Ut Southwestern Medical Center

NIH Research Projects · FY 2026 · 2008-02

Project Summary: It is widely accepted that mitochondrial metabolism contributes to the development and progression of non- alcoholic fatty liver disease (NAFLD), but the mechanisms of this process are poorly understood. Hepatocellular mitochondria are unique in their ability and requirement to support biosynthetic, catabolic, and substrate trafficking pathways. These functions are mediated by anaplerosis, non-oxidative pathways of the TCA cycle that allow its intermediates to produce and recycle substrates. The downstream pathways that require anaplerosis (e.g., gluconeogenesis and urea cycle function) are energetically costly. They are also notably dysregulated by obesity and insulin resistance, but it is unknown how mitochondrial anaplerotic function impinges on the progress of liver disease. It is suspected that changes in anaplerotic pathways of liver mitochondria alter apparent mitochondrial function, redox state, and antioxidant capacity. This project tests the hypothesis that the equilibrium between anaplerosis and downstream pathways impinge on antioxidant capacity by modulating redox-mediated reactions in liver. Hence, seemingly unrelated intermediary metabolism may have secondary effects on mitochondrial function and contribute to factors like oxidative stress and inflammation in NAFLD. To test the hypothesis, we will use state-of-the-art stable isotope tracer methods, NMR and MS to evaluate metabolic flux, and conditional knockout mice to establish mechanism. Emphasis is placed on identifying how TCA cycle intermediates modulate antioxidant function and the role of metabolic compartmentation. In the process, we will develop new tools and concepts that can be tested and applied against human disease.

NIH Research Projects · FY 2026 · 2007-09

PROJECT SUMMARY The overall goal of the proposed research is to provide a better understanding of how cilia move by dissecting the structure and function of ciliary complexes that regulate dynein activity and ciliary motility. Cilia and flagella are conserved and ubiquitous microtubule-based organelles with important roles in cell locomotion, fluid transport, sensation, cell signaling, and development, which are critical processes for the survival and proper function of many eukaryotic cells and tissues. In humans, defects in the motility and assembly of cilia are responsible for numerous congenital diseases, such as primary ciliary dyskinesia, chronic respiratory disease, infertility, brain developmental defects, congenital heart disease, and randomization of the left-right body axis. Our previous studies of both inhibited and actively beating wild type and mutant cilia have opened a new window into the functional organization of motile cilia. However, long-standing fundamental questions remain, for example, about how regulatory signals change dynein’s activity on a molecular level, what are the roles of the different regulatory complexes during ciliary motility, and how dyneins are spatially and temporally coordinated to generate the oscillatory beating typical for cilia. Building on a strong premise of both published and preliminary data, this proposal directly addresses these critical open questions through three specific aims that are directed at (Aim 1) revealing the proteome and near-atomic resolution structure of the full-length radial spoke RS3 in mouse respiratory cilia, (Aim 2) understanding the functional roles of the regulatory ATPase domain of DRC11 – a nexin-dynein regulatory complex subunit – for proper regulation of ciliary motility, and (Aim 3) characterizing ciliary components that assemble only on specific doublets to ascertain if their inherently asymmetric distribution contributes to generating ciliary beating and/or different waveforms. We use a powerful and innovative combination of modern approaches, including a multi-scale imaging approach that combines near-atomic resolution cryo-EM single particle analysis, cryo-electron tomography to image mutant cilia and tagged proteins with molecular resolution, and expansion light microscopy to determine the doublet-specific distribution of specific ciliary proteins. We expect that our combined studies will provide important new conceptual and mechanistic insights into ciliary motility and regulation, which will also impact our understanding of ciliary diseases.

NIH Research Projects · FY 2026 · 2007-09

PROJECT SUMMARY Healthy adults produce 2 million erythrocytes every second through the process of basal erythropoiesis. Insufficient erythrocyte production causes anemia, which is a significant global human health problem. During regeneration or “stress erythropoiesis” to recover from anemia, erythrocyte production further increases. Stress erythropoiesis is critical for recovery from surgery, chemotherapy, bone marrow transplantation and infection; however, the underlying mechanisms remain unclear. Both basal and stress erythropoiesis are regulated by erythropoietin (Epo) and its receptor EpoR. Epo binding to the EpoR activates the associated tyrosine kinase JAK2, which initiate downstream signaling leading to survival, proliferation and differentiation of erythroid cells. While EpoR signaling in more differentiated erythroid precursors has been extensively studied, EpoR signaling in early progenitors has not been elucidated. This proposal is based on our recent findings of a previously unrecognized population of early colony-forming erythroid progenitors (CFU-E), which we named stress CFU-E or sCFU-E. sCFU-E are targets of Epo, are only expanded in erythroid stress, and are essential for recovery of the erythron. sCFU-E are also hijacked by the activating JAK2 mutant, JAK2(V617F), to drive erythrocytosis in myeloproliferative neoplasms. In preliminary studies, we discovered that sCFU-E proliferation and differentiation involve novel Epo/EpoR signaling. We found that Epo induces expression of Nocturnin, a NADP(H) phosphatase that regulates cellular oxidative stress to promote sCFU-E proliferation. Epo also induces expression of SLC23A2, an ascorbate (Vitamin C) transporter, in sCFU-E. sCFU-E accumulates high levels of ascorbate, and ascorbate accelerates sCFU-E differentiation. The goal of this proposal is to elucidate the mechanism by which Nocturnin and ascorbate drive proliferation and differentiation of sCFU-E in the context of stress erythropoiesis and erythrocytosis. Aim 1 will determine the role of ascorbate import on sCFU-E function. Aim 2 will elucidate mechanisms underlying ascorbate-dependent sCFU-E differentiation. Aim 3 will determine the role of Nocturnin and oxidative stress signaling in sCFU-E proliferation. These results will elucidate mechanisms controlling stress erythropoiesis and erythrocytosis, and may lead to novel therapeutic interventions for anemia and those that can target erythrocytosis while preserving basal erythropoiesis.

