Washington University

NIH Research Projects · FY 2026 · 2023-09

Project Summary The goal of this project is to understand how ribosomal RNA methylation can regulate translation of specific proteins to regulate aging. Disruption of the proteome is a hallmark of aging. Having the capacity to express the appropriate protein in response to environmental cues is an essential and evolutionarily conserved process. Therefore, preserving the proteome is critical for maintaining organismal health and healthy aging. However, how aging-responsive mRNAs are selectively translated is unknown. We recently identified that ribosomal RNA methylation could facilitate the translation of a specific subset of proteins. Additionally, we characterized how ribosome occupancy changes as an organism ages and determined that changes in ribosomal DNA methylation are sufficient to project the organismal age. Whether ribosomal RNA methylation plays a role in preserving proteome integrity as organisms age is still unclear. We have recently found that enzymes which regulate RNA methylation and RNA methylation itself are dysregulated during aging and in response to stress. We found that an N6-adenosine methyltransferase, METL-5, directly methylates adenosine 1717 on 18S ribosomal RNA in C. elegans. Methylation of adenosine 1717 enhances ribosomal binding and selective translation of specific mRNAs. Our preliminary data shows that metl-5 deficient animals grow normally under homeostatic conditions; however, metl-5 mutants are resistant to a variety of stresses, including heat shock and UV irradiation. We also have preliminary data that deletion of an N6-dimethyl adenosine (m6,2A) methyltransferase, DIMT-1, which methylates adenosines 1735 and 1736 on 18S rRNA regulates selective ribosomal binding and translation of specific mRNAs and causes increased longevity and stress resistance. Thus, methylation of specific residues of the 18S rRNA by METL-5 or DIMT-1 selectively enhances translation of specific transcripts to regulate stress resistance and longevity. However, whether rRNA methylation more broadly can regulate age and stress-responsive translation and how this dysregulation drives the aging process is still unknown. Our preliminary findings suggest that ribosomal RNA methylation can facilitate selective translation of specific transcripts providing another layer of regulation of the stress response and aging. Capitalizing on this preliminary data we will use genetic, biochemical, and molecular approaches both in vitro and in vivo to dissect the role of rRNA methylation in regulating aging and stress resistance. Our underlying hypothesis is that rRNA methylation promotes ribosome heterogeneity in response to stress conditions and aging to facilitate the appropriate translation of stress resistance transcripts.

NIH Research Projects · FY 2025 · 2023-09

Aging affects all tissues and is associated with functional deterioration. Each tissue has specific aging kinetics, and the female reproductive system is the first to age. Female reproductive aging is associated with a decrease in oocyte quality and quantity as well as a reduction in the ovarian hormones, which accelerates women physiologic aging. Reproductive transitions, such as reproductive aging, are a priority of the Fertility and Infertility branch of the National Institutes of Health, and thus my proposed research is tightly aligned with the mission of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. A major contributor to the age-associated reduction of female fertility is the decrease in oocyte quality due to an increase in oocyte aneuploidy, but our work and others have demonstrated that other factors, such as the tissue microenvironment, might contribute to the age-associated reduction in oocyte quality. Physical cues from the tissue environment are major regulators of cell behavior. In the ovary, stiffness is relevant for normal follicle development but also associated with pathological conditions. In mice, stiff environments maintain primordial follicles in a quiescent state. However ovarian stiffness is also a characteristic of polycystic ovarian syndrome in humans. In my postdoctoral work I pioneered the use of instrumental indentation to measure the biomechanical properties of the ovary and I found that mice ovaries become stiffer with advanced reproductive age. During the K99 phase of this award, I utilized in vitro follicle culture and alginate gels to demonstrate that the age-associated increase in ovarian stiffness impacts folliculogenesis and oocyte quality. My work on ovarian stiffness and folliculogenesis laid the foundation of this R00 application where I will test the overarching hypothesis that the age-associated and spatially-dependent increase in ovarian stiffness creates a physical environment that the follicle senses through the activation of mechanotransduction pathways. This hypothesis will be tested in three specific aims. First, I will determine the subcellular features that define ovarian stiffness by performing a 3D spatiotemporal architecture map of the ovarian stiffness in an age and estrous cycle-dependent manner using a stiffness mapping system optimized during the K99 phase. Second, I will employ an in vitro system that enables precise control of the physical environment. In the K99 phase, I discovered that increased levels of

