalization and dysregulation in the mPFC and 2) Determine if impaired social dominance behaviors are driven by hTDP expression in the mPFC. As behavioral changes are a major feature of FTD, determining the role of TDP-43 in the mPFC could be vital for developing future therapeutics. The overall goal of the training plan is to instruct the PI in neurodegeneration research and provide a solid foundation for a successful career as a physician scientist. A project based in translational approaches, while focused on a disease-oriented pathogenesis, is the ideal training environment for any aspiring physician scientist. Included in the training plan are experiences that help the PI: 1) gain competence in a variety of techniques in neurobiology 2) collaborate with other scientists, 3) develop hypothesis-driven research, 4) present data in a written and oral format, 5) effectively integrate research with clinic, and 6) responsibly conduct research.

NIH Research Projects · FY 2026 · 2024-05

ABSTRACT: OVERALL The thematic focus of the UAB Alzheimer’s Disease Research Center (ADRC) is Deep South disparities in dementia. Individuals born in the Deep South (traditionally defined as the five-state region spanning LA, MS, AL, GA, and SC) have high rates of Alzheimer’s disease (AD) and related dementias (ADRD) relative to other regions. The region is home to the nation’s largest population identifying as Black or African American, who are estimated to be at as much as double the risk of AD. Our vision is a future in which these Deep South disparities in AD are eliminated. Realizing this vision requires a deeper understanding of how this unique amalgamation of factors drives higher rates of dementia, which is at the heart of our plans. As a P20 Exploratory Alzheimer’s Disease Research Center (ADRC), we have established the teams, programs, and infrastructure to pursue this theme, and have exceeded our recruitment goals with a cohort that is 47% Black/African American. Here we propose building on this initial track record of success with a P30 ADRC that will advance our long-term vision of reducing dementia in the Deep South by eliminating these disparities, by (1) providing coordinated infrastructure leveraging UAB’s strengths to answer questions necessary to reduce Deep South disparities in dementia; (2) recruiting a cohort that reflects the unique and diverse population of the Deep South; (3) collecting a broad dataset from ADRC participants that informs about potential bases for Deep South disparities in ADRD, including clinical, SDOH, activity/sleep, genetic, and biomarker data; (4) collecting and distributing biospecimens from participants in a unique Deep South cohort; (5) increasing our participants involvement in national ADRD initiatives; (6) fostering innovative and impactful ADRD research, especially projects addressing Deep South disparities in dementia; (7) attracting and training the next generation of ADRD researchers; and (8) serving our community, increasing awareness of ADRD both among the public and at UAB.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY Bacillus anthracis is a Gram-positive soil bacterium that forms spores when starved for nutrients and contact with these spores causes anthrax in animals and humans. B. anthracis spores are surrounded by three protective layers, the outermost of which is a loosely fitting exosporium. The exosporium plays key roles in spore survival and disease progression. Over the past two decades, there has been significant progress in identifying the proteins that comprise the exosporium and their functions, however, the assembly process is poorly understood. This proposal is designed to elucidate major components of exosporium assembly. The exosporium is a bipartite structure consisting of a paracrystalline basal layer and an external hair- like nap. Each filament of the nap is formed solely by a trimer of the collagen-like glycoprotein BclA. In contrast, the basal layer contains ~25 different proteins. One of these proteins called BxpB is required for the attachment of nearly all BclA in the exosporium. BclA attachment occurs through and requires only its 38- residue amino-terminal domain (NTD), which is proteolytically processed during sporulation to remove residues 1-19. Cryo-electron micrographs reveal that each filament of the nap—through BclA residues 20-38—is attached to a basal layer surface protrusion that appears to be a trimer of BxpB. When extracted from spores, BclA and BxpB are present primarily in >250-kDa complexes, the stability of which suggested that the two proteins are attached through a covalent bond. Recent studies from this lab have demonstrated that complexes between purified BxpB and BclA residues 20-38, that are as stable as BclA-BxpB complexes found in spores, can be formed in vitro. These complexes do not contain covalently cross-linked peptides, indicating that BclA-BxpB attachment is noncovalent. Furthermore, we recently determined the crystal structure of BxpB trimers, with monomers that are all b-strand with connecting loops. The orientation of three of these loops suggest that they can interact with and entrap the BclA NTD. The primary goal of this study is to use structural and genetic methods to describe the amino acid contacts that account for the stable BclA-BxpB attachment. Structural tools include X-ray crystallography, focusing on a BclA NTD-BxpB complex, and hydrogen deuterium exchange by mass spectrometry to reveal contacts between the BclA NTD and BxpB in solution. Targeted mutagenesis of BxpB and the BclA NTD will reveal specific roles for individual amino acids in the attachment process. Related studies will examine the mechanism of BxpB attachment to and stabilization of the basal layer scaffold and the requirement for BclA NTD cleavage in BclA-BxpB complex formation. The expected outcome is a detailed model for BclA-BxpB attachment and insertion into the exosporium. This study will further impact the field as this model is likely to be shared by many other spore-forming bacteria, including important Bacillus and Clostridium pathogens.

