Washington University

NIH Research Projects · FY 2025 · 2006-09

Abstract Cancer is a major public health problem worldwide and the second leading cause of death in the United States. Molecular oncology is an interdisciplinary medical specialty at the interface of medicinal chemistry and oncology that refers to the investigation of the molecular basis of cancer and tumors and the development and application of targeted therapies. The field includes a diverse group of investigators with strengths in cancer stem cells, DNA damage repair and genomic instability, tumor-host interactions, and other fundamental areas of cancer biology. Areas of scientific focus in our program include basic cancer biology, computational oncology, solid tumor oncology, and hematopoietic malignancies. The Molecular Oncology Training Program at Washington University proposes to train the next generation of basic scientists, including 4 predoctoral and 4 postdoctoral trainees per year. Predoctoral PhD students follow the curriculum of the Washington University graduate school. After passing their qualifying examination, they enter the laboratory of participating faculty Mentors for 3-4 years of laboratory research to complete their dissertation. Postdoctoral Ph.D. trainees from around the world apply to participating laboratories. The duration of postdoctoral training depends on prior experience, but typically they conduct research for 2-3 years before transitioning to an independent research position. The current training program provides funding for 2 years for each trainee within a structured program. Trainees receive intensive mentoring and career counseling, participate in program- specific annual retreat, didactic course and clinical-translational mentoring rotations, journal clubs, and a variety of specific scientific and career building workshops, as well as training in Methods for Enhancing Reproducibility. Other courses, including those in Responsible Conduct of Research, are provided by the Washington University graduate school and the Institute of Clinical Translational Science. Completion of this program will prepare talented trainees for careers in basic and translational cancer research, to make discoveries that will transform the diagnosis and treatment of malignant disorders.

NIH Research Projects · FY 2025 · 2005-07

Overall: Project Summary/Abstract “Antecedent Biomarkers for Alzheimer Disease: The Adult Children Study” (ACS) will determine when during the lifespan molecular markers of Alzheimer disease (AD) appear in the brain of cognitively normal, largely middle-age individuals and also will characterize the course of preclinical AD. With maturation of the original ACS cohort, we now will identify the factors that mediate the transition from preclinical AD to symptomatic AD (the latter term in this application is used to encompass both mild cognitive impairment due to AD and AD dementia). This renewal application examines the hypothesis that disrupted neural integrity predicts the transition from preclinical to symptomatic AD and thus proposes four Cores (Administration, Clinical, Fluid Biomarker, and Data Management and Biostatistics) to support four Projects: Project 1 (JC Morris and T Benzinger, Co-Project Leaders), “Tau burden and spatial spread in preclinical Alzheimer disease”; Project 2 (AM Fagan, PL), “Plasma and cerebrospinal fluid (CSF) biomarkers that predict risk for symptomatic Alzheimer disease”; Project 3 (B Ances, PL), “Alzheimer disease progression, host gut microbiome, and enteric dysfunction”; and Project 4 (D Head, PL), “Mechanisms and moderators of the effects of physical activity in preclinical AD”. Although these Cores and Projects each address unique Specific Aims, they will generate a wealth of cross-sectional and longitudinal data from ACS participants to permit a cohesive and comprehensive examination of the overarching Aims of this renewal application. Hence, the ACS as a whole is far greater than the sum of its Cores and Projects.

NIH Research Projects · FY 2025 · 2004-04

The senses of hearing and balance are mediated by the cochlea and vestibular organs of the inner ear. In these organs, mechanical motion (generated either by sound vibrations or by head movements) is detected by sensory hair cells and transmitted to the brain by the auditory and vestibular nerves. Hair cells are essential for sensory function, but can be injured by noise exposure, ototoxicity or infections, and are also lost as a consequence of normal aging. After injury, the timely removal of cellular debris from the sensory epithelium helps promote repair and homeostasis. This process is mediated by two distinct cell types: (1) Supporting cells, which can engulf cellular debris and – in nonmammalian vertebrates – generate replacement hair cells, and (2) Macrophages, which are effector cells of the innate immune system that also recognize and engulf dying cells. Supporting cells are present in all hair cell-containing epithelia. The tissues of the inner ear also contain resident populations of macrophages, and macrophage-mediated inflammation occurs after most types of otic injury. When responding to hair cell injury, it is critical that both supporting cells and macrophages correctly distinguish between healthy and dying cells, and then target and remove only those cells that are irreversibly damaged. A key objective of this project is to understand how this process occurs. One set of experiments will examine a signaling pathway known to be essential for evoking phagocytic responses in macrophages and other cell types, but has not been previously studied in the inner ear. In addition, we will determine whether inhibiting phagocytosis after acute injury may permit some damaged hair cells to survive, and whether the engulfment of injured hair cells is an important trigger for sensory regeneration. Studies will employ both mammalian and zebrafish models, in order to best utilize the unique advantages of both systems. A second set of experiments will enhance our very limited knowledge of the role of inflammation in the vestibular organs. Projects will focus on two clinically relevant situations. First, it is known that prenatal infection with cytomegalovirus (CMV) can cause developmental deficits in both hearing and balance, but the underlying mechanisms are completely unknown. Using a validated mouse model, we have shown that CMV infection leads to a massive inflammatory response in the vestibular maculae, which is accompanied by phagocytosis of sensory cells. We will determine whether this inflammation is the cause of CMV-induced pathology and also whether macrophages transport CMV into the vestibular periphery. Additional studies will characterize vestibular injury and inflammation in a mouse model of cochlear implantation. Completion of the studies will greatly enhance current knowledge of the cellular signals that regulate inflammation in the inner ear. Such knowledge will permit development of methods for modulating such inflammation, so as to reduce pathology and enhance functional recovery after injury.

NIH Research Projects · FY 2026 · 2004-04

This proposal seeks continued funding for the Tetrahymena Stock Center to enable maintenance of its current operations, expand its capabilities, and ensure its sustainability as the primary resource for the preservation and distribution of genetically defined strains of Tetrahymena. Investigations aimed at understanding Tetrahymena biology have contributed many novel and important findings on cellular mechanisms that have direct relevance to human health and disease including cancer, infertility, and aging. Tetrahymena has also shown great promise as a platform for the production of recombinant proteins, including vaccine antigens and difficult-to-express human ion channels. Furthermore, it serves as an engaging teaching tool in K-12 and undergraduate classrooms. Specifically, our overall aims for the resource are to 1) continue to act as a strain repository accepting new strains and making cultures of Tetrahymena available to scientists and science educators at reasonable cost; 2) expand the resource by integrating additional large collections; 3) increase the visibility of Stock Center resources and increase publication of research findings by partnering with microPublications Biology; 4) curate new genomic information into the Tetrahymena Genome Database; 5) improve curation of stocks by assigning RRID designations to new acquisitions and use bioinformatics to link genes associated with specific stocks to human disease-associated genes; 6) increase the interoperability of genomic data by updating the current gene annotations and expanding the use of Gene Ontology designations; 7) facilitate new analyses by displaying gene expression data sets; 8) improve the Stock Center website and increase its capacity to gather assessment data; 9) use genomic data to identify the genetic lesions of strains in the repository with striking phenotypes thereby spurring additional research; 10) optimize gene knockout strategies to allow for timely completion of Tetrahymena strain engineering services offered by the Stock Center. Together, these activities aim to keep Tetrahymena at the forefront of biomedical research and achieve the Overall outcome of increasing research capacity of investigators using ciliates to make significant discoveries.