NIH Research Projects · FY 2025 · 2007-05

Project Summary The long-term goal of our research project is to define mechanisms that govern the development and maintenance of motor neurons, as well as the formation and maturation of the synaptic connection between the motor neuron and the skeletal muscle - the neuromuscular junction (NMJ). The mammalian NMJ is a classic model of cholinergic synapses; it contains all elements of cholinergic synapses, including the neurotransmitter acetylcholine (ACh) and the ACh receptor (acetylcholine receptor, AChR), as well as the enzymes responsible for biosynthesis and degradation of ACh, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), respectively. We use the NMJ as a model for understanding synapses as it can provide information pertinent to both peripheral and central synapses. Its relatively simple structure and easy accessibility make it more amenable to investigation than those of the central nervous system (CNS). Furthermore, the NMJ has a significant advantage over the CNS because genes can be deleted separately in the pre verses post-synaptic compartment, thereby facilitating the study of compartment- specific functions. This project addresses a fundamental question in the interaction between the nerve and the muscle – how does muscle signal to the nerve to promote motor neuron survival, and to regulate synapse formation and maturation? Using targeted gene deletions in mice, we found that muscle activity, mediated through muscle dihydropyridine receptors (DHPRs) and a newly identified protein, STAC3 (SH3 and cysteine-rich domain- containing protein 3), plays a key role in regulating motor neurons and the NMJ. Like DHPR, STAC3 is localized at the T-tubules and is required for excitation contraction coupling in skeletal muscles. Our preliminary findings open a new avenue of investigation for identifying feedback mechanisms from the muscle to the nerve, and will provide important insights supporting future development of therapeutic strategies to prevent motor neuron loss and treat neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).

NIH Research Projects · FY 2025 · 2006-09

Pelvic Floor Disorders Network Cycle V Renewal – UT Southwestern PROJECT SUMMARY / ABSTRACT Our primary goal is to actively engage in the Pelvic Floor Disorders Network (PFDN) through efficient patient recruitment, participation, and retention of a racially and ethnically diverse patient population in all studies examining pelvic floor disorders (PFDs) in women. Our second goal is to bring innovative research proposals to this Network with emphasis on translational aims that explore the pathophysiology and prevention of PFDs in well-defined clinical study populations. A final goal is to lead as primary site a multicenter trial studying prevention of urinary and fecal incontinence. To accomplish these aims, we describe the qualifications and experience of the Female Pelvic Medicine and Reconstructive Surgery (FPMRS) faculty and research teams at the University of Texas Southwestern Medical Center and Parkland Hospital, the facilities and patient population available to carry out clinical protocols, and our state-of-the-art scientific approaches to the study of PFDs. Our clinical and research clinics serve both medically indigent patients (Parkland Hospital) and private, insured patients (university practice) in the southern US. These clinics provide a diverse patient population which has allowed us to continually be the lead recruiter of Latina women in the PFDN. Throughout Cycles III and IV, even when not a full clinical site (Cycle III), we have remained committed to the successful retention and long-term follow-up of our PFDN study participants. In Cycle IV, we actively partnered in all aspects of the PFDN including concept proposal, committee participation, and manuscript preparation. Unique to our research team are urogynecology basic and translational scientists whereby our site has led the effort to manage and direct the Biorepository for the PFDN, which has remained housed at UT Southwestern for 15 years and has become integral to multiple recent translational research endeavors. Further, the scientific resources and infrastructure within our Ob/Gyn department are centrally focused on the role of proteomics, genomics, epigenetics and gene regulation in various aspects of women’s health. Moreover, we continue to contribute scientifically with multiple publications and ongoing writing team participation. Since 2015, when new hospitals opened for both UT Southwestern and Parkland, the FPMRS clinic population base has been surging. The FPMRS physicians at UT Southwestern remain dedicated to rigorous controlled trials intended to objectively evaluate principles of non-surgical and surgical care consistent with the mission of the PFDN. With a growing, diverse clinical patient population, a committed and seasoned research team with a pedigree of successful internal and external collaborations, and the resources and expertise to champion additional translational PFD research, UT Southwestern is ready and energized to continue in the PFDN as a clinical site.

NIH Research Projects · FY 2025 · 2006-02

Project Summary Bacterial flagella function as two machines: a type III secretion system (T3SS) that secretes most of the extracytoplasmic components of the flagellum and a reversible rotary motor that promotes swimming motility required for many bacteria pathogens to infect hosts to promote disease. Peritrichous flagellates such as E. coli and Salmonella species have served as models to understand various processes for flagellar biogenesis and function. However, many significant bacterial pathogens, including Campylobacter jejuni, Vibrio cholerae, Helicobacter pylori, and Pseudomonas aeruginosa are polar flagellates that produce flagellar motors in limited numbers only at polar regions. These polar flagellar motors are characteristically more structurally complex than their peritrichous counterparts. By using C. jejuni as a model system to understand polar flagellar motor biogenesis and function in bacterial pathogens, we found that the increased structural complexity in polar flagellar motors is due to both unique structures and conserved substructures formed by a different collection of proteins. Importantly, these structural alterations enhance mechanical functions of both the C. jejuni flagellar T3SS and the rotary motor. We discovered that the C. jejuni flagellar T3SS has an enhanced ability to secrete flagellar proteins and assemble flagella even when lacking components usually essential for other T3SSs to function. Furthermore, we discovered the structural alterations in the C. jejuni flagellum contribute to a common feature of polar flagellar motors of many pathogens – the generation of higher torque for high motility velocities in a range of physiological viscosities. We also identified C. jejuni flagellar T3SS and motor components that promote its ability to multitask in cellular activities beyond motility. The major goal of this proposal is to analyze how these specific structures and substructures form and adapt the C. jejuni flagellum with enhanced mechanics to augment its function as a secretory machine and rotary motor. In Aim 1, we will analyze the composition and arrangement of proteins forming the C. jejuni flagellar T3SS and determine how fueling mechanics are altered relative to other T3SSs to allow it to secrete proteins and assemble flagella even without usually essential parts. In Aim 2, we will analyze how novel disk structures form and how the rotor component of the motor has expanded to affect the number and placement of stator units required to generate high torque for flagellar rotation and a high velocity of motility. In Aim 3, we will explore two C. jejuni proteins that we hypothesize function as a unique molecular brake or clutch to control output of a high-torque polar flagellar motor and regulate optimal motility velocities in different viscosities. Completion of these aims will provide new insights into many bacterial pathogens for: 1) how T3SSs can alter and ensure fueling to enhance secretory activity and organelle assembly; 2) how polar flagellar motors are naturally endowed to generate high torque for propulsion; 3) how novel substructures of polar flagellar motors form; and 4) how motility velocities facilitated by high-torque polar flagellar motors can be modulated in environments with different viscosities.