NIH Research Projects · FY 2026 · 2024-05

Infectious diseases continue to have a major impact on global health. Clinician-investigators have an important role in addressing infectious diseases through research whose findings can advance the development of new diagnostic, treatment, and prevention strategies. However, there is a decreasing number of clinician-investigators in infectious diseases to meet this need. Innovative training schemes to reinvigorate the next generation of clinician-investigators to address infectious diseases concerns are needed. The University of Alabama at Birmingham (UAB) is committed to training and retaining a pipeline of clinician-investigators and has established a physician scientist development office (PSDO) that provides support and resources for this pipeline. Residency is a pipeline stage with heavy clinical burden and there is a need for mentored research and training opportunities during residency to help retain those with an interest in a clinician-investigator career. The goal of the UAB StARR Program is to recruit, train, and accelerate the research independence of UAB resident-investigators to help build the next generation of clinician-investigators addressing infectious diseases. The program will achieve its goal through three specific aims: Aim 1 (Pre-StARR Phase): Identify, recruit, and cultivate resident-investigators interested in infectious diseases – starting in post-graduate year 1, multiple strategies will be used to identify and recruit resident-investigators for the UAB StARR program from a resident pool within the UAB Internal Medicine, Pediatrics, OB/GYN, Pathology, and General Surgery residency programs who have interest in infectious diseases. Aim 2 (StARR Research Phase): Provide mentored research and career development activities for resident-investigators to promote curiosity in and preparedness for a career involving infectious diseases investigation - up to 4 residents who apply and are selected for UAB StARR each year will complete a 12-month program that includes: 1) research mentored by one of 34 preceptors with an excellent mentoring track record and funding in research on infectious diseases and/or immune mechanisms impacting them, and 2) career development activities leading to core competencies in research methodology, responsible conduct of research, communication of findings, scientific writing, and team science. Aim 3 (Post-StARR Phase): Maintain continued mentorship and career development engagement to retain resident-investigators’ interest in and preparedness for a clinician-investigator pathway - after completing the 12-month StARR program, participants will have continued mentored research opportunities (up to 12 months), career advising through regular meetings with StARR leadership and preceptors, and participation in career development activities, research conferences, and a monthly interactive StARR Cohort “Next Steps” series. The impact of UAB StARR will be the development of a group of highly motivated, well-trained, early clinician-investigators who are prepared for a successful transition towards a career as an independent clinician-investigator with a research focus on infectious diseases.

NIH Research Projects · FY 2025 · 2024-05

Abstract Children with in-utero exposure to hypertensive disorders of pregnancy (HDP; gestational hypertension, chronic hypertension, preeclampsia, and superimposed preeclampsia) have an increased risk for hypertension and cardiovascular disease (CVD). Our preliminary data indicate that administering first-line antihypertensives during pregnancy improves neonatal outcomes. However, the long-term impact of in-utero exposure to antihypertensive treatment on childhood subclinical CVD risk factors (i.e., high oxidative stress, inflammation, and arterial stiffness) is unknown. Further, it has not been established whether environmental exposures influence the association of in-utero exposure to HDP on childhood subclinical CVD. Assessing subclinical CVD in childhood is particularly important because longitudinal research shows that poor cardiovascular health in childhood is associated with a higher incidence of hypertension, atherosclerosis, and other cardiovascular events in later life. Thus, the objectives of this study are to 1) Investigate whether in-utero exposure to antihypertensive treatment (compared to no treatment) is associated with improved childhood (ages 5–10 years) subclinical CVD, and 2) Examine whether neighborhood deprivation (i.e., a composite measure of environmental exposures) influences the association between in-utero exposure to HDP and offspring subclinical CVD. The central hypothesis is that in-utero exposure to antihypertensive treatment is associated with improved subclinical CVD among children born to mothers with HDP. We also posit that neighborhood deprivation significantly influences the association between in-utero exposure to HDP and offspring subclinical CVD. Completion of the research aims in this proposal will inform the development of an intervention to improve vascular outcomes among children born to mothers with HDP. This research plan will be augmented by intensive mentoring from a multidisciplinary team of experts, didactic coursework, and formal training at the University of Alabama at Birmingham and the National Heart, Lung, and Blood Institute. The training plan was crafted to ensure that Dr. Martin achieves her specified career development goals, which are to 1) Develop advanced skills to assess subclinical cardiovascular risk factors in children and gain a deep understanding of the intergenerational transmission of CVD, 2) Develop expertise in the assessment of social determinants of health and environmental exposures, 3) Develop a comprehensive knowledge of intervention approaches and statistical analysis for clinical research in maternal-fetal-child health; and 4) Refine grant writing skills for future grant mechanisms. Completion of the training aims in this proposal will transform clinical care by providing new insight regarding the long-term impact of in-utero exposure to antihypertensive treatment and will uniquely position Dr. Martin for a career that allows her to make a significant contribution to slowing the progression of CVD for high-risk children born to mothers with HDP and other exposures.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY / ABSTRACT Although behavioral interventions for obesity achieve clinically meaningful weight loss, post-treatment weight regain remains a pernicious challenge. Extended care interventions that include evidence-based behavioral strategies can improve weight loss maintenance (WLM), but many of these strategies require significant effort and resources that can hinder treatment adherence. Thus, strategies are needed that increase individuals' capacity (i.e., resources, abilities, and readiness) to consistently engage in WLM behaviors while minimizing the effort required of treatment. However, the most effective strategies for this are unknown. By leveraging the multiphase optimization strategy framework and a factorial experimental design, this application proposes an extended care optimization trial to efficiently test four “minimally disruptive” intervention components (i.e., effective treatments designed to enhance capacity with limited participant burden). Following an initial 6-month weight loss phase, participants achieving •5% weight loss (N=272) will be randomized into a 12-month trial to receive 0-4 of the intervention components in addition to a core, extended care program. The minimally disruptive components include: 1) reduced food variety (i.e., limiting number of energy-dense dinners and snacks), 2) home-based resistance training (i.e., low-dose prescriptions performed x2/week), 3) buddy training and support (i.e., leveraging individuals from existing social networks to provide support), and 4) acceptance and commitment therapy (ACT) workshops (i.e., condensed ACT skills training). These components have empirical support for weight management but are distinct from conventional behavioral WLM recommendations. Further, all are designed to enhance individuals' capacity with limited burden. The primary outcome is WLM between randomization and month 12. An optimized intervention package will be assembled based on the combination of minimally disruptive components most effective for WLM. In addition, hypothesized mediators of each treatment component and participant characteristics moderating treatment response will be examined. This project will lead to an optimized WLM intervention package that can be evaluated in a subsequent confirmatory randomized controlled trial. This line of research can inform best practices for the provision of WLM interventions, improve long-term outcomes for individuals, and strengthen the overall public health impact of available weight management interventions for disease prevention and management.