NIH Research Projects · FY 2025 · 2003-06

Abstract Zinc is an essential nutrient that profoundly affects human health, since ~10% of the proteome binds zinc. A key to zinc homeostasis is storage during times of excess and release during periods of deficiency. Lysosomes, which have a well-established role in the degradation of macromolecules, are emerging as a conserved site of zinc storage. How lysosomes integrate the dual functions of zinc storage and degradation is not well defined. Our data indicate that lysosomes mediate these dual functions in separate compartments. We used C. elegans to demonstrate excess zinc is stored in lysosomes of intestinal cells; CDF-2 (ZnT2 in mammals) is the SLC30 family transporter that loads zinc into lysosomes, and ZIPT-2.3 is the SLC39 family transporter that releases zinc. Reciprocal regulation of CDF-2 and ZIPT-2.3 regulates the direction of zinc flow; in excess zinc, CDF-2 is upregulated to increase storage and ZIPT-2.3 is downregulated to decrease release. How do lysosomes rapidly change the composition of transporters on their surface? Using super-resolution microscopy, we discovered that lysosomes have an expansion compartment connected to the acidified central compartment. The expansion compartment is contracted in zinc-replete conditions, but grows dramatically in response to high zinc. Our overall hypothesis is that the expansion compartment allows the rapid delivery of CDF-2 to lysosomes to promote zinc homeostasis –without disturbing degradative processes in the acidified compartment. This hypothesis is innovative, since we only observed the expansion compartment with the recent availability of super-resolution microscopy. To determine if this mechanism is conserved, we examined lysosome dynamics in mammalian cells; the ZnT2 zinc transporter alters its localization on lysosomes in response to high zinc, consistent with lysosome remodeling. To test the predictions of our model, we will characterize the molecular nature of the compartment, identify transcriptional changes during assembly and disassembly, and validate our findings in mammalian cells. Specific Aim 1, First, we will use TEM to determine whether lysosomes have a second membrane-bound compartment that contains CDF-2. Second, we will use X-ray fluorescence microscopy to test whether zinc is sequestered in this structure. Specific Aim 2, we will extend these findings to mammalian cells. We will test whether the ZnT2 transporter is required to store zinc, identify the ZIP protein that releases zinc, and test whether these transporters are reciprocally regulated to remodel lysosomes. Specific Aim 3, we will analyze the regulation of lysosome remodeling. We demonstrated that the lysosome biogenesis regulator HLH-30 (TFEB in mammals) is required for remodeling. We will determine how the transcriptional response to high zinc mediates lysosome remodeling. These studies will have a major impact by defining a new aspect of lysosome biology that is critical for zinc homeostasis.

NIH Research Projects · FY 2025 · 2003-04

OVERALL PROJECT SUMMARY This competitive renewal application (P01CA100730) seeks funds to continue our highly integrated studies of retrovirus models to elucidate cellular mechanisms of lymphocyte transformation and associated lymphoproliferative disease. Infection of CD4+ T-cells with the human retrovirus, human T-cell leukemia virus type 1 (HTLV-1), induces their immortalization and enables those cells to accumulate genetic mutations leading to the lymphoproliferative malignancy, adult T-cell leukemia lymphoma (ATLL). The advantage of the HTLV-1 model to study leukemogenesis is the rapid induction of T-cell immortalization brought about by the viral infection. This model of leukemogenesis allows careful examination of the biologic changes and response patterns of virus infected preneoplastic cells while under the influence of cellular and viral factors that control and perhaps promote progression to cancer. In the previous funding period we made substantial advances in our understanding of: 1) how the HTLV-1 transforming gene, hbz, contributes to cell immortalization; 2) how chromatin insulator, CTCF, controls HTLV-1 gene expression and pathogenesis; 3) and how HTLV-1 infected cells contribute to bone destruction through production of extracellular vesicles; and 4) how ATLL can be targeted for anticancer therapy and HTLV-1 infection prevented by an envelope mRNA vaccine. In the next funding period, the overall theme of the Program Project is to continue our studies with the HTLV-1 lymphoproliferative disease model with a focus on discovering how key viral, cellular and microenvironmental factors work in concert to promote T-cell malignancy. We now recognize three interrelated areas of study that are major gaps in our understanding of the pathogenesis of HTLV-1-associated T-cell leukemogenesis: 1) Immune correlates of prevention and treatment with envelope and hbz vaccines; 2) The effect of HTLV-1 chromatin insulators on T- cell immortalization, reactivation from latency, and contribution to the transition to and progression of ATLL, and; 3) Bone microenvironmental factors that contribute to the survival and expansion of HTLV-1-infected T-cells and their progression to ATLL.

NIH Research Projects · FY 2026 · 2002-07

This proposal is the third renewal application for support of the Pediatric Physician-Scientist T32 training program in the Department of Pediatrics (DOP) at Washington University School of Medicine (WUSM). Pediatric physician-scientists play a crucial role in advancing knowledge that improves child health. To meet the ongoing national need to replenish the pediatric physician-scientist pipeline at the clinical post-postdoctoral fellowship level, our program supports a mentored career development pathway for 4 Trainees per year (typically for 2 years each) by leveraging a wealth of biomedical research resources across the WUSM campus, the DOP and our Child Health Research Center (NICHD CHRCDA K12). For the past 20 years and going forward, the long-term objective of this program is to develop Trainees who focus their research efforts on pediatric disease-oriented biology by applying recent advances in the basic and translational sciences, such as developmental biology, cell biology, immunology, genetics, multi-omics systems biology, and bioinformatics. The specific aims of this program are to provide selected pediatric subspecialty fellow Trainees with 1) protected mentored research experiences with well-established investigators across a wide range of disciplines related to child health at WashU Medicine and its Department of Pediatrics, 2) NIH-compliant educational programs in laboratory management, scientific rigor, biostatistics, grantsmanship, responsible conduct of research, and biomedical informatics, 3) individualized specific coursework based on each Trainee’s area of investigation (e.g., genomics, computational biology, biostatistics), 4) ongoing constructive feedback to Trainees, mentors, and program leadership, and 5) a flexible environment that facilitates the individualized development of Trainees to achieve their career goals. The program, now 20 years old, has an excellent track record by exceeding national benchmarks (15-year T to K conversion rate = 52%; this cycle = 57%), and will ultimately close the knowledge gap between basic/translational scientists and pediatric clinicians. Gary A. Silverman, M.D., Ph.D., and David Hunstad, M.D. again serve as the Program Director, and the Training Director, respectively. Our Trainees will continue to utilize a vast array of institutionally funded, state-of-the-art research core facilities that provide, for example, whole-genome/exome DNA sequencing, single-cell RNA sequencing, induced pluripotent stem cells and organoids, bioinformatics, cryo-EM and other advanced imaging, CRISPR-CAS9 genome editing and model animal development, to facilitate the study of pediatric disease states. The long-term goals of this program are being realized as its Trainees contribute to our understanding of development and childhood diseases for decades to come, while evolving into the next generation of scientific leaders, role models, and mentors for subsequent generations of pediatric physician- scientists.