NIH Research Projects · FY 2026 · 2005-09

The Big South/West Node of the NIDA Clinical Trials Network (CTN) has been a part of the CTN since 2005 (originally as the Texas Node, expanding to the Big South/West Node in 2020). The Node is led by the shared leadership of Madhukar H. Trivedi, MD of University of Texas Southwestern Medical Center (UTSW), providing expertise in multisite clinical trials, and Steven Shoptaw, PhD of University of California Los Angeles (UCLA), providing internationally recognized expertise in stimulant use disorder (StUD). This fourth competing renewal application builds on our successful track record of leading CTN trials, being excellent network partners by providing exceptional sites for multi-site studies, high productivity in publishing, and training the next generation of scientists. During the 2020-2025 funding cycle, our team completed the largest pharmacotherapy trial for the treatment of methamphetamine use disorder to date (CTN-0068, ADAPT-2), which now has six publications and three additional manuscripts under review. We also developed and led four large randomized controlled concepts for novel interventions in adults with stimulant use disorders (CTN-0108 STIMULUS, CTN-0109 CURB-2, CTN-0110 MURB, CTN-0132 KMD) and two implementation study concepts for: universal screening and measurement-based care for buprenorphine treatment (CTN-0090, MBC4OUD), and remote methadone monitoring (CTN-0120, RMIST). For this renewal application, we capitalize on the experience of the PIs, who collectively have expertise in the treatment of StUD, treatment of and public health response to the opioid crisis, and treatment and care of comorbid conditions. Additional investigators bring content expertise spanning addiction science and clinical care, translational science, dissemination and implementation science, and trial implementation. Our geographical region is unique in that the South and West are experiencing a public health crisis of overdose deaths that involve stimulants. We will continue our efforts to conduct large multi-site studies on StUD treatments. In addition, our existing partnerships with primary care networks, emergency settings, and medical specialty care settings (e.g., cardio-pulmonary clinics) will allow us to scale up efficacious treatments in these healthcare settings. Our research agenda includes 1) conducting clinical trials on new and repurposed treatments for StUD; 2) implementing efficacious treatments in clinical settings to address comorbid conditions; 3) conducting implementation science to disseminate research findings and impact policy; and 4) exploring biomarkers to improve StUD treatments. Our team has experience with innovative study designs that target all areas of the translational science continuum and equip our Node to successfully and significantly improve the care of persons with StUD.

NIH Research Projects · FY 2025 · 2005-06

Project Summary The intestinal epithelium regulates the development of adaptive immunity to gut microorganisms, yet little is known about the underlying mechanisms. Filling this knowledge gap is crucial, as many human intestinal diseases arise from dysregulated intestinal immunity. Dietary vitamin A absorbed by the intestinal epithelium is essential for key intestinal adaptive immune responses, including the homing of T and B cells to the intestine and immunoglobulin A production. These vitamin A-dependent immune responses depend on specialized intestinal myeloid cells that enzymatically convert the vitamin A derivative retinol to retinoic acid (RA). In the previous project period we unraveled a molecular mechanism by which intestinal myeloid cells acquire retinol. We discovered that serum amyloid A (SAA) proteins – microbiota-inducible epithelial cell proteins – are retinol chaperones that deliver retinol to myeloid cells via the endocytic receptor LRP1 (low density lipoprotein-related receptor 1). We found that this mechanism is essential for the development of intestinal adaptive immunity and for immune protection against pathogenic bacterial infection. This R01 renewal application will build on these findings to further define the biochemical, cell biological, and microbiological mechanisms that regulate retinol delivery to intestinal myeloid cells and thus promote vitamin A-dependent immunity. In Aim 1, we will determine how SAA-retinol complexes are assembled and secreted from intestinal epithelial cells. In Aim 2, we will identify the SAA-LRP1 interface and determine its importance for myeloid cell retinol uptake and vitamin A-dependent immunity. In Aim 3, we will define the role of the intestinal microbiota in regulating myeloid cell retinol acquisition and vitamin A-dependent immunity. These studies will provide mechanistic insight into how vitamin A is mobilized to intestinal immune cells and advance our understanding of how the gut microbiota regulates the intestinal adaptive immune system. Our findings will help identify new strategies for inhibiting or enhancing vitamin A mobilization to the intestinal immune system in order to treat infection and inflammation.

NIH Research Projects · FY 2025 · 2004-09

Modified Project Summary/Abstract Section ADPRylation (ADPRylation) is a reversible of post-translational modification (PTM) of proteins resulting in the covalent attachment of ADP-ribose (ADPR) units derived from β-NAD+ on a variety of substrates. It plays key roles in the control of cellular processes, such as transcriptional regulation, that drive physiological outcomes, such as adipogenesis. ADPRylation is catalyzed by the poly(ADP-ribose) polymerase (PARP) family of enzymes, including the nuclear enzyme PARP-1. Although PARP-1 and ADPRylation have historically been linked to DNA repair, growing evidence now supports their role in the regulation of gene expression. However, key gaps in knowledge remain. For example, the molecular mechanisms underlying PARP-1-mediated gene regulation have not been fully elucidated in signal-regulated biological systems. Moreover, the role of site-specific ADPRylation as a mediator of tissue-specific physiological processes is poorly understood. Our recent studies have begun to address these questions. We have shown that PARP-1 modulates transcriptional responses in preadipocytes and macrophages that are (1) linked to site-specific modification of core histones and (2) controlled by signal-regulated transcription factors (TFs) (e.g., C/EBPβ). The long-term objective of these studies is to achieve a better understanding of the molecular, biochemical, genomic mechanisms underlying the control of signal-regulated transcription by PARP-1-mediated site-specific ADPRylation of key regulatory proteins, as well as the downstream physiological consequences of these regulatory events in adipose tissue. Our broad hypothesis is that the gene regulatory activities of PARP-1 are mediated through site-specific ADPRylation of histones and TFs. We will test this hypothesis using an integrated approach with a complementary of set tools from biochemistry, molecular biology, cell biology, chemical biology, proteomics, genomics, and mouse genetics. In addition, we will test specific mechanistic hypotheses related to the role of PARP-1 in signal-regulated gene expression driven by ADPRylation of histones and C/EBPβ in preadipocytes and macrophages in fat tissue. Our specific aims are to: (1) Explore the role of site-specific histone ADPRylation in signal-regulated gene expression in preadipocytes, as well as macrophages (Aim 1); (2) Determine how dynamic ADPRylation of C/EBPβ regulates enhancer function and target gene expression in macrophages (Aim 2); and (3) Determine the effects of site-specific ADPRylation of C/EBPβ on adipogenesis (Aim 3). Collectively, these studies will provide new insights into the molecular mechanisms of gene regulation by PARP-1-mediated site-specific ADPRylation in adipogenesis. Given the important role of PARP-1 in human disease, as well its potential “drugability,” our studies could lead to new ways to exploit these factors as therapeutic targets. Furthermore, our studies have the potential to reveal new information that will shape the future of the field and may shed light more generally on the functions of ADPRylation.