NIH Research Projects · FY 2026 · 2024-05

The Center for Clinical and Translational Science (CCTS), the CTSA Hub at the University of Alabama at Birmingham (UAB), serves a region of the country with a heavy burden of chronic diseases. The high toll of these chronic diseases on health outcomes including mortality and morbidity has brought into sharp relief the critical importance of translating new scientific discoveries into interventions that improve the health of patients and their communities in an efficient, effective and balanced manner. The unique health challenges faced by our communities previously prompted the creation of the CCTS Partner Network – spanning Alabama, Mississippi and Louisiana – to ensure that our research and training efforts serve the populations in our region while maximizing collaborative synergies in clinical and translational science (CTS) investigation to catalyze discovery and accelerate the dissemination and implementation of evidence toward health impact. As it continues to serve as a national resource for responding to public health emergencies, the CCTS Partner Network will provide programmatic leadership and shared governance (Aim 1) to mobilize the resources and talents throughout the region as it brings together academic, health system, industry and community partners to advance discovery science in concert with the CTSA consortium. The CCTS will further the development of a vibrant, skilled clinical and translational research workforce (Aim 2) by expanding programs that provide both didactic and experiential training to convey new skills, perspectives and understanding of the translation process for faculty, trainees, clinical research professionals and community alike. The Center will promote community and stakeholder engagement (Aim 3) in trusting, bidirectional relationships in all aspects of the research process to develop, demonstrate, disseminate and implement new discoveries to enhance the impact of health insights on those who will most benefit. It will leverage expertise in health informatics, clinical research informatics and translational bioinformatics to extend collaborative, coordinated data analytics and digital innovations across the Partner Network and the CTSA consortium (Aim 4) that allow full utilization of real-world data together with rich, deep clinical information to enable discovery research from the bench to the learning healthcare system. The CCTS Hub and Network will support ethical, scientifically rigorous, informative clinical trials and pilot studies by providing a range of specialized services, resources and consultations (Aim 5) guided by NCATS principles of effective translational science. Through these efforts, the CCTS will formalize its CTS Research Program (Aim 6) to identify, develop and test novel approaches to overcome significant roadblocks in biomedical research, generating new insights that can be generalized to other CTSA Hubs. By achieving these aims, the CCTS will harness the Network’s vibrant collaborative energy to accelerate the discovery, dissemination and implementation of new findings, deliver treatments to all people more quickly, reduce the burden of chronic disease and advance health in the Deep South and beyond.

NIH Research Projects · FY 2026 · 2024-05

Dissemination and implementation (D&I) science is the study of how to effectively translate research findings into practice and policy. By integrating dissemination and implementation science into the clinical and translational science spectrum, researchers and practitioners can better understand the factors that influence the uptake of evidence-based practices and develop strategies to overcome barriers to implementation. However, in the Deep South, there is a critical shortage of professionals broadly. This limits the ability of researchers and practitioners to develop and implement effective interventions to address health challenges and improve health. Hence the objective of this proposed program is to launch the first T32 postdoctoral training program dedicated to the integration of dissemination and implementation science within and across the translational science spectrum. We seek applications from MDs, PhDs, and doctoral candidates, from a wide range of clinical and scientific disciplines and broad regional representation. The proposed program will take full advantage of the stellar resources of the Clinical and Translational Science Center at the University of Alabama at Birmingham and related Deep South Partner Network. The program’s aims are to: [1] Identify, recruit, and train an interdisciplinary cadre of postdoctoral scientists with the knowledge, skills, and experience to become independent investigators who will continue to expand the field of dissemination and implementation; [2] Establish a rigorous, innovative training program in dissemination and implementation science to facilitate nuanced integration of D&I domains within and across the translational science spectrum; [3] Enhance the integration of D&I and clinical and translational science by embracing the health challenges affecting communities served by the Center as a critical, key focus area of scientific advancement. This proposal has 4 distinguishing characteristics: (1) Integration with an NCATS-supported Clinical and Translational Science Hub at UAB and Partner Network comprised of 11 institutions across the Deep South of the US; (2) D&I mentors and resources representing an extraordinary breadth of disciplines across the translational spectrum; (3) A focus on D&I research centered in addressing health needs in the Deep South, and (4) a training design anchored in broad representation. Didactic components leverage coursework developed by UAB and Partner Network investigators and additional UAB programs that have trained generations of scientists in clinical investigation, translational science, and public health research methods. The training duration will be 2 years. We will have 5 slots per year. Successful candidates must show evidence of a strong commitment to D&I science and a commitment to health research. Trainee progress will be monitored and evaluated by the Program Directors, mentors, and advisory committees.

NIH Research Projects · FY 2026 · 2024-05

The Deep South Translational Science Mentored Career Development Program K12 will support the training and advancement of Scholars to address the growing gap between research and the translation into clinical practice. Our Center for Clinical and Translational Science (CCTS) Partner Network of 11 institutions brings existing training infrastructure and ongoing partnerships. Integrating interdisciplinary and complementary approaches within our clinical translational science (CTS) teams will accelerate scientific innovations and promote enhanced prevention, treatment, wellness, and improved health for the individual, the community, and ultimately the population in our region, which is disproportionately burdened by chronic disease and poor health outcomes. We aim to create a career development program that instills Scholars with mastery of translational research (TR) core competencies through a curriculum that will nurture “translational thinking” and working with those outside their discipline. To be successful translational researchers, Scholars will acquire knowledge of translational science (TS). Over the grant period, we will provide career development for 24 Scholars who will be supported by a collaborative research base (136 mentors) with more than $277 million in extramural funding. Our overall goal for this career development program is to facilitate new, and expand existing, innovative early career training opportunities across the translational spectrum in areas such as drug discovery, integrative “omics”, clinical informatics, community engagement, and dissemination and implementation science with the goal of addressing disease and health challenges that disproportionately impact residents of the Deep South. We will mentor early career investigators and facilitate their growth into academic leaders within our Partner Network and nationally. Our specific aims are to: 1) Identify, recruit, and matriculate a cohort of Scholars across the CCTS Network from multiple scientific disciplines and institutions; 2) Provide an intensive multidisciplinary, continually updated curriculum and collaborative, experiential TS training program with emphasis on chronic diseases prevalent in the US Deep South; 3) Enhance the individualized career development of translational scientists representing a broad range of clinical and methodological disciplines through individual-, peer-, and team-based mentoring approaches, with a focus on future grant development and submission support to assist in successful career transition; 4) Advance mentoring, foster “team science,” and continue the expansion of cross-institutional training experiences for K12 Scholars and other early career investigators. The Deep South Translational Research K12 will provide new and expand existing infrastructure across our Partner Network to recruit and train individuals with significant potential to be highly successful translational scientists and to mentor them toward becoming leaders nationally with the ultimate goal to improve health outcomes in the Deep South.