NIH Research Projects · FY 2025 · 2002-07

The Brown School at Washington University, together with the School of Medicine, is seeking an additional five years (years 21-26) of support for a pre-doctoral and post-doctoral research training program, called Transdisciplinary Training in Addictions Research (TranSTAR). Funded since 2002, this program reflects an integration of social work and medicine in the development of services to, treatment of, clinical correlates of and policies that affect populations impacted by poverty and disease and vulnerable to substance use disorders and co-occurring and comorbid conditions. Maximizing an effective transdisciplinary collaboration between the two schools, the program provides a stimulating and collaborative research training environment to produce exceptionally well-trained addictions researchers. Organized into four cores (Substance Use and Mental Health, Populations, Translational, and Methods), TranSTAR faculty are particularly well-suited for addressing challenging addiction research topics (e.g., polydrug users, non-treatment seeking, incarcerated populations, mental health/health comorbidities) and populations disproportionately impacted by social determinants of health including poverty, housing insecurity and educational disparities. TranSTAR holds a stellar training record: 100% of pre-doctoral and post-doctoral trainees who have completed training in the most recent two funding cycles are addictions researchers, with excellent records of publications and acquisition of funding. The record is similarly positive when the entire cohort of past trainees is assessed. With a highly diverse training faculty, led by two faculty from social work and psychiatry, TranSTAR has demonstrated success in recruiting and retaining a productive cohort of pre-doctoral and post-doctoral trainees. Further, TranSTAR leverages successes and “lessons learned” with on-going monitoring and evaluation to ensure that trainees (three pre- and two postdocs/year) have the necessary knowledge and skills to: (1) conceptualize meaningful research questions with practical service and policy implications; (2) execute rigorous, cutting-edge empirical studies; (3) develop competitive grant applications suitable for NIDA and other NIH funding; and (4) translate and disseminate results with potential for high impact. TranSTAR provides: (a) transdisciplinary and specialized substance misuse and addictions coursework, workshops and seminars taught by leading faculty in social work, public health, psychiatry, biostatistics, and the social sciences; (b) structured mentoring, advising, and “hands-on” experience on addictions research projects for trainees; (c) proposal critique review sessions; (d) predoctoral teaching assistantships in addictions, comorbidity, and other areas; (e) professional development sessions on presentation skills, effective communication of research, and networking and effective collaborative team science; (f) on-going training in rigor and reproducibility and in responsible conduct of research.

NIH Research Projects · FY 2025 · 2001-08

PROJECT SUMMARY/ABSTRACT This project is intended to support Dr. Nusayba Bagegni as an early career cancer clinical investigator and clinical trialist with a focus on breast cancer and developmental therapeutics at Washington University School of Medicine, Siteman Cancer Center to support NCI-funded clinical research activities and training. The Applicant's interest is in designing and conducting early-phase breast cancer clinical trials and identifying predictive biomarkers of response and resistance to improve breast cancer outcomes for those with aggressive breast cancer subtypes and advanced breast cancer. The Applicant is committed to establishing an academic career in clinical research, serving both as site and overall PI for a number of NCI-funded therapeutic and interventional clinical trials. The Applicant is vigorously involved in developing and implementing investigator-initiated trials to address unmet need for aggressive breast cancer subtypes requiring novel therapeutic approaches, as well as trials of therapy efficacy monitoring.

NIH Research Projects · FY 2025 · 2001-07

PROJECT SUMMARY Wnt signaling and mechanical loading are key regulators of skeletal health. Wnt signaling initiates when a Wnt ligand binds to frizzled (FZD) and LRP5/6 co-receptors. Several Wnt pathway factors (Lrp5, Sost) have known roles in bone’s anabolic response to loading. In the past funding period, we focused on the Wnt ligands (‘Wnts’), which have been relatively understudied. We discovered that Wnt ligand secretion by Osx+ bone cells (osteoblasts/osteocytes) is essential for the anabolic response to skeletal loading, and that Wnt1 upregulation in particular is required. But with aging, loading induces less Wnt1 upregulation and less bone formation. We now shift focus to intervention, and to test the overall hypothesis that molecules that mimic Wnts can rescue the loss of bone mass and mechanoresponsiveness that are hallmarks of aging. The ability to test this hypothesis is enabled by the recent development of Wnt surrogates – antibody-based molecules that function like Wnt ligands by directly binding FZD and LRP5/6. In contrast to sclerostin antibody-based treatments that work by “inhibiting the inhibitor”, Wnt surrogates directly activate Wnt signaling. Our pilot data show that a novel tetravalent molecule that targets several FZD receptors and LRP5 potently increases bone formation, bone mass and strength in young-adult mice. We propose to test whether this LRP5-binding Wnt surrogate is effective in increasing bone mass in two mouse models of osteoporosis – aging and Wnt1 conditional deletion (which models the early-onset osteoporosis that afflicts people with WNT1 mutations). We also will evaluate the possible synergy between Wnt surrogate treatment and mechanical loading, and test whether the surrogate rescues the impaired response to loading seen in aged mice and in Wnt1 mutant mice. Next, because LRP5 and LRP6 are each required for skeletal health, we will take advantage of the modularity of the Wnt surrogate platform to compare cell and bone responses to LRP5-binding and LRP6-binding surrogates. Finally, we will test whether the LRP6-binding surrogate can rescue osteoporosis in mice with conditional deletion of Lrp5, which models human osteoporosis-pseudoglioma (OPPG) syndrome. Development of Wnt surrogates addresses a need for new, targeted anabolic therapies that can be used for a personalized approach to the treatment of osteoporosis.