NIH Research Projects · FY 2026 · 2004-08

Project Summary / Abstract My long-term scientific goal is to understand the molecular mechanisms that specify retina cell number. Using the compound eye of Drosophila as an experimental model, my laboratory has discovered the Hippo pathway as a central mechanism underlying this process. The core of the Hippo pathway comprises a kinase cascade in which the Ste20 kinase Hippo (Hpo) phosphorylates and activates the NDR family kinase Warts (Wts). Wts, in turn, phosphorylates and inactivates the oncoprotein Yorkie (Yki) by excluding it from the nucleus, where it normally functions as a coactivator for the DNA-binding transcription factor Scalloped (Sd). Our research further established a critical role for the Hippo pathway in controlling organ size in mammals, underscoring the importance of Drosophila as a powerful model to discover universal developmental mechanisms. Despite recent progress in elucidating the molecular underpinnings of the Hippo signaling pathway, our understanding of this growth-regulatory pathway remains incomplete. In the current grant period, we have further advanced our mechanistic understanding of the Hippo pathway, including a critical role for Spectrin in coupling cortical tension, cell shape and Hippo signaling in retinal morphogenesis and the discovery of biomolecular condensates as a unified mechanism by which upstream regulators of the Hippo pathway integrate diverse physiological inputs into Hippo signaling. Our research also shed light on Hippo pathway evolution by uncovering a critical role for Hippo signaling in a unicellular relative of metazoans. Meanwhile, we continued to extend our Hippo pathway discoveries from Drosophila to mammalian biology. Highlights include our elucidation of default repression as well as polyamine biosynthesis and DNA demethylation as key transcriptional output of mammalian Hippo signaling and aberrant Hippo signaling as the pathological basis for epithelioid hemangioendothelioma (EHE). In the next grant period, we will further elucidate the molecular underpinnings of the Hippo pathway through the following specific aims. First, we will investigate the function and regulation of Slmap condensates in mechano- regulation of Hippo signaling. This aim will not only expand our understanding of Hippo pathway regulation by mechanical forces, but also define endoplasmic reticulum as a novel subcellular hub for mechano-transduction. Second, we will dissect the molecular and cellular mechanisms by which phosphatidylinositol-4-phosphate (PI4P) on plasma membrane integrates upstream inputs of Hippo signaling to regulate Merlin function. This aim will shed light on the control of plasma membrane PI4P level and distribution in developing tissues and define how diverse signals converge on PI4P to regulate Merlin function. Lastly, we will characterize novel regulators of the Hippo pathway identified from a sensitized genetic screen. This unbiased genetic approach will shed light on previously unforeseen regulators/mechanisms underlying Hippo pathway regulation. Besides revealing fundamental mechanisms of eye development, the proposed studies will have general implications for the development of other tissues.

NIH Research Projects · FY 2025 · 2003-02

Cholesterol is continually acquired by de novo synthesis or from the diet and must be metabolized or excreted in order to maintain cholesterol homeostasis. In vertebrate animals, cholesterol can be actively excreted via members of the ATP-binding cassette G (ABCG) subfamily. In the liver, cholesterol is secreted into bile by a heterodimer of ABCG5 and ABCG8 (G5G8). In the intestine, G5G8 limits the absorption of dietary sterols. Inactivation of G5 or G8 causes sitosterolemia, a recessive disorder associated with sterol accumulation and premature atherosclerosis. Another ABCG family member, ABCG1 (G1) also transports cholesterol. Unlike G5/G8, G1 functions as a homodimer and promotes the export of phospholipids and sphingomyelin, as well as cholesterol, from cells. G1 participates in the transport of cholesterol from peripheral tissues, where is it synthesized, through the circulation to the liver for excretion into bile. The overall goal of our research program is to determine how G5G8 and G1 promote the translocation of neutral sterols across biological membranes. In the last funding period, we used X-ray crystallography and cryo-electron microscopy (EM) to obtain high-resolution structures of nucleotide-free G5G8 with its cholesterol substrate at 2.7-3.0 Å resolution and both nucleotide-free and ATP-bound G1 at 3.1-3.7Å resolution. These results provided the first insights into the basic structure-function mechanisms of ABCG transporters and formed the basis of this grant application, which is designed to address 3 fundamental questions: 1) How do the conformations of G1 and G5G8 change during the transport cycle, and how do these changes relate to sterol translocation? 2) How do G1 and G5G8 recognize highly insoluble neutral sterols that are embedded in lipid bilayers and what accounts for the substrate specificity of the two transporters? And 3) How is substrate binding related to ATPase activity, and what is the structural basis for substrate-stimulated ATPase activity? Each of these questions is organized as a Specific Aim. The studies proposed take advantage of new developments in cryo-EM, our expertise in functional reconstitution of polytopic membrane proteins in vivo and in vitro, and our discovery of missense mutations in G5 and G8 with very specific effects on G5G8 and G1 function (e.g. large changes in substrate specificity or ATPase activity) that provide unique mechanistic insights. We have marshalled the reagents and expertise required to ensure successful completion of the studies proposed. Elucidation of the transport mechanisms of G1 and G5G8 will reveal how cells and organisms efflux lipids and maintain sterol balance, thus preventing two common disorders: coronary artery disease (CAD) and gallstones.