NIH Research Projects · FY 2020 · 2024-04

SUMMARY / ABSTRACT Chronic kidney disease (CKD) may alter the homeostatic relationship between human hosts and their intestinal tract microbial inhabitants (i.e., the gut microbiota) due to the enhanced delivery of urea to the gut microbiota, alterations in diet, and the decrease in urinary excretion of small molecules produced by the gut microbiota. As a result, both the composition of the gut microbiota and its metabolite byproducts may be altered in patients with CKD. We propose a set of inter-related specific aims to examine the association between CKD, gut microbiota and the fecal metabolome, the plasma metabolome, and the development of clinical outcomes using a longitudinal prospective cohort within the Chronic Renal Insufficiency Cohort (CRIC) Study. The results of our study will provide new insights into interventions, such as modulation of diet, that may alter the metabolome of the gut microbiota to help prevent and/or treat diseases associated with the development of CKD.

NIH Research Projects · FY 2026 · 2024-04

Oxylipins comprise a rapidly growing in numbers class of lipid mediators derived from polyunsaturated fatty acids such as arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, linoleic acid, etc. Collectively, oxylipins have been implicated in the regulation of a vast variety of physiological responses from pain and inflammation to blood clotting and gastric acid secretion. As a result of important physiological roles played by oxylipin mediators, their metabolic interconversions received an intense scrutiny. To date, these efforts allowed to identify the main metabolic pathways responsible for the biosynthesis of major classes of oxylipins. On the other hand, their catabolic interconversions, i.e. subsets of biochemical reactions which frequently alter their biological activities, still remain rather poorly understood. Recently, we demonstrated that human microsomal dehydrogenase reductase 9 (DHRS9) exhibits a robust activity oxidizing hydroxyl groups of many important oxylipins such as pro-inflammatory mediator leukotriene B4 or pro-resolving mediators such as resolvin D1 and lipoxin A4, for example. These findings strongly suggest that DHRS9 activity can alter the tissue balance between pro-inflammatory and pro-resolving mediators and, thereby, affect the progression of inflammation as well as the resolution of inflammation. In agreement with this hypothesis, our preliminary data show that lungs of naïve, untreated DHRS9 deficient mice display all characteristic signs of inflammation, which are further exacerbated by lipopolysaccharide treatment. Together, these observations suggest that DHRS9 deficiency promotes lung inflammation and makes the lungs more susceptible to injury. Thus, experiments outlined in this application have been designed to test our major working hypothesis that DHRS9 is a highly potent oxylipin dehydrogenase with broad substrate specificity which plays a critically important role in body’s ability to control inflammation. This hypothesis will be explored through the following Specific Aims: 1) to elucidate the molecular basis underlying the broad substrate specificity of DHRS9 in order to define the spectrum of its naturally occurring substrates and 2) to establish the physiological role of DHRS9 in controlling lung inflammation and injury. The results of these studies will define the pathways of oxylipin metabolism controlled by DHRS9 and will lay the foundation for development of better informed therapeutic approaches targeting lung inflammation.

NIH Research Projects · FY 2026 · 2024-04

Human memory B and T cells (Bmem, Tmem) can be found in circulation and residing in lymphoid and non- lymphoid tissues. After infection and vaccination, we can follow antigen (Ag)-specific phenotypically-defined memory cells in blood, but we can't easily track Ag-specific clones of memory cells in blood over time and the cells are lost to us if they leave circulation and move into tissues. Our knowledge of the antigen (Ag)-specific Tmem and Bmem compartments in tissues, particularly non-lymphoid tissues, has been largely limited to single timepoint analyses. While we have learned much about the human immune system from these static and serial approaches, at the end of the day, these analyses still only provide us with “immune snapshots” of the Ag-specific memory clones and tissue resident memory cells. This limits us from asking key questions such as which signals facilitate or prevent the recruitment, retention, and survival of specific populations of tissue resident human memory cells. We are also unable to precisely measure the evolution of Ag-specific clones over time or assess whether microenvironment or immune perturbations influences the evolution and durability of these clones of cells. This knowledge gap is the basis for the Cooperative Centers in Human Immunology (CCHI) U19 application entitled “Evolution and Durability of Human T and B cell Responses”. The goal of this Program is to address the knowledge gap by leveraging our access to samples from organ transplant recipients to: (i) monitor cellular trafficking of memory cells from circulation into tissues over time; (ii) study the evolution of memory cells that reside in the tissue or respond to tissue specific Ags; and (iii) assess the durability of these memory populations over time and in response to changes in the environment. The central hypothesis addressed in this program is that the human immune memory compartment is constantly evolving in response to local and systemic signals that influence both the durability and reactivity profile of these cells. We will address this hypothesis in three research Projects that are supported by three scientific service Cores. Project 1 will address the factors that control the evolution and durability of memory B cells and antibody secreting cells that contribute to organ failure and rejection in kidney transplant patients. Project 2 will study the generation and durability of memory T cells that reside in the endometrium of uterus transplant patients. Project 3 will assess B cell and antibody responses in lung transplants. The three science service Cores will support the overarching goals of the Program and will provide the individual projects with the tools needed to track and analyze memory T cells, memory B cells and antibodies. We believe that the studies in this Proposal are important because they are designed to address fundamental questions about the generation, evolution and durability of human memory B and T cells. In the future, these data may be used to develop immune-modulating modalities that can be used to appropriately tune protective and damaging memory cell-driven immune responses.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY - OVERALL The Collaborative Network for Nurturing Ecosystems of Common Fund Team Science (CONNECT) Integration and Coordination Center (ICC) is dedicated to revolutionizing biomedical research within the Common Fund Data Ecosystem (CFDE) through exceptional efficiency, transparency, and innovation. Led by Prof. Jake Chen at the University of Alabama at Birmingham (UAB), with support from Prof. Casey Greene, Prof. Sean Davis, Prof. Peipei Ping, and Prof. Wei Wang, our synergistic Administrative, Evaluation, and Sustainability Cores underpin the ICC's ability to fulfill its mission. The significance of the CONNECT ICC lies in its alignment of missions, goals, and efforts to drive transformative discoveries and applications within the CFDE. Through comprehensive operation guidelines and protocols, our Administrative Core, led by Prof. Chen, ensures effective coordination, tracking, and project management across CFDE-participating entities. This core spearheads the implementation of an Agile project management system, utilizing advanced collaboration tools like U-BRITE, to optimize communication, coordination, and collaboration among CFDE stakeholders. By fostering efficient operations and transparent communication, the Administrative Core promotes software- assisted agile project management methodology innovation and accelerates scientific progress. The Evaluation Core, led by Prof. Greene and Prof. Davis at the University of Colorado at Anschutz, is vital in driving continuous quality improvement within the CFDE. By establishing evaluation metrics aligned with CFDE principles and engaging with stakeholders, this core ensures the effectiveness and impact of CFDE activities. The Evaluation Core's innovative approaches, including developing a report generator and continuous engagement for feedback and improvement, drive the advancement of the CFDE and facilitate evidence-based decision-making. The Sustainability Core, led by Prof. Ping and supported by Prof. Wang at UCLA, addresses the long-term viability and reusability of CF program data and resources. Through the MATCH approach and the CFDE Digital Asset Repository Roadmap, this core promotes seamless data transitioning, maximizes data dissemination, and enhances community reuse. By developing best practices for data management, coordinating data transfer strategies, and identifying suitable repositories, the Sustainability Core ensures the preservation and accessibility of invaluable CF program data for future research and discoveries. Overall, our CONNECT ICC's innovation lies in its ability to harmoniously integrate the efforts of the Administrative, Evaluation, and Sustainability Cores. By fostering efficient operations, promoting continuous quality improvement, and ensuring data sustainability, the ICC drives transformative biomedical discoveries, facilitates collaborative research, and accelerates the impact of the CFDE. Through the expertise and dedication of our team, the CONNECT ICC is poised to help CFDE revolutionize the biomedical research landscape and advance the mission of the Common Fund.