NIH Research Projects · FY 2026 · 2001-02

Understanding the molecular logic of bacterial infection is leading to development of antibiotic-sparing strategies an urgent need as incidence of antibiotic resistance in common pathogens is becoming a dire threat. The pathogenic pathway to many bacterial infections requires adhesion to host tissues and environmental surfaces and biofilm formation, which in Gram-negative bacteria typically require chaperone usher pathway (CUP) pili tipped with adhesins that bind to host and environmental receptors with stereochemical specificity. The pangenome of E. coli encodes thirty-eight distinct CUP pilus types and single Escherichia coli (E. coli) genomes, including uropathogenic E. coli (UPEC), which causes 75-95% of urinary tract infections (UTI), encode as many as 16 distinct, CUP operons, each likely mediating colonization of a particular host and/or environmental habitat. Like most CUP adhesins, FimH is a two-domain molecule consisting of a C-terminal pilin domain that links the adhesin to the pilus tip and an N-terminal receptor-binding domain. FimH binds mannosylated glycoproteins in the bladder to mediate colonization and invasion. Molecules that neutralize this binding, called mannosides, are in Phase 1b human clinical trials for the treatment and prevention of UTI. FimH from both UPEC and Klebsiella pneuomonia (Kp) can interchange between high and low affinitiy states driven by interactions between the pilin and lectin domains that allosterically modulate a critical conformational equilibrium between high and low affinity states. Another E. coli CUP adhesin, YehD, is a pectin binding adhesin hypothesized to play a role in introducing UPEC into the gut through ingestion of plant fibers. YehD possesses a double helical flap that controls access to the binding pocket. FimH as well as Acinetobacter baumannii (Ab) fibrinogen binding Abp2D adhesins, which mediate Ab catheter associated UTIs, also regulate binding via loop movements that can occlude access to the ligand binding site. Importantly, coordinated interconnected regulation of expression between the fim genes encoding assembly of type 1 pili and other virulence factors such as other CUP operons, flagella, and type 6 secretion is critical for UPEC pathogenesis and can differ between clinical strains. This proposal seeks to determine: i) the role of conformational equilibriums in diverse CUP adhesins, which regulate the association with their respective ligands using structural, molecular dynamics and biochemical techniques; ii) the ultra-structures of diverse pili and the major subunit interactions that govern overall fiber morphology using phylogenetic genetic biochemical

NIH Research Projects · FY 2026 · 2000-09

SUMMARY Over the past 20 years, the scope of Vision Science has expanded enormously and in multiple directions. New methods from different scientific disciplines were pioneered in the visual system (e.g., single-cell RNA sequencing to characterize neuronal diversity, large-scale electrophysiological recordings to characterize visual processing, screens of adeno-associated virus serotypes and promoters to deliver genes to specific cell types). These advances have transformed our understanding of the biology of the visual system and the pathogenesis of its diseases. Despite these advances, many blinding diseases remain without effective treatments. In the face of this remarkable expansion, graduate education faces three challenges. First, although the body of knowledge relevant to Vision Science has increased in breadth and depth, students also face increased pressure to conduct research, publish, and get independent funding early in their careers. Second, Vision Science is conducted in multiple Departments and Ph.D. programs. Yet, students coming from different disciplines often do not speak each other’s language. Third, a successful career in science requires a broad portfolio of professional skills – writing papers and grant proposals, collaborating with colleagues with different scientific backgrounds, presenting results in scientific venues and to wider audiences, navigating the academic job market – that exceed the normal coursework. We overhauled the Interdisciplinary Training in Vision Science (ITVS) program in response to these challenges. The new ITVS is an elite program available for graduate students in Training Years 3-4, with eligibility from multiple Ph.D. programs relevant to Vision Science broadly defined. The emphasis of the ITVS program is on interdisciplinary training and professional skills development. To access the program, students must complete (in Training Years 1-2) pre-requisite foundational courses of their parent Ph.D. programs. In Training Years 3-4, ITVS students take three additional courses: one providing foundational knowledge about the biology of the visual system and its diseases, one combining theory and practice of the advanced methods that drove recent breakthroughs in Vision Science, and one that introduces challenges and opportunities to translating research findings into benefits to patients and connects students to clinicians treating disease relevant to the student’s research. In addition, ITVS students participate in Project Building, where they develop an interdisciplinary grant proposal – that could become an NRSA application – shaped by peer, instructor, and committee feedback. Throughout the ITVS program, students participate in multiple Career Development activities, including mentoring junior students, organizing scientific events, interacting with external speakers, participating in informal dinners with ITVS faculty, and participating in community outreach. The ITVS program has existed for > 20 years and has a demonstrated history of remarkable success. We believe that the recent program overhaul will enhance this success. Here, we request funds for 6 fellowships (3 per Training Year).

NIH Research Projects · FY 2025 · 2000-03

PROJECT SUMMARY Inherited retinal degeneration (IRD) is a group of genetic diseases featuring progressive loss of photoreceptor neurons in the retina and eventual blindness. Affected photoreceptors largely die through apoptosis that was once thought to be irreversible. However, recent studies in different systems have reported a phenomenon called “anastasis”, in which some cells that received an apoptotic signal become resilient and return to a healthy state. The presence of resilient photoreceptor cells after light damage was suggested by several studies, but there is no clear data on photoreceptors in retinal degeneration or knowledge of underlying cellular/molecular mechanisms. This application aims to close this knowledge gap by testing our hypothesis that each photoreceptor cell has an intrinsic capacity to “self-repair” or recover from apoptosis, and that therapeutic treatments enhancing this capacity will maintain photoreceptors in IRDs. To test our hypothesis, we will use mouse models to identify resilient vs. vulnerable rod/cone cells during retinal degeneration. We have established an in vivo genetic tool, the living-color reporter mouse line, named CaspBiosensors. In this model, we take advantage of a well-known apoptotic marker, activated Caspases 3/7 (Casp) to label cells that undergo apoptosis (present) with red fluorescence and cells that have survived apoptosis (past) with green fluorescence. Our preliminary results demonstrate that we can detect present/past Casp+ photoreceptors in a relevant model by both imaging in live animals and histological sections. In this grant, we propose experiments to confirm and expand these findings at the cellular and molecular levels. Specific Aim 1 will determine the survival outcome of vulnerable (red) and resilient cells (green) under environmental (light damage) and genetic (three IRD models) insults, using chronic in vivo imaging-based analyses complemented by histological examination at end-points. Specific Aim 2 will identify molecular signatures of cellular resiliency using single-cell RNA sequencing. We will validate selected candidate genes using loss-of-function and gain-of- function manipulations. We will also investigate the capacity/mechanisms of gene therapy and a proven neuroprotection reagent in preventing photoreceptors degeneration in IRD models. The outcome of this research is expected to significantly impact our understanding of apoptotic photoreceptor degeneration in IRDs and the development of more effective therapeutic approaches. Improving long-term efficacy of gene therapy is essential as photoreceptors have continued to degenerate even in the few successful ocular gene therapy clinical trials. Our study will inform potential improvements by adding neuroprotection strategies to prolong the life of targeted photoreceptors.