NIH Research Projects · FY 2025 · 2001-09

PROJECT SUMMARY Background: The coenzyme and metabolic substrate nicotinamide adenine dinucleotide (NAD+) is involved in hundreds of cellular reactions. Work from many groups now link acquired deficiency in NAD+ biosynthesis to enhanced susceptibility to acute kidney injury (AKI). Whether the benefits of NAD+ augmentation extend to chronic kidney disease is contested in the literature. Others and we observe persistent suppression from onset of AKI through to late time points of a critical bottleneck enzyme in one of the NAD+ biosynthetic pathways, quinolinate phosphoribosyltransferase (QPRT). This enzyme participates in an eight-step conversion of dietary tryptophan to NAD+. Among major organs, significant flux through this pathway is restricted in mammals to the kidney and liver. QPRT is the body’s sole metabolizing enzyme for quinolinic acid (Quin). Concomitant with persistent suppression of QPRT, systemic and renal levels of Quin accumulate in AKI and CKD, reaching a remarkable twenty-fold elevation in human circulation as CKD transitions to end-stage disease. Little is known about the renal biology of Quin; however, our preliminary data show that excess Quin is alone nephrotoxic, that excess Quin exacerbates renal fibrosis, that NAD+ augmentation cannot rescue late outcomes of AKI—whereas Quin disposal via QPRT can—and that even low concentrations of Quin can promote potent deleterious effects on multiple renal cell types. Hypothesis: In this application, we will test the central hypothesis that persistent suppression of the Trp- dependent biosynthetic pathway after an AKI insult results in Quin buildup to promote adverse late outcomes. Aims: Three Aims are proposed: (1) to test intra- vs. extra-renal strategies to deplete Quin in AKI models to examine prevention of AKI; (2) to compare the benefits of distinct renal tubular NAD+ biosynthetic pathways in the prevention and treatment of AKI by implementing inducible, tissue-specific transgenic models; and (3) to elucidate mechanisms of Quin nephrotoxicity through a combination of candidate and systems based approaches. Outcomes: To support these parallel Aims, we are joined by established collaborators and experts in the domains of metabolic assays, mitochondrial assessments, and experimental liver biology. The experiments span cells and in vivo models to address innovative, fundamental scientific questions that hold translational significance. Successful execution of this project may catalyze new pharmacological and nutritional approaches to foster resilience to acute kidney stress.

NIH Research Projects · FY 2026 · 2001-05

PROJECT SUMMARY This proposal is a reapplication from the University of Texas Southwestern (UTSW) Medical Center to participate as a clinical center in the Eunice Kennedy Shriver NICHD Neonatal Research Network (NRN). Myra Wyckoff, MD became Principal Investigator (PI) in September 2013 and will remain as PI. Luc Brion, MD and Roy Heyne, MD will continue to serve as Alternate PI and Follow-up PI, respectively. As an NRN clinical center since 1986, UTSW has the necessary academic, research and clinical infrastructure to assure continued rigor and reproducibility for NRN studies (Aim 1). UTSW Neonatal-Perinatal Medicine (NPM) Faculty have broad experience in translational and multi-center, randomized clinical trials with the NRN and other networks and will contribute to NRN concept proposals, studies, and publications. As an international leader in newborn resuscitation science, Dr. Wyckoff will provide the NRN with expertise on issues of perinatal transition, stabilization and resuscitation following birth. Other faculty will bring expertise in Neuro-Neonatal Intensive Care and hypoxic-ischemic encephalopathy (Dr. Chalak), oxygen use in the delivery room (Dr. Kapadia), placental effects on the fetus (Dr. Leon), gut microbiome (Dr. Mirpuri), breast milk and nutritional elements (Dr. Brion), use of clinical informatics for research (Dr. Lehman) and effects of perinatal interventions on metabolic syndrome and neurodevelopment (Dr. Heyne). UTSW will work to support trials from a wider range of investigators both within UTSW but also from investigators outside the core NRN centers (Aim 2) and to leverage resources for wider sharing of data and biospecimens (Aim 3). The NPM Division has consistent strong support from the UTSW Pediatric Department as well as its clinical facilities, Parkland Memorial Hospital (PMH), UTSW Clements University Hospital (CUH) and Children’s Medical Center (CMC) of Dallas. PMH has one of the largest inborn delivery services in the United States with ~12,000 births per year. CUH has a growing delivery service with a significant focus on high risk pregnancies and a state-of-the art facility. The CMC NICU is one of the largest referral units in the region and continues to expand its reach through telemedicine. The Obstetric Department at UTSW has active referral and research programs across all clinical sites which ensures that high-risk pregnant women deliver on our campus. The patient population at PMH and CUH is predominantly under-represented minorities of Hispanic ethnicity and/or Black/African-Americans. Their inclusion in clinical trials is essential to reduce frequent health disparities (Aim 4). A high percentage of eligible infants at UTSW clinical sites are enrolled in randomized trials. Protocols are meticulously followed and complete data is obtained. Follow-up of study infants is integrated within the infant’s primary medical home at CMC, and follow-up rates are among the highest in the NRN. Thus, UTSW has much to offer in support of the NRN.

NIH Research Projects · FY 2025 · 2001-02

PROJECT SUMMARY Mechanical interactions between cells and extracellular matrix (ECM) drive fundamental processes such as morphogenesis, wound healing, and organization of bioengineered tissues. Our research focuses on how these interactions regulate corneal keratocyte behavior through development of culture models that mimic the 3-D tissue environment, and use of multi-dimensional imaging approaches in vitro, in situ, and in vivo. In the previous funding period, we used these tools to perform a comprehensive assessment of the differentiation and patterning of corneal keratocytes following photorefractive keratectomy (PRK) surgery in the rabbit. These studies provided novel insights into the nature of the transition between native stromal and fibrotic tissue, and how cells use the collagen lamellae as a template for tissue remodeling and regeneration. Subsequent studies combining superficial phototherapeutic keratectomy (PTK) and UV cross-linking (CXL) showed that CXL induces a disruption in normal cell patterning within the stroma, and appears to block the development of fibrosis on top of the stroma. These studies highlight the profound impact that changes in corneal structure and stiffness can have on overall corneal wound healing responses. However, the large size and overall symmetry of standard CXL procedures extends the normal time course of healing after PTK, and limits the scope of biomechanical insights that can be made. Using our in vitro 3D culture models, we also performed mechanistic studies on how cell spreading and collective migration are regulated in fibrin matrices, and identified key roles for fibronectin, 51 integrin, and local cell-induced matrix reorganization in this process. We also demonstrated for the first time, that inhibition of vimentin filament organization alters corneal fibroblast spreading, morphology and motility in 3-D matrices. Vimentin has been associated with myofibroblast transformation of corneal keratocytes in vivo, and recent studies in other systems suggest it can play a central role in regulating key aspects of cell mechanical behavior, including mechanosensing, polarization, and directional migration. Based on these and other published and pilot data, we now propose to: 1) Investigate the effects of tissue stiffness and anisotropy on corneal wound healing following PTK, by applying UV cross-linking in specific patterns determined from finite element modeling simulations, 2) Establish the time course of cell differentiation and cell/matrix patterning during the development and resolution (remodeling) of fibrosis following full thickness incisional injury, and determine the effects of modulating the wound boundary conditions and mechanical environment on these processes, and 3) Apply our established 3-D culture models and engineered 2-D substrates to investigate the role of vimentin in regulating corneal fibroblast differentiation, patterning and mechanical behavior. Given the general importance of cell mechanics in numerous fields of cell biology, these findings could have broad significance.