NIH Research Projects · FY 2025 · 2024-04

The overall objective of this K23 Career Development Award is to support the training and mentorship necessary for Dr. Wise to transition to an independent investigator and enable her to build and sustain a program of research developing, implementing, and testing behavioral interventions to reduce cardiovascular disease (CVD) risk among women living with HIV (WLHIV). Completion of the proposed research and training aims will enable Dr. Wise to gain the critical skillsets necessary to transition to independence and generate the data necessary to support an R01 at the end of this award period. CVD is the number one cause of morbidity and mortality among women in the United States (US). WLHIV have 2-4-fold higher risk for CVD compared to women without HIV-infection. HIV and CVD disparities are particularly prevalent among women in the Southern US. While increased prevalence of traditional risk factors (e.g., hypertension, diabetes, and obesity) partially explain this risk, evidence suggests that increased exposure to adverse social stressors among WLHIV in the South negatively contribute to CVD disparities through their impact on stress. Stress is an established risk factor for CVD. WLHIV have 4-5x increased risk for stress and stress-related disorders compared to the general population. While exposure to social stressors is difficult to change, behavioral interventions to reduce an individual’s stress response are effective in reducing stress and may mitigate CVD risk. The Stress Management and Resiliency Training (SMART) Intervention is an evidence based behavioral intervention offered as an integral part of Massachusetts General Hospital’s Intensive Cardiac Rehabilitation program. The SMART intervention is proven to reduce physiologic responses to stress. The intervention works to decrease stress responses and CVD risk by improving resiliency to environmental stressors and decreasing sympathetic nervous system activation. While the SMART intervention has demonstrated efficacy in a wide range of populations and settings, it has not been designed or tested among WLHIV in the South, where unique cultural and faith-based context may diminish the uptake and value of the intervention to mitigate CVD risk. To that end, the overarching goal of this proposal is to develop the critical skillsets necessary to build a program of research focused on developing, testing, and implementing behavioral interventions to reduce CVD risk. With the help of my mentors, I will develop critical skillsets in 1) stress and CVD and interventions to reduce risk, 2) the adaptation of interventions to maximize feasibility, acceptability, and impact, and the 3) design and conduct of behavioral-implementation trials as we systematically adapt, implement, and pilot test the SMART intervention for WLHIV in the Southern US. Data generated on the feasibility, acceptability, and preliminary impact of the adapted intervention to reduce stress and mitigate CVD risk will directly support the development of an R01 application to test the efficacy of the adapted SMART intervention at the end of this award period.