NIH Research Projects · FY 2025 · 2000-03

This application seeks renewed funding for the Washington University (WU) Digestive Diseases Research Core Center (DDRCC). Our overall objective is to support collaborative, multidisciplinary investigation in “Host-environment interactions in Digestive Disease.” The WU-DDRCC provides infrastructure that promotes basic and translational research of its 55 Full (+ 5 PF) and 18 Associate members, and nurtures career development of junior investigators. Our Research Base is productive, and collaborative as evidenced by 250 original peer reviewed publications citing the DDRCC (65% collaborative involving ≥2 members), including 133 (53%) in journals with impact factors >10. Since 2019, our members also expanded their extramural funding ($30.86M$34.64M; 12% increase). Our members have appointments in 10 different Clinical and Basic Science Departments across WU. Our Research Base interests are organized around three mechanistic themes: (1) Host-microbial interactions, inflammation, and mucosal immunity; (2) Stem cells, epithelial renewal, and preneoplasia; (3) Metabolic homeostasis, nutrient transport and enterohepatic signaling. Three Biomedical Cores support the Base by leveraging institutional resources and evolve by responding to members’ needs for a cost-efficient and high-quality service infrastructure. Our Biomedical Cores include (1) Tissue Analysis and Imaging Core (TAnIC), which provides sophisticated imaging technologies; (2) Organoids and Gene Editing Core (OGEC), which offer organoid and genetic engineering technologies; and (3) Biobank and Big Data Core (BBDC), which shares human specimens from normal and disease states, guides study design, and analyzes large-scale human data. These Cores, overseen by an Administrative Core (ARAC) and guided by Internal and External Advisory Boards (with a newly convened Community Advisory Board), promote collaborative and synergistic interactions by offering advanced services and specialized expertise that reflect current and future needs of the Base. The WU-DDRCC also sponsors an Enrichment Program with visiting researchers and events promoting collaboration, and new initiatives in digestive diseases research. The Enrichment Program especially supports careers of promising trainees by nurturing interests of postdoctoral trainees, fellows, and junior faculty, via targeted retreat and summer student program. The WU-DDRCC has invested considerable resources to nurture new investigators with its Pilot and Feasibility (PF) Program. 95% of PF awardees from 2013 still pursue digestive disease research and they garnered $49.4M in extramural funding (36:1 ROI). The WU-DDRCC also promotes and shares technology development with NIDDK funded Centers locally as well as regionally, via Midwest Alliance of DDRCCs and the NIDDK Center program. Our proposal seeks to continue WU-DDRCC’s contributions to science, bringing discoveries to the broad populations we serve, diversification of our workforce community and nurturing the next generation of digestive diseases researchers. Our aims and practices are compliant with all NIH guidelines.

NIH Research Projects · FY 2026 · 1999-09

PROJECT SUMMARY/ABSTRACT – OVERALL COMPONENT This application seeks continued funding for the Washington University (WU) Nutrition Obesity Research Center (NORC). Since our NORC was first funded in 1999, it has served as a nidus for the growth and development of nutrition and obesity research at WU. The infrastructure provided by the NORC has created an environment that supports and stimulates cost-effective and high-quality research, collaborations between investigators, training and career development in nutrition and obesity. Our NORC has a talented and multi- disciplinary research base consisting of 136 investigators (103 Regular Members and 33 Associate Members) from 3 different schools (School of Medicine, Brown School Program in Public Health, and the College of Arts and Sciences) and 20 different administrative units within the School of Medicine. These investigators have 193 nutrition/obesity-related grants, generating $84.7 million/year in direct costs; 89% of NORC Regular Members have NIH funding and 86% of total grant support is from Federal sources. The major research themes of the WU NORC are: 1) Obesity: Pathophysiology, Complications, and Therapeutics and 2) Nutrient Metabolism in Health and Disease. We propose an Administrative Core, an Enrichment Program, a Pilot and Feasibility (P&F) Program, which provides four P&F awards/year to junior faculty and helps mentor them on their projects and careers, and 3 Biomedical Research Core laboratories: 1) the Clinical Science Research Core, which provides assistance with: i) design and performance of complex metabolic studies, ii) body composition assessments, iii) acquisition of adipose tissue and muscle samples, iv) cardiovascular assessments, v) exercise and physical performance testing, vi) lifestyle interventions, vii) assessment of substrate kinetics in vivo by using stable isotope tracers, viii) mathematical modeling of tracer and non-tracer data, ix) plasma substrate and hormone concentrations, x) dynamic metabolomics, and xi) biostatistical support; 2) the Animal Model Research Core, which provides: i) training in breeding and animal husbandry, ii) biochemical and molecular analyses of blood and tissue samples, iii) body composition analyses, iv) genotyping, v) energy balance studies, and vi) metabolomics and tracer-based metabolomics; and 3) the Cellular and Molecular Biology Core, which provides: i) adipose tissue morphology, ii) adipocyte and muscle cell lines for culture, iii) gene and protein expression, iv) mitochondrial physiology, v) extracellular vesicle isolation, and vi) training in specialized research techniques. The collaborative interaction among our NORC research base and our three Core laboratories encourage interdisciplinary approaches to address important issues in nutrition and obesity.

NIH Research Projects · FY 2024 · 1997-04

Project Summary. The Vision Center Core at Washington University serves a large and diverse group of clinicians and basic scientists studying the biology and pathology of the visual system. In partnership with the Department of Ophthalmology & Visual Sciences, the Vision Center Core will achieve three main goals. First, it will provide NEI-funded researchers (and others directly involved in vision science) with access to state-of-the-art instrumentation and technical support to enhance their individual research efforts. Second, it will enhance the environment for vision research at Washington University by fostering collaborations and attracting talented scientists to the field. Third, the Center Core will support the career development of the next generation of vision scientists. These goals will be achieved by provision of four Resource Cores, supported by an Administrative Core. Together they will provide the following services: 1. An Imaging Core will provide technical support in the preparation of ocular tissue for anatomical analysis. The core supports immunocytochemistry and in situ hybridization. Core investigators have ready access to confocal and multiphoton microscopes and OCT imaging. 2. A Visual Function Testing (VFT) Core will provide expertise, instrumentation, and training on equipment used to quantify visual performance in mice and other model systems. ERG, VEP and optomotry analysis are supported. 3. A Biostatistics & Bioinformatics Core (BBC) will provide statistical and methodological expertise in study design, assuring the validity of statistical analyses and reported results. Support is now provided for analysis of large data sets, such as those generated in the course of genomic or RNA sequencing experiments. 4. A Molecular Genetics Core will provide customized services for the production of transgenic and knockout mice using CRISPR/Cas9 technology. Assistance is also provided with design and production of gene targeting constructs, viral vectors, IVF services, and sperm/embryo cryopreservation. Provision of these support services and resources will greatly enhance the research capabilities of investigators at Washington University and facilitate collaboration among new and established vision scientists.