NIH Research Projects · FY 2025 · 2000-09

Project Summary/Abstract Cellular signaling by estrogens plays a critical role in the development and physiology of a wide variety of tissues, including the reproductive organs, mammary glands, bone, heart, vasculature, adipose, liver, and central nervous system, as well as diseases of the same tissues. Within an individual, estrogen levels may fluctuate dramatically and acutely across multiple time scales: hours, days, months, years, and decades. The circulating levels of 17b- estradiol (E2), the predominant naturally-occurring estrogen, fluctuate dramatically in women from lows of ~70 pM to highs of ~1.8 nM in the non-pregnant state. In contrast, most molecular, cellular, and genomic studies use saturating supraphysiological levels of E2 (e.g., 10-100 nM). Although the importance of dose, and the frequency and duration of administration, have long been recognized as important aspects of the therapeutic use of steroid hormones, the effects of physiological doses of E2 on molecular, cellular, and genomic endpoints have not been well characterized. Our proposed studies will address these key gaps in knowledge. The molecular actions of E2 are mediated through estrogen receptor proteins (e.g., ERa), which function primarily as ligand-regulated transcription factors that drive cell type-specific patterns of gene expression by promoting the coordinated assembly of transcriptional enhancers at ERa binding sites. There is a growing interest in the mechanisms and functions of signal-regulated enhancers, but many questions remain. For example, we do not have a detailed understanding of (1) how different doses of E2 may differentially regulate the assembly and function of ERa enhancers across the genome and (2) how different dose sensitivities of ERa enhancers may lead drive distinct biological outcomes in different estrogen-responsive biological systems. The overarching goal of these studies is to gain a better understand the molecular mechanisms by which E2 controls ERa enhancers to regulate gene expression and downstream biological outcomes. Our broad hypothesis, which is supported by considerable preliminary data, is that different ERa enhancers and target genes exhibit different sensitivities to the dose of E2, specifying different classes of enhancers with different mechanisms of action. We will test this hypothesis in two ERa-positive cell types (i.e., human breast cancer cells and primary mouse myometrial cells) using an integrated set of experimental approaches. Our specific aims are to: (1) Characterize dose-effects of E2 on molecular and genomic endpoints of estrogen signaling (Aim 1); (2) Determine the molecular mechanisms by which different doses of E2 promote enhancer activity (Aim 2); and (3) Explore genetic determinants underlying dose-effects of E2 on biological endpoints (Aim 3). Our studies on the molecular mechanisms and functions of ERa enhancers seek to challenge and expand current approaches and biological models for studying the mechanisms of steroid hormone signaling. These studies will yield new knowledge about the molecular mechanisms of E2 signaling; a diverse collection of genomic data; and new concepts about E2 signaling that may suggest new ways to target ERa therapeutically.

NIH Research Projects · FY 2024 · 2000-05

Adipocytes are professional secretory cells. Many adipose tissue-secreted signaling mediators (adipokines) have been identified since the discovery of leptin and adiponectin. As such, much has been learned about how adipose tissue communicates with other organs of the body to maintain systemic homeostasis. Beyond proteins, additional factors such as lipids, metabolites, non-coding RNAs and extracellular vesicles released by adipose tissue participate in this process. However, major gaps still persist in our basic understanding of how leptin and adiponectin achieve their profound actions on target cells. In this renewal application, we focus on adiponectin, a protein we first described in 1995. The previous funding period has shed much light on how adiponectin and its receptors achieve anti-inflammatory, anti-apoptotic and insulin sensitizing effects through the ceramide axis, primarily through gain-of-function approaches. In the proposed studies in this application, we aim to elucidate why adiponectin knock out models generated by different groups give rise to seemingly different metabolic phenotypes. In preliminary studies, we attribute this phenomenon to different strategies for gene elimination. While our own knock out mouse completely lacks all relevant exons for the adiponectin gene, other models leave behind exon 3 that has the potential to encode a non-secreted form of globular adiponectin. We believe it is this remnant fragment that is responsible for the different phenotypes. Furthermore, we believe that endogenous adiponectin, even in the absence of any gene manipulation, may also have a non-secreted, cytoplasmic / nuclear form that exerts unique functions locally in adiponectin expressing cells. In fact, adiponectin is expressed in the proximal tubules of the kidney, specifically in the cortex. We show that adiponectin exerts a major role on renal gluconeogenesis. Adiponectin is also expressed in hepatic stellate cells, where it prevents the activation of stellate cells into fibrotic myofibroblasts. Inducible gain- and loss-of-function experiments will shed more light on the relevance of these phenomena. Finally, we are well positioned to eliminate both adiponectin receptors inducibly in target cells in the adult animal. This has not been possible so far due to embryonic lethality of double-knock out animals. We will focus our efforts initially on the hepatocyte and the adipocyte, in which we will inducibly eliminate both adiponectin receptors. Combined, these experiments will significantly broaden our knowledge of adiponectin function in “non-conventional” areas of metabolism studies. “Non-conventional” in the sense of adiponectin expression in cells other than adipocytes. Furthermore, “non-conventional” in the sense of adiponectin action not mediated through its passing through the secretory pathway, but rather through its actions as a non-secreted fragment in the cytoplasm and/or nucleus. Particularly the latter efforts have been inspired by studies in the various adiponectin knock out models, which have given rise to a large amount of confusing and discrepant data that we aim to explain and clarify for the field.