NIH Research Projects · FY 2026 · 2024-04

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder where clusters of cysts develop in the kidneys. Still, despite being most often caused by mutations in PKD1 or PKD2 (encoding the polycystin 1, PC1, and polycystin 2, PC2, proteins, respectively), disease presentation is phenotypically heterogeneous. Most ADPKD patients have reduced quality and length of life, and while tolvaptan was approved as the first and only ADPKD therapy, it does not cure ADPKD, shows no benefit for other PKD manifestations, is associated with liver toxicity, and is expensive. Novel approaches to identifying and prioritizing ADPKD biomarkers and therapeutic candidates are desperately needed. Mitochondrial dysfunction and preference for aerobic glycolysis (i.e., the Warburg effect) over oxidative phosphorylation (oxphos) are suggested hallmarks of ADPKD based on both animal models and ADPKD patient tissue studies. Mitochondrial differences have been shown broadly to account for much of the observed variation in gene expression, alternative splicing (also known to promote the Warburg effect), translation, and, ultimately, protein levels. Intriguingly, in PKD kidney tissues and single-cell profiles, thousands of genes are differentially expressed, the PC1-PC2 complex can regulate oxphos directly by mediating mitochondrial calcium uptake and indirectly through multiple mechanisms (e.g., maintaining mitochondrial DNA copy number, mtCN), and mitochondrial abnormalities have been shown to promote cyst formation and act as a modifier of disease progression. We anticipate that similar to other conditions where mitochondria have central disease pathogenesis roles, cell-specific mitochondrial dysfunction, metabolic reprogramming, and transcriptional diversity are critical for renal cystogenesis and progression and are suitable disease biomarkers and therapeutic targets. With innovative genomics and data science approaches, we will profile ADPKD mouse model kidney tissue and patient urinary cells with mitochondrial single-cell ATAC-Seq (mtscATAC-Seq) and long-read single-cell RNA-Seq (lrscRNA-Seq). We will test the hypotheses that a greater number of cell types and proportion of cells are impacted by mitochondria dysfunction in rapidly compared to slowly progressive ADPKD (Aim 1) and that proximal tubular cell alternative gene splicing and glycolysis and oxphos molecular signatures distinguish slow from rapidly progressive ADPKD (Aim 2). This proposal is responsive to the Katz program, does not include unpublished data, and targets research different from the Lasseigne Lab’s previous focus and training (i.e., mitochondrial and metabolic contributions to disease, kidney cyst pathophysiology). In addition to depositing all data in GEO and hosting version-controlled code with a digital object identifier on Zenodo, we will develop an interactive web application to make the ADPKD mtscATAC-Seq and lrscRNA-Seq maps widely available. Collectively these studies have the potential to transform unmet clinical ADPKD needs by prioritizing biomarkers for monitoring disease progression and prioritizing precision-targeted therapeutics.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY/ ABSTRACT Sickle cell disease (SCD) affects millions worldwide, 100,000 individuals in USA, and nearly 1000 children in UAB. Sickle cell anemia (SCA, HbSS or HbSB0 thalassemia) is the most severe form of SCD and is associated with morbidity, mortality, and health care burden. Acute pain is the hallmark complication for SCA, and inflammation is a driver of pain. Opioids are used to treat acute pain but lead to adverse clinical outcomes. Therefore, non-opioid therapies are desperately needed. Recent data and my preliminary data suggest gut microbial dysbiosis is present in SCD. My data also suggests that a different microbiota profile is present in children with SCA pain. Therefore, dietary interventions manipulating the gut microbiome represent a novel therapy for treating SCA pain. Marine based ω3FA (fish oil) decreases pain in children with SCA but its acceptance is limited by its fishy odor and taste. In contrast, plant-based ω 3FA (Flaxseed-FS) has a neutral taste and reduced pain in patients with rheumatoid arthritis. My preliminary tasting trial identified that children with SCA accept FS added products with over 80% of participants expressing a willingness to be contacted for this feasibility study. Therefore, I am proposing a feasibility study of FS trial in children with SCA. My overarching hypothesis is that FS enriched diet will be acceptable, impact the gut microbiome, decrease inflammation, and reduce pain in children with SCA. The focus of this study is to recruit, retain and monitor for side effects of a FS diet in children with SCA (Aim 1) while evaluating changes in gut microbiota profile (Aim 2) and improvement in inflammation driven pain outcomes (Aim 3) on this diet. The applicant has dedicated her career to becoming a physician scientist investigating inexpensive, sustainable nutritional interventions that impact the microbiome and improve inflammation driven outcomes in SCD. To fulfil this long-term goal, she moved to the University of Alabama at Birmingham (UAB) where she has a supportive research environment in the Department of Pediatrics and School of Medicine, including the Center for Clinical and Translational Science (CCTS), Life span sickle cell disease comprehensive research center, UAB microbiome center, the Immunology Institute and the Nutrition and Obesity Research Center. She has assembled an excellent mentorship team, and she plans to complement this mentorship in formal course work including advanced statistics, clinical trials, metagenomics, nutrition, mucosal immunology, and pain psychology. This award will allow her develop expertise in her identified training needs, acquire the skills to transition into a successful independent physician scientist and grow into a leader in the field.