NIH Research Projects · FY 2025 · 1997-04

This proposal is for a renewal of NIH funding for Washington University’s Genome Analysis Training Program (GATP). The overall goal of the GATP is to train multidisciplinary, quantitatively sophisticated leaders in genomic technology, science, and medicine. In this renewal, we are focusing exclusively on training predoctoral students, because Washington University has an outstanding pool of highly talented PhD and MD/PhD students from which we can recruit the very best for the GATP. We are requesting funds to support 10 predoctoral trainees. If we are granted these slots, the university will provide matching funds to support an additional 3 trainees. The GATP is designed to produce trainees who are sophisticated in their knowledge of both the experimental and the mathematical / computational aspects of genome science. This is achieved through a rigorous set of required classes and through research-based training. We have an outstanding group of 40 training faculty who run world-class research labs and provide careful mentoring to our trainees. Our PhD programs in Computational Biology and Genetics/Genomics were jointly ranked #5 in the nation in the 2022 US News & World Report rankings. We have made significant changes to our training program based on feedback from our trainees. Our trainees consistently express an interest in learning about the full range of career paths that utilize their skills. In response, we have designed a set of mini-internship programs that take advantage of our connections to the pharmaceutical and biotechnology industries and clinical genomics services. The opportunities are aimed at cultivating the leadership capability of our trainees and fostering a broad understanding of the different work environments and career paths in which genomics plays an important role. Many of our trainees are also interested in how machine learning is applied to problems in the genome sciences. To encourage and support this interest, we made changes to the GATP that ensure that all trainees are exposed to the foundational concepts underlying machine learning and artificial intelligence. We have also made changes to our evaluation protocols to make sure that we are meeting our goals in a way that is responsive to our trainees.

NIH Research Projects · FY 2026 · 1997-01

SUMMARY/ABSTRACT The rising rate of antibiotic resistance is increasingly complicating treatment for infections that, not long ago, were easily treated. Prominent among these are catheter-associated urinary tract infections (CAUTIs), which are the most common hospital-associated infection (HAI), and infections of ureteral stents. Over 15 million UTIs occur in the USA each year with accompanying deterioration in the quality of life and increased health care costs. As a result, 15% of all antibiotics prescribed are for the treatment of UTIs, making these infections a leading cause of antibiotic use. Complicating treatment decisions for CAUTI/stent-related infections is that most of these infections are polymicrobial, with multiple bacterial species simultaneously colonizing the implant. Current treatment guidelines typically focus on a single infecting organism and do not consider the underlying polymicrobial foundation of the infection, as reflected by the fact that treatment is often ineffective, requires the removal and replacement with a new catheter/stent, which typically then becomes infected by the same consortia of bacterial species. There is a significant gap in knowledge of the specific composition of these consortia, including fastidious species not amenable to detection by traditional approaches. Other knowledge gaps include: i) the mechanisms that promote and sustain these polymicrobial infections; ii) which communities/members are responsible for symptoms; iii) why certain consortia show resilience and reappear even in the presence of antibiotic treatment; and iv) development of antibiotic and antibiotic-sparing strategies that efficiently disrupt the cycle of polymicrobial infection on urinary catheters and stents. To address this problem, experimental murine CAUTI models have been developed for several prominent Gram-negative and Gram-positive uropathogens, including important multi-drug resistant (MDR) genera such as Enterococcus, Staphylococcus, Klebsiella and Acinetobacter and cutting-edge small molecule therapeutics and immunotherapies have been developed that are highly effective in murine monomicrobial CAUTI models. This proposal will build upon this foundation to: i) characterize human samples from patients with long-term indwelling catheters or stents using a third-generation metagenomic sequencing approach to determine (in <7 hours from sample collection) all members of the infecting consortia and their antibiotic resistance profiles; as proof of concept same day diagnosis and antibiotic prescription in the clinical setting; ii) correlate measures of UTI symptomatology and disease outcomes with specific community members; iii) use mouse and in vitro biofilm models to investigate mechanisms of bacterial-bacterial interactions critical in catheter-associated polymicrobial communities; and iv) investigate the ability of therapeutics, known to be efficacious against one species, to treat polymicrobial CAUTIs. These studies will provide important insights into; i) polymicrobial communities found in the clinic; ii) mechanisms by which polymicrobial communities persist; and iii) development of new treatment strategies.

NIH Research Projects · FY 2026 · 1996-12

PROJECT SUMMARY: Center Overview The Washington University (WashU) School of Medicine (WUSM) Diabetes Research Center (DRC) has a goal of decreasing human suffering by pursuing the scientific theme of interdisciplinary cooperation across the translational research spectrum to develop new therapies and improve the health of Americans with or at risk for diabetes, its complications, and related endocrine and metabolic disorders. The DRC is needed to catalyze innovative thinking that includes diabetes as a biological variable by investigators in the research base with complementary skills. Consisting of 126 members supported by >$57 million in direct costs, the exceptional research base has expertise spanning the translational spectrum including groups that focus on Metabolic Regulation, Islet Biology and Immunology, Prevention and Control, and Complications. Their creativity is facilitated by the evolving services of six biomedical research Cores: Cell and Tissue Imaging Core, Diabetes Models Phenotyping Core, Metabolic Tissue Function Core, Mass Spectrometry Core (which has been substantially expanded), Translational Diagnostics Core, Diabetes and Infection Core (which is new). Novel approaches are nurtured by the WashU Pilot and Feasibility Program, which continues to launch the careers of high impact diabetes scientists, as well as the expanded Pilot and Feasibility Program, which fosters interdisciplinary research at the Universities of Kentucky, Utah, and Wisconsin. Dynamic Enrichment Program activities include fluid interactions with diabetes related T32 programs at WashU, the NIDDK Medical Student Research Program, and other NIDDK supported centers to raise awareness and interest in diabetes research. Now in its 45th year, the DRC at Washington University is positioned to continue translating new findings into strategies that improve the health of people with diabetes.