NIH Research Projects · FY 2025 · 1997-09

PROJECT SUMMARY/ABSTRACT The University of Texas Southwestern Medical Center (UTSW), one of the premier academic medical centers in the world, requests continued support for a graduate and post-graduate Molecular Microbiology Training Program (MMTP) that has existed for 25 years. This MMTP supports five predoctoral students and two postdoctoral fellows for two-year training periods each. A particularly attractive feature of this highly successful training program has been its departure from conventional "program-" or "departmental-based" training to an interdisciplinary program that maintains a strong microbiology orientation while, at the same time, broadens the scope of the training mission to include many other aspects of molecular and cell biology. The highly diverse backgrounds of the 31 trainers, comprised of a core group of highly accomplished established investigators and an expanding, impressive new faculty, embody interdisciplinary research programs bound by the common theme of molecular and cellular microbiology. The training faculty are from nine different departments (Microbiology, Immunology, Cell Biology, Molecular Biology, Pharmacology, Biochemistry, Internal Medicine, Dermatology, and Pediatrics). The MMTP serves as a primary focus for formal interactions among this overlapping group of talented trainers who have strong records of accomplishment in research and training. Our goal is to train students and fellows for research careers in the general areas of the molecular basis of microbial pathogenesis, cellular microbiology, host defense mechanisms, regulation of virulence expression, pathogen adaptation, drug development, structural biology, and many other related areas. The research interests of the majority of the faculty include bacterial and viral pathogenesis, innate and adaptive immune mechanisms, antimicrobial drug design, RNA metabolism, bacterial secretion systems, microbial physiology, viral evolution, and structural biology (as it pertains to microbial pathogenesis). There is a strong emphasis on molecular mechanisms, molecular biology, and the application of the most contemporary methods in molecular technologies, all of which provide the thread that unites and integrates the diverse research areas. Trainees who complete this program are expected to be able to apply state-of-the-art molecular approaches towards important problems in the microbiological sciences and for the improvement of preventive and/or therapeutic intervention strategies for infectious diseases. There is solid evidence of major successes for this training program over the past funding interval.

NIH Research Projects · FY 2024 · 1997-09

Overall SPORE Summary/Abstract Targeting Lung Cancer Vulnerabilities. The University of Texas SPORE in Lung Cancer represents a unique collaboration between the University of Texas Southwestern Medical Center (UTSW) and the University of Texas MD Anderson Cancer Center (MDACC), both of which have outstanding strengths in lung cancer translational and clinical research. The overarching goal of the SPORE is to develop new therapeutic paradigms based on recently identified “vulnerabilities” acquired during lung cancer pathogenesis, including a molecular understanding of lung cancers in individual patients, and using this information to “personalize” therapy for each lung cancer patient. Thus, our strategy is to identify lung cancer “therapeutic quartets” which include: 1. a specific vulnerability; 2. the mechanism of action thus defining therapeutic target(s) for the vulnerability; 3. a deliverable treatment for the target(s); and 4. tumor molecular biomarkers for the vulnerability predicting specific therapies for each patient. The UT Lung Cancer SPORE builds on a 20-year productive history, incorporating recent advances made by our SPORE investigators and the rest of the lung cancer translational research community in the molecular and mechanistic understanding of tumor autonomous and microenvironment changes, acquired vulnerabilities, and important immuno-oncology effects. These advances include novel approaches to identifying and molecularly classifying vulnerabilities in lung cancer metabolomic changes, cancers immunologically “inert” to PD1/PD-L1 checkpoint blockade, the lung cancer fibrotic stroma (microenvironment), and tumorigenesis-induced replication stress. Our contributions also include preclinical human and mouse model systems for testing the different vulnerabilities, as well as large legacy molecular and clinically annotated preclinical model and clinical specimen datasets. The SPORE is composed of 4 projects, all of which have Human Endpoints: 1. Targeting metabolic vulnerabilities in lung cancer; 2. Targeting vulnerabilities in immunologically-inert lung cancer; 3. Targeting vulnerabilities in the fibrotic extracellular matrix (ECM) of lung cancers; and 4. Therapeutic targeting of oncogene-induced replication stress for tumor cell killing and anti-tumor immunity in small cell lung cancer (SCLC) (which includes a clinical trial targeting replication stress combined with immune checkpoint inhibtion. There are three cores: A. Administrative (including patient advocates); B. Molecular Pathology and Tissue Resources; and C. Data Sciences, as well as strong Developmental Research and Career Enhancement Programs (DRP, CEP). Our SPORE features leading lung cancer multi-disciplinary clinical and laboratory scientists, a cadre of experienced patient advocates, and an outstanding publication record. Moving forward, this SPORE will provide information on newly identified lung cancer acquired vulnerabilities, biomarkers for personalizing individual patient therapy, and important preclinical and information to facilitate clinical translation that has the possibility of changing the face of lung cancer therapy.

NIH Research Projects · FY 2026 · 1997-01

The UT Gastroenterology / Hepatology research training program is aimed at producing the next generation of scientific leaders focused on understanding digestive and liver diseases. The program involves a variety of disciplines broadly categorized into two main areas: basic scientific research and patient-oriented clinical and translational research. The training program accepts individuals with a clinical training background in Internal Medicine (M.D. or M.D./Ph.D. candidates), as well as in Pediatrics, Surgery or Pathology. In addition, trainees without clinical training (Ph.D. candidates) are also part of our program. Trainees benefit from a vast array of potential mentors including 45 Faculty that participate directly in this program, as well as a very rich milieu of scientific investigators across our campus. The scientific base of the training program includes research expertise in multiple areas critically important to the field, including 6 main themes: (i) immunity, (ii) microbial effectors, (iii) cancer biology, (iv) metabolism and fatty liver, (v) nutrition and obesity, and, (vi) development and stem cell biology. The training curriculum is flexible, but has two basic components. First, all of our trainees participate in a structured lecture series that highlights cutting edge research in fields of gastroenterology and hepatology, and career development training offered through the postdoctoral affairs office, which includes a course in responsible conduct of research as well as other pertinent training experience for this stage of career development. A number of ad hoc training experiences are also devised to address gaps of individual trainees. In addition to core educational activities, direct training in research takes place primarily under the research mentor’s guidance in a basic laboratory or as part of a clinical research group. Typically, our trainees devote 2 to 3 years to their research training. The basic science training experience includes learning a variety of techniques in biochemistry, physiology, molecular biology and genetics, as well as participation in works-in-progress seminars and national or international scientific meetings relevant to the particular discipline. On the other hand, clinical and translational research involves formal training in study design, including ethics and biostatics, through formal training programs offered at our University. Finally, for our trainees with a clinical background in Internal Medicine, this research training program is integrated with our clinical fellowship in Gastroenterology and Hepatology, which includes a minimum of 18 months of dedicated clinical rotations. Therefore, in most instances the training period will last from 4 to 6 years for the six individuals for whom support is being requested. Altogether, this program is designed to train individuals who will be effective investigators and academic leaders in the fields of Gastroenterology and Hepatology.