NIH Research Projects · FY 2026 · 2024-04

Extramedullary infiltration of leukemic cells to the meninges (CNS disease/relapse) is a poor prognostic factor for patients with T-cell acute lymphoblastic leukemia (T-ALL). To date, few studies have investigated the roles of chemokine receptors and other mediators of signal transduction in driving T-ALL influx to the meninges. The CXCR3-CXCL10 signaling axis plays a critical role in regulating the entry of specific leukocyte subsets into inflamed meninges. However, its role in regulating leukemic cell migration and trafficking to the meninges remains poorly understood. The focus of this proposal is on a unique mechanism by which leukemic cells hijack an inflammatory pathway to pave the way to the meninges/CNS. We discovered upregulation of CXCR3 chemokine receptor levels in a subset of high-risk T-ALL with CNS disease. Our preliminary findings provide strong evidence that CXCR3 potentiates T-ALL cell migration and meningeal infiltration. We have compelling evidence that, in the meningeal microenvironment, T-ALL cells migrate to the meningeal pericytes, which induce CXCL10 in response to leukemia-derived cytokines. The goal of this study is to address how the CXCR3-CXCL10 axis mediates T-ALL trafficking to the meninges. We hypothesize that T-ALL exploits the inflammatory CXCR3-CXCL10 pathway to facilitate meningeal infiltration. Our rationale is that leukemic cells may adopt pro-inflammatory signaling governing normal T-cell influx during meningitis and neuroinflammation to trigger meningeal colonization. Using ΔE Notch1-induced T-ALL mouse model and a panel of well- characterized T-ALL patient derived xenografts we propose to study how the CXCR3-CXCL10 signaling axis regulates T-ALL cell migration and influx into the meninges. In addition, we will seek to establish a proof of principle for the therapeutic potential of targeting this signaling pathway for the treatment of CNS-involved T- ALL. Furthermore, we propose to use microfluidic 3D cell culture systems to model T-ALL cell migration in the meningeal niche. In Aim 1, we will determine the roles of CXCR3 in T-ALL trafficking to the meninges and will conduct mechanistic studies unraveling the roles of USP7/TAL1 in regulating CXCR3 expression in migrating T-ALL cells. In Aim 2, we will investigate how leukemic cells induce a pro-inflammatory phenotype in meningeal pericytes and how pericyte-derived CXCL10 confers T-ALL tropism to the meninges. Our goal will be to demonstrate that disseminated leukemic cells induce pro-inflammatory chemokine CXCL10 in the meningeal microenvironment, forming a supportive niche for leukemic cell influx and colonization. The identification of the mechanism by which leukemic cells infiltrate the meninges will lead to the development of novel therapies.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY Flaviviruses are small, enveloped viruses with positive-sense, single-stranded RNA genomes of about 11 kilobases. Upon cell entry and uncoating, the vRNA traffics to the endoplasmic reticulum (ER) where it is translated as a single polyprotein that is then post-translationally processed by the viral and cellular proteases into 10 functional subunits, consisting of three structural proteins and seven non-structural (NS) proteins. Among the NS proteins are NS2B and NS3. NS3 consists of a serine protease and a helicase domain while NS2B is anchored to the ER and has a cytoplasmic loop that serves as a cofactor required for the catalytic activity of the NS3 protease domain. The NS2B3 complex is responsible for all cytoplasmic cleavage events of the viral polyprotein, making it an essential protein complex with functions required for the viral lifecycle. Many studies have reported on the structure, function, and importance of the NS2B3 protease; However, the molecular determinants for flavivirus protease cleavage of intracellular substrates and how these factors affect viral fitness is unknown. Using an intracellular protease activity reporter developed by our laboratory, we found that a soluble form the reporter was not cleaved whereas an ER-anchored reporter was efficiently cleaved, suggesting there are multiple determining factors within a substrate required for protease cleavage. Aim 1 will test the hypothesis that there are other molecular determinants for flavivirus protease cleavage of substrates outside of primary cleavage sequence. This will be addressed through manipulation of the intracellular localization of the reporter substrate and the distance of the cleavage site from organelle membranes. Although the typical cleavage motif of substrates is known, there is still some variability in the primary sequences cleaved by the protease at different junctions within the viral polyprotein. We were interested in understanding the variability in cleavage efficiency between the different sequences present in the viral polyprotein junctions of DENV, ZIKV, WNV, and YFV. Our preliminary data showed that each flavivirus protease has its own unique cleavage profile and that each flavivirus protease tested processed the sequence located at the junction between NS4A and the 2K peptide of its polyprotein least efficiently. Further, we determined that introducing a more efficient cleavage site into the NS4A/2K junction of a DENV infectious clone leads to the complete loss of viral recovery. Aim 2 will test the hypothesis that aberrant cleavage at the NS4A/2K junction of the flavivirus polyprotein causes detrimental effects to viral fitness. Using multiple genetic tools, we will assess the effect of this mutation on different stages of the viral lifecycle, including replication, polyprotein stability/processing, and replication organelle formation. Together, the results produced from this proposal will advance our understanding of the molecular determinants of flavivirus protease cleavage and the role that sequence specificity plays in infection. Understanding the infectious role of flavivirus protease specificity will aid in the development of antiviral therapeutics targeting this viral protein.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY Substance use disorder (SUD) is a national health crisis, with over 93,000 deaths due to overdose in 2020. Currently, no FDA-approved therapeutics exist for SUD, with targeted therapeutics out of reach due to incomplete understanding of the neurobiology of addiction. Our lab has identified expression of Reln mRNA as necessary for cocaine-responsiveness in NAc Drd1+ medium spiny neurons (MSNs). Reelin is a secreted glycoprotein that plays a critical role in cortical cell migration during brain development, with mutations leading to lissencephaly, defined by a smooth-brain phenotype. In the adult brain, Reln expression remains high in the cerebellum, hippocampus and striatum. Brain-wide Reelin signaling blockade attenuates response to methamphetamines, indicating a critical role for Reelin in the striatum. Despite high striatal Reln expression and evidence suggesting Reelin modulates behavioral output of the striatum, Reelin’s role in the striatum remains under-studied. Using RNA single-molecule fluorescent in-situ hybridization (smFISH), I have validated our single-cell data showing Reln marks cocaine-sensitive Drd1+ cells. I have also found Drd1+ cells are enriched in Reln compared to Drd2+ cells in both rat and human brain tissue. My smFISH data show Reln expression is restricted to the dorsal striatum and nucleus accumbens (NAc) core and absent in the NAc shell. As these regions have distinct functions, this pattern may reflect the functional relevance of Reelin signaling. I have assessed the role of Reelin signaling using a CRISPR-interference (CRISPRi) strategy to knockdown Reln. NAc whole-cell patch clamp demonstrates that CRISPRi at Reln significantly impairs MSN excitability. Critically, in vivo CRISPRi-knockdown of striatal Reln attenuates cocaine preference in a rat model. Given these findings, I hypothesize that Reelin facilitates the dopamine-induced neuronal adaptations that follow drug exposure and promote drug-seeking behavior. The proposed study will take a multidisciplinary approach to rigorously investigate the following aims: (1) Reelin is required for cocaine-related behavioral adaptations and (2) Reelin regulates membrane excitability to facilitate dopamine signaling. The proposed studies will deepen our understanding of the molecular underpinnings of SUD, providing avenues for therapeutic exploration for a disease completely lacking targeted treatments. Under this award, I will master intravenous self-administration and locomotor sensitization assays to assess the relevant consequences of genetic manipulations. I will hone patch clamp electrophysiology skills to assess mechanisms behind behavioral adaptations. These techniques will aid my success as a physician-scientist studying mechanisms of and engineering therapeutics for brain disorders.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY Hepatocellular carcinoma (HCC), the most common type of liver cancer, accounts for over 30,000 deaths each year in the United States alone. Regrettably, current therapies provide limited clinical benefits in patients with advanced HCC. Thus, new and more effective therapies for HCC are urgently needed. Most drug target discoveries and validation approaches employ cell culture-based screening methods or in vivo immunocompromised or immunodeficient mouse models (e.g., nude mice, NSG mice, etc.). However, multiple cell culture related artifacts (e.g., 2-D culture, high concentrations of growth factors in media, etc.) and use of immune-defective mouse models limit the rigorous identification of clinically relevant drug targets and ultimately negatively impact their translation to clinic. To overcome these limitations and to rigorously identify novel therapeutic targets in HCC, we combined two state-of-the-art approaches; namely an in vivo epigenome-wide CRISPR-based functional genomics screening with a humanized mouse model with functional human immune system. Using these systems, we identified the chromatin modifier NSD3 as a factor that promoted HCC tumor growth and metastasis in mice with functional human immune system. Mechanistically, NSD3 loss promoted NK cell-mediated HCC eradication and a highly-selective and efficacious inhibitor of NSD3, BI-9321, blocked HCC tumor growth in mice with human immune system. Based on these results, we hypothesize that NSD3-mediated suppression of NK cell-mediated anti-tumor immunity is necessary for the HCC tumor growth and metastasis and targeting NSD3 represents a novel therapeutic opportunity for treating HCC. The overall objective is to determine the in vivo role of NSD3 in driving HCC tumor growth and metastasis via suppressing NK cell-mediated anti-tumor immunity and evaluate in vivo pharmacological targeting of NSD3 for HCC treatment. In Aim 1, we will first determine the in vivo role of NSD3 in facilitating HCC tumor growth and metastasis. Next, we will determine the mechanism of suppression of NK mediated anti-tumor immunity by NSD3 and its role in the regulation of NSD3-mediated HCC tumor growth and metastasis. To answer these questions, we will use a novel liver fibrosis model that we have developed to study HCC tumor growth and metastasis in conjunction with immunocompetent humanized mice with transplanted human immune system. Additionally, using organ-specific and orthotopic spontaneous HCC metastasis models, we will study the role of NSD3 in HCC metastasis. In Aim 2, we will rigorously and comprehensively test the effectiveness of NSD3 inhibitors (BI-9321 and a NSD3-specific Proteolysis Targeting Chimera (PROTACs)) either alone or with other anti-cancer agents for HCC treatment in vivo. These studies will utilize established HCC cell lines and HCC patient-derived xenograft (PDXs) and use humanized mice transplanted with human immune system. Collectively, these studies will determine the role of NSD3 as a driver of HCC and establish the efficacy of NSD3 inhibitors for treating advanced HCC.