NIH Research Projects · FY 2025 · 1996-09

PROJECT SUMMARY/ABSTRACT APOE genotype is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). The ε4 allele of APOE increases risk for AD by ~3.7 fold for one allele and by ~12-15 fold for 2 alleles relative to ε3 homozygotes, while one copy of the ε2 allele decreases the risk for AD by ~50%. In addition, recent data have shown that rare APOE variants protect against either late-onset AD (V236E and R251G) or against autosomal dominant AD (APOE3 Christchurch (Ch) R136S). A complete understanding of apoE’s role in AD pathogenesis remains unclear. In addition to effects of apoE on Aβ aggregation and clearance, apoE is also highly likely to influence risk for or progression of AD via additional mechanisms. The main recent work on this grant has been to determine whether and how apoE influences amyloid-induced tau seeding/spreading, tau pathology, neurodegeneration, and the brain’s innate/adaptive immune response. There is robust evidence that Aβ accumulation drives the “spreading” of tau pathology but how this happens is not well understood. In addition, the neuronal and synaptic loss that occurs in AD correlates well with the location and accumulation of tau pathology. We have shown that apoE produced by astrocytes plays a key role in Aβ deposition and that apoE4 strongly contributes to tau-mediated neurodegeneration. We have also found that microglia suppress Aβ- mediated tau seeding and spreading and that apoE isoforms can strongly regulate this effect. Interestingly, the apoE3Ch variant strongly suppresses Aβ-induced tau seeding and spreading with the effects appearing to potentially occur via microglial apoE receptors. We also found that once tau-mediated neurodegeneration begins, microglia can exacerbate neurodegeneration which is strongly influenced by apoE with apoE4 worsening this and lower levels of apoE leading to less injury. Tau-mediated neurodegeneration is associated with large increases in microglial cholesterol esters and other lipids that is associated with endosomal/ lysosomal defects. Our data suggests that apoE is at the nexus of how Aβ induces tauopathy and how tauopathy leads to neurodegeneration. This and other data lead us to hypothesize that apoE variants affect 1) uptake and degradation of aggregated tau via competitive interactions with HSPG-LRP1 and 2) microglial lysosomal function. These effects of apoE variants and the HSPG-LRP1 pathway then impact Aβ-induced tau seeding and spreading as well as tau-mediated neurodegeneration and lysosomal lipid accumulation. This hypothesis will be evaluated in the following aims: Aim 1: To determine if LRP1 in microglia or neurons mediates the effect of apoE isoforms on Aβ-induced tau seeding and spreading Aim 2: To determine if LRP1 in microglia or neurons mediates the effect of apoE on tau-mediated neurodegeneration. Aim 3: To determine whether and how apoE variants influence microglial lysosomal function, lipid accumulation and activation state as well as LRP1-dependent tau uptake and clearance.

NIH Research Projects · FY 2026 · 1996-07

Motor axon loss is a cardinal symptom of motor neuron disorders including amyotrophic lateral sclerosis (ALS). Schwann cells (SCs) myelinate and provide trophic support to axons in the peripheral nervous system (PNS) and disruption of SC metabolism often leads to axon degeneration, both symptoms of peripheral neuropathy. The lactate shuttle hypothesis proposes that glycolytic glial support cells supply lactate to axons to sustain their high metabolic demands, a process that requires interconversion of lactate and pyruvate via lactate dehydrogenase (LDH) in both glia and neurons. To test this hypothesis in the PNS, we deleted LDH subunits LDHA and LDHB specifically in motor neurons (MNs), sensory neurons (SNs), or SCs. We find that LDH deletion in SCs or MNs leads to progressive degeneration of motor axons, whereas LDH loss in SNs causes no apparent abnormalities in sensory axons. These results support a model in which lactate shuttling from SCs selectively sustains motor but not sensory axons and suggest that LDH activity and lactate shuttling play a role in motor- dominated neuropathies such as ALS. Indeed, LDHB-deficient mice develop progressive motor dysfunction similar to ALS mouse models, and LDH deficiency synergizes with a slowly progressing ALS model to induce severe, early onset disease. In conjunction with these studies, we identified rare loss-of-function LDHB mutations in ALS patients. In this proposal, we outline experiments to examine the differential responses of MN and SN neurons to loss of LDH function to identify pathways involved in the observed selective motor axon degeneration. We will use a cellular complementation assay utilizing iPSC-derived neurons to dissect components involved in support of peripheral motor axons. We will use biochemical and cellular complementation assays to examine LDHB variants found in ALS patients and controls to determine if deleterious variants are enriched in ALS. We will study mice lacking specific LDH isoforms in defined cell types to determine the cells involved in motor axon metabolic support and the pathways they invoke to influence axon health. Additionally, we will use these LDH mutant mice to interrogate how compromised lactate/pyruvate metabolism interacts with other ALS risk factors to speed disease progression. Results of these studies will establish the relationship between LDH, lactate/pyruvate metabolism in the PNS, and development of motor neuron diseases including ALS, and stimulate development of new axo-protective therapeutics for these devastating disorders.

NIH Research Projects · FY 2025 · 1995-08

This renewal application requests funding for the Brown School’s Training Program in Mental Health Services Research at Washington University in St. Louis (Wash U). Our program will prepare 2 pre- and 2 post-doctoral trainees per year to acquire advanced mental health services research skills to address challenges faced by persons living with mental disorders who seek care at the intersection of multiple services sectors, experience high needs for care, and are the least likely to secure needed services or to obtain high quality care. Our training program includes five knowledge domains: mental health services research, research with populations affected by poverty and disease, intervention research, implementation science, and advanced research methods (e.g., systems science, mixed methods). A team of 31 highly talented mentors, co-led by Dr. Leopoldo J. Cabassa, Professor, and Dr. Byron Powell, Associate Professor at the Brown School, supports our training program. Our faculty are drawn from 3 Schools and 6 Departments across Wash U. They have a distinguished record of accomplishment in mentoring and active NIH-funded research in the critical knowledge domains of our program. An exceptional transdisciplinary training environment, including 24 research centers at the Brown School, the Institute of Public Health, and the Institute of Clinical and Translational Science supports our program. Building on our 29-year history of successfully training mental health services researchers, our program continues to innovate with the following enhancements. We strengthened our methodological training, aligning with innovations in mental health services research by adding new courses and faculty mentors in implementation science, systems science, health disparities research, global mental health, and advanced data analytics. We added a new implementation science concentration option for our pre- and post-doctoral fellows. We enhanced trainees’ scientific networking by continuing to require a learning site visit to existing NIH-funded mental health services and implementation studies across the U.S. We continued to require science communication workshops to improve trainees’ communication skills to better disseminate their work to a broader audience, thus enhancing the impact of their work. We developed new roles and training opportunities for our early career faculty to enhance their mentoring skills. The overall mission of our program is for our trainees to acquire mental health services research knowledge and skills to meet the most pressing needs in the field of social work and to advance the public health significance and impact of NIMH services research.