NIH Research Projects · FY 2024 · 1994-12

Project Summary This proposal represents the continuation of our long-running program to understand the biology of polyamine metabolism in the trypanosomatid parasites and to exploit the pathway for drug discovery. Trypanosomatids are the causative agents of human African trypanosomiasis (HAT), Leishmaniasis and Chagas disease, all of which are listed by the WHO as neglected tropical diseases (NTDs). Collectively 18-20 million people are infected with one of these parasites, yet drug therapies remain inadequate for all three diseases. Polyamines are small organic polycations that are synthesized from L-ornithine and S-adenosylmethionine. In eukaryotes, the polyamine spermidine is absolutely essential for growth due to its role as a substrate for the hypusine modification of the translation factor eIF5A. Eflornithine, which inhibits the polyamine biosynthetic enzyme ornithine decarboxylase (ODC), is a frontline therapy for the treatment of HAT. Interest in understanding the biology and regulatory mechanisms of this pathway led to the finding that, while the trypanosomatids share in common the essential role for hypusination, they have evolved both unique polyamine-containing metabolites and their own regulatory strategies in comparison to other eukaryotic cells. This includes our discovery that two of the biosynthetic enzymes S-adenosylmethionine decarboxylase (AdoMetDC) and deoxyhypusine synthase (DHS) each require oligomerization with inactive pseudoenzmes for activity. Despite significant understanding of the metabolism and biological roles of polyamines in trypanosomatids, a number of key questions remain unexplored and are the subject of this proposal. In Aim 1, we plan studies to build on our observation that the AdoMetDC pseudoenzyme (termed prozyme) is translationally regulated in response to perturbations that reduce levels of the product decarboxylated AdoMet, suggesting dcAdoMet functions as a novel metabolic signal for regulation of the polyamine pathway. In Aim 2, we will focus on unexplored metabolic pathways and functional roles of the upstream polyamine metabolites L-Orn and Put. Our questions are: does Put play additional roles beyond its requirement as a precursor for Spd synthesis; and can T. brucei synthesize L-Orn using an uncharacterized amidinotransferase. In Aim 3, we will study the function and composition of enzymes (DHS and deoxyhypusine hydroxylase (DOHH)) required to modify eIF5A with the hypusine cofactor. Our approaches will be a combination of genetic strategies and pharmacologic tools to perturb cell metabolism, state of the art metabolomics, genomic strategies to identify candidate genes, and biochemistry (protein expression, enzyme assay and crystallography). While our work will focus on T. brucei, the unusual metabolic features of this pathway have been found in all three pathogenic trypanosomatids, so it is likely that the discoveries we make in T. brucei will translate to T. cruzi and Leishmania. Finally, while our past grant also focused primarily on biological discovery, the results from our work laid the foundation for us to spin off two separate drug discovery programs targeting the trypanosomatids.

NIH Research Projects · FY 2024 · 1982-07

PROJECT SUMMARY The MD/PhD program at University of Texas Southwestern Medical Center has been in existence since 1978 and continuously funded as an NIH Medical Scientist Training Program since 1982. The goal of the program is to train the next generation of diverse physician scientists as leaders in biomedical research and academic medicine, helping meet the urgent needs identified by the NIH for the future biomedical and translational research workforce. Program alumni include a dean, department chairs, two MSTP directors, and many faculty members at leading academic medical centers. Outcomes of trainees in the past 15 years, described in this application, are excellent; 91% of graduates who have completed all their training are physician-scientists in academia or industry. Attrition over this same period was 7.6%. The large institutional commitment to the program is evidenced by the investment of significant resources to pay for stipend and tuition costs not covered by NIH, program administration, operations, and salary support for committed effort by the directors. Our program integrates rigorous predoctoral training in basic biomedical sciences leading to the PhD degree with intensive medical education leading to the MD degree, producing graduates who are superbly prepared to become physician-scientists engaged in translational research. The MD and PhD phases of training are distinct, but with numerous integrative and social activities, including seminars, retreats, dinners, journal clubs, grand rounds, to promote program cohesion and inculcate identity among trainees as future physician- scientists. There are presently 90 trainees in the program, all of whom are fully funded. Continued funding of 22 slots is requested to partially support trainees, generally for 24 months.

NIH Research Projects · FY 2025 · 1978-07

We seek support for the continuation of a highly successful, multi-center and multi-departmental training program at UT Southwestern Medical Center that provides M.D. and Ph.D. trainees with a firm basis in state-of-the-art methodologies, in addition to preparing them for future academic careers in metabolism research. The program under the auspices of this T32 has been running for the past 44 years. Established investigators from several Departments and a number of Centers join forces to provide our trainees with a multi-facetted and diverse training program. Participating Centers include the Touchstone Center for Diabetes Research, the Center for Hypothalamic Research, the Center for Human Nutrition, the Advanced Imaging Research Center, the McDermott Center for Human Genetics, Center for the Genetics of Host Defense and the Simmons Cancer Center. Areas of expertise include systemic and cellular metabolism, diabetes, lipid biosynthesis, obesity, human genetics related to metabolic disorders and tumor metabolism. Our T32 mentors direct highly competitive research programs of national and international stature. Our trainees can take advantage of a very strong research infrastructure that allows them to address physiological, biochemical and cell biological problems with emerging technologies and the latest instrumentation. The 56 mentors are chosen from a tightly interwoven, highly integrated group of investigators, which cover all of the relevant areas in metabolism research and a number of sub-specialties in endocrine research. Metabolism research at UT Southwestern has flourished over the past 15 years, due to the programmatic expansion over the previous period from 2007-2022. The school has made a major commitment towards complementing existing areas of expertise by targeted recruitment of key personnel to fill existing gaps over the past decade. Here, we build upon the historic strengths of our training program, while taking advantage of the programmatic expansion experienced at UT Southwestern. This T32 is an important cornerstone of metabolic research at UT Southwestern. We have implemented a number of changes that have proven highly successful to further improve the quality of our training experience. During the previous funding period (2018-2022), 7 trainees completed the program, or are currently in the program; most of which have successfully applied for external funding. The current epidemic of obesity and its pathophysiological sequelae is on an exponential rise. It is paramount to train the next generation of metabolism researchers and endocrinologists to cope with this enormous public health problem, and further, to develop innovative approaches to combat metabolic dysfunction. Furthermore, we now appreciate that we are facing a serious public health issue in light of the fact that Covid-19 further increases the potential to become a type 2 diabetic risk if certain factors are already present at the time of infection. We aim to train the next generation of researchers that will be able to successfully shed light on the mechanistic basis for metabolic dysregulation in this context.