NIH Research Projects · FY 2026 · 2024-04

Project Summary The activity of midbrain dopamine (DA) neurons, and bulk DA release in the ventromedial striatum (VMS), encodes reward prediction errors (RPE). However, there is also evidence that DA activity reflects value- orthogonal aspects of learning, including value-less sensory prediction errors (SPE). Reconciling these two bodies of data would greatly advance our understanding of DA transmission in normal and pathological conditions. One proposition is that DA release might signal a multi-factorial prediction-error. This would explain recent findings demonstrating that DA neuron ensembles encode the sensory properties of outcomes that violate learned predictions. This requires that this information, observable at the level of neuronal firing, be transmitted to downstream regions via DA release. This proposal will test the hypothesis that DA neurons encode a multi- dimensional error signal by examining specific spatiotemporal patterns of DA release in downstream regions. The current proposal takes advantage of a new methodological approach that I developed during my postdoc to image DA release in freely moving rats across a wide area at cellular resolution, as well as new technologies for gene editing and neuronal manipulation. Rats will perform an odor-guided choice task that induces both RPEs and SPEs, while DA release in the VMS will be recorded using dLight1.2 combined with GRIN lens implants and the UCLA miniscope. These recordings will be analyzed with machine learning algorithms to determine whether the specific spatiotemporal pattern of DA release encodes both value-based and value-orthogonal information (Aim 1). It will also be examined if these signals may be degraded in a pathological condition, by performing recordings in rats with chronic cocaine use experience (Aim 2). For the independent phase of the proposal, I will first examine the role of upstream cortical circuits in the encoding of this information by using chemogenetics to silence the orbitofrontal cortex (OFC) (Aim 3). I will then focus on how a specific biophysical property of DA neurons may shape this information encoding, by using gene editing techniques to delete a key K+ modulator in DA neurons while imaging DA signals in the proposed task (Aim 4). During the mentored phase of the current proposal, I will receive training critical for my short- and long-term success, including analysis of high-dimensional neural data, genetic editing using CRISPR-Cas9, and rodent self-administration models of drug use. The proposed training program combines hands-on training with expert experimenters, independent study, formal coursework, establishment of an independent collaboration, and professional scientific meetings. This program will equip me to lead a laboratory focused on the interaction of behavioral, computational, and molecular approaches to study the function of neural circuits.

NIH Research Projects · FY 2026 · 2024-03

Abstract Cervical cancer is the leading cause of cancer morbidity and mortality among women in low-and-middle-income countries (LMICs) such as in Africa where screening by visual inspection with acetic acid (VIA) is the primary strategy. Although in 2021 the World Health Organization (WHO) recommended human papillomavirus (HPV) testing as the preferred screening test in all settings, VIA will remain the most common screening test for the foreseeable future in many LMICs, and the main triage test after the transition to HPV screening. However, incomplete visualization of the transformation zone (TZ) of the cervix (Type 3 TZ) which accounts for about 15% of women undergoing cervical cancer screening, is associated with missed lesions during VIA. Therefore, interventions to increase complete visualization of the TZ (i.e., conversion), reducing Type 3 TZ at VIA, remain a priority for cervical cancer prevention. Prostaglandin E1 (misoprostol), with cervical modulating effects, is a promising intervention due to wide availability, low cost ($1/dose), single vaginal dose, benign side effects, and small trials suggesting efficacy. However, misoprostol efficacy remains uncertain and it is unclear whether it will vary by duration of misoprostol, age/menopause, parity or previous precancer treatment, or whether such a program is acceptable, particularly in Africa, a region with the highest risk of cervical cancer. To address these gaps, and building on our preliminary data, we propose a double-blind RCT (N=420) to evaluate the effectiveness and acceptability of misoprostol to convert Type 3 TZ in patients attending a screening program in Cameroon. The ultimate goal is to prevent cervical cancer and morbidity by improving detection of pre-/cancerous lesions. Aim 1: Test the effectiveness of vaginal misoprostol 600 mcg vs. placebo to convert Type 3 TZ. Hypothesis 1: In women with Type 3 TZ, misoprostol given up to 6hrs prior to VIA will increase the rate of conversion by over 50% (primary outcome) and detect more cervical pre-/cancer lesions (secondary outcome). Sub Aim 1a: Identify optimal timing of misoprostol placement prior to same day evaluation to optimize efficacy and other factors that influence the rate of conversion of Type 3 TZ. Hypothesis 1a: Cumulatively, conversion rates at 4-6 hours after misoprostol will not be materially higher than at 2-3 hours and conversion rates will vary by maternal age, parity, prior pre-cancer treatment and menopausal status. Aim 2: Examine the acceptability and satisfaction of integrating misoprostol for Type 3 TZ into a cervical cancer screening program in Africa from patient and health care worker perspectives. Hypothesis 2: Patients with Type 3 TZ and clinical providers will have high acceptability and satisfaction rates with this approach. Cameroon is a low-resource setting with a high burden of cervical cancer and has a VIA-based comprehensive prevention program which provides a framework for the proposed study. If successful, this simple inexpensive intervention will reduce the risk of missed cervical lesions and improve early treatment and prevention cervical cancer.