NIH Research Projects · FY 2026 · 1993-07

Project Summary Movement is vital for health and quality of life, and the need for movement science and rehabilitation research is increasingly apparent. A primary goal of the National Center for Medical Rehabilitation Research, nested within NICHD, is to bring the health-related problems of people with physical disabilities to the attention of America's best scientists in order to capitalize upon the myriad advances occurring in the biological, behavioral, and engineering sciences. The purpose of this training program in Movement Science is to prepare pre- and postdoctoral investigators who can integrate knowledge from basic and clinical sciences to answer relevant questions concerning movement and movement dysfunction as they relate to rehabilitation. The training program, while administratively housed within the Program in Physical Therapy, is strongly interdisciplinary, interfacing with engineering, neuroscience, radiology, orthopaedic surgery, and other medical disciplines. Our training program utilizes the expertise of outstanding investigators from throughout Washington University to provide interdisciplinary guidance in academic and research activities. The curriculum is built on the concept of the movement system and encompasses three core areas: biocontrol, biomechanics, and bioenergetics. The engagement of established investigators with an interest in integrating basic science and clinical manifestations of disease and injury results in the production of top quality, interdisciplinary research in rehabilitation. This training grant provides essential support for this Movement Science training program, facilitating continuous innovation and exceptional training. Our trainees are highly successful, with an average of ≥ 6 peer-reviewed publications during their training. Average time to completion is 4 years in the full-time, predoctoral program, which has a graduation rate of 100% (excluding those still in training). Our graduates go on to academic (>85%) or industry positions and become nationally and internationally recognized leaders. In this application, we demonstrate the impact of this T32 on the field of rehabilitation. We share how the T32 continues to be the driving force behind innovation in interdisciplinary PhD training, with important changes this cycle related to including a major university transition of PhD education governance, systematic succession planning to maintain excellence, and new training experiences in quantitative analyses. We request support for one additional postdoctoral slot per year (total of 3 predoc and 2 postdoc). We are fully committed to the MSP, recognizing its unique position and key role in training the next generation of movement scientists.

NIH Research Projects · FY 2025 · 1991-09

Addictions are heritable, polygenic and multifactorial disorders that pose substantial burden to persons and communities. A biomedical approach to substance use and addictions, encompassing genetics, neuroscience, neuroimaging, pharmacology, statistics, biology, informatics and psychiatry/psychology, along with access to multi-modal data, provides a strong foundation upon which translational studies aimed at understanding the neurobiological underpinnings of drug use and misuse are built. This competing continuation requests another 5 years (years 31-35) of support for 6 postdoctoral training slots that will provide research training and career development to 3 MDs and 3 PhDs pursuing postdoctoral research with 27 preceptors across 7 departments (Psychiatry, Anesthesiology, Genetics, Neuroscience, Neurology, Psychological & Brain Sciences, Biomedical Engineering). The fellowship will typically encompass a 3-year period for MDs, and a 2-3 year period for PhDs, depending on the scope of the project. Co-led by Drs. Agrawal and Moron-Concepcion (with complementary expertise in human and animal neurobiology of addictions), the Biomedical Research Training in Drug Abuse (BRTD) is the only T32 which offers biomedical addictions training, with an emphasis on neurobiology, at Washington University in St. Louis (WUSTL), which is home to 20 additional postdoctoral institutional training grants. BRTD has a long history of recruiting highly qualified trainees (1-2 first-authored publications at entry) and securing their continued academic success. Prior trainees are now tenured faculty members at WUSTL and elsewhere, science officers for pharmaceutical or biomedical entrepreneurial companies, and are themselves mentoring the next cohort of scientists. The 27 preceptors are NIH-funded investigators with a history of mentorship in addiction-related biomedical research. The trainees devote 70% of their effort towards mentored research. The remaining effort is devoted to didactics (coursework, workshops and seminars) that advance the trainees' breadth of knowledge and provide new skills (e.g., programming, bioinformatics, data mining) that keep apace of accelerating big data and computational approaches. In addition, trainees undertake career development activities in science communication, NIH PI-ship and diversity in neuroscience, as well as required instruction in Responsible Conduct of Research (including content specific to addiction) and Reproducibility in Science. Recognizing that trainees may choose different career trajectories, they may also engage in grant writing and mock NIH review, teaching, public speaking or entrepreneurship training. This renewal maintains our strong emphasis on neurobiology, while adding in novel scientific components (greater emphasis on multi-modal research, e.g., genetics and human neuroimaging, neuro-pharmacology and genetics) as well as a robust career development program that rounds out scientific training. Preceptors with new expertise (including participation of Biomedical Engineering) and new course offerings in data science add fresh perspectives to our objective of training highly competitive addiction researchers.

NIH Research Projects · FY 2025 · 1991-07

PROJECT SUMMARY/ABSTRACT The goal of this training grant is to equip junior investigators with the skills to make enduring contributions to child digestive health, which encompasses processes that are critical for the survival, growth, and well-being of people and populations. We achieve this goal by providing immersive research training at Washington University in fields relevant to digestive health of children worldwide. The rationale for our training program is based on two premises: (1) high quality early career training is critical for producing individuals who will make meaningful and lasting impact on the field, and (2) too few individuals are adequately trained to solve problems relevant to the childhood digestive system. Mentors across all disciplines share dedication to research relevant to digestive health of children, have strong training records, are very well supported by federal and foundation grants, and integrate our T32 trainees into existing projects to prepare them for productive scholarly careers. Track I (Microbial–Host interactions in the Gastrointestinal Tract) trainees determine how gut pathogens and microbial populations beneficially or harmfully affect childhood digestive health. Track II (Cellular and Molecular Biology of the Developing Gastrointestinal Tract) trainees dissect molecular and genetic aspects of congenital and acquired disorders of the childhood gastrointestinal system and host response to inflammatory stimuli. Track III (Translational Biology of the Gastrointestinal Tract) trainees use data from humans and populations to further knowledge of digestive disorders of childhood. This program will fund four post-doctoral (MD, PhD, or MD-PhD) drawn from our traditional base of pediatric gastroenterology fellows and post-doctoral trainees, strengthened in the past five years by extension to surgical residents. We will also fund members of the expanding community of PhD and MSTP students interested in the problems we strive to solve by also funding pre-doctoral candidates and Medical Scientist Training Program enrollees. Applicants to the program will receive two years of highly mentored support, including an external mentor system. We will also expand our portfolio of training opportunities to include large data base analysis, nationwide cohort study training, and implementation science. We will also co-sponsor an annual retreat focused on issues of diversity, equity, and inclusivity in our training, research, and clinical care. The program will also remain integrated into the Washington University Digestive Diseases Research Core Center (DDRCC). The trainees we fund also strengthen multilevel collaborations between gastroenterology and surgical research in our institution. Our intent is to produce scientists with enduring interests in childhood digestive diseases and their causes, treatments, and prevention, by our cohorts of trainees and mentors who share complementary goals and skills.