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Opioid use disorder (OUD) is an escalating public health concern that has resulted in over 570,000 overdose deaths between 1999 and 2020. Exposure to prescription opioids (such as oxycodone) is frequently an initiating factor in OUD, with 9.9 million people reporting misusing prescription opioids annually (Centers for Disease Control). While many individuals can use opioids as prescribed, a subset of individuals transition to problematic drug use, which is defined as continued drug intake despite negative consequences and is a hallmark feature of OUD. These individual differences have been modeled in rodents: most subjects will readily self-administer opioids but will suppress drug intake when drug seeking is paired with punishment such as a foot shock (punishment-sensitive). Conversely, ~20-30% of individuals will persist in drug seeking despite this punishment (punishment-resistant). Elucidating the neural mechanisms underlying individual differences in punishment-resistant drug seeking is critical for understanding susceptibility to compulsive drug use in OUD. The ventral pallidum (VP) has emerged as a central brain area for encoding the relative value and motivation for rewards and translating this motivation into action. Recent work has also established that VP activity is necessary for drug seeking and relapse, and critically modulates reward seeking under conflict. The VP is an incredibly heterogeneous nucleus, with distinct neurochemically- and anatomically-defined populations playing discrete and dissociable roles in behavior. However, our understanding of how the VP subpopulations work in concert to orchestrate motivated behavior in the context of OUD is severely limited by the inability to identify functionally-relevant VP populations. Here we will use state-of-the-art omics platform to obtain high resolution cellular information of comprehensive cell types in the VP and their role in OUD. Our long-term goal is to elucidate the molecular and neural circuit basis of punishment-resistant opioid self- administration, and to leverage this understanding to develop targeted therapies to prevent or reverse the transition to punishment-resistant opioid intake in patients with OUD. The outcomes of this proposal will lay the foundation for this goal by creating a comprehensive cellular atlas of the VP and characterizing transcriptional adaptations induced by self-administration of oxycodone (Aim 1), and by profiling ensembles of VP neurons that are activated in the context of oxycodone self-administration (Aim 2). By profiling transcription factor binding using cutting edge “calling card” technology, we will establish whether transcriptional profiles distinguishing punishment sensitive- and resistant- individuals emerge with repeated self-administration, or whether these differences are antecedent to opioid exposure and only revealed upon introduction of punishment (Aim 3). This work will help inform future therapies for OUD and will identify molecules capable of modulating functionally-relevant ensembles of VP neurons as a therapeutic strategy for OUD.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Long COVID manifests differently for each person and can contribute to disabling, life-changing symptoms such as extreme fatigue, cognitive dysfunction, breathing difficulty, and autonomic dysfunction in people across the age spectrum, including in people who were previously healthy and in people who had minimal or no symptoms associated with acute COVID-19 infection. Multidisciplinary Long COVID clinics were a mainstay of patient support during the initial phases of the COVID-19 pandemic, but as the pandemic is shifting to a new phase, care models must also evolve in order to meet the complex medical, rehabilitative, and social needs of the continually growing number of people who are affected by Long COVID. The purpose of this project is to transform an existing, university-based Long COVID clinic into a broader Long COVID community network in order to expand equitable access to care, improve the patient care experience, and support primary care practitioners. This project will invest in two particularly underserved populations: 1) the Black community in St. Louis, Missouri, which is a historically mistreated population who continues to be marginalized by previously sanctioned segregation practices; and 2) rural communities across Missouri. Aim 1 is to expand equitable access to Long COVID care by: 1) building clinical capacity, and 2) removing structural barriers to care. This will be accomplished by: 1) hiring additional clinicians for the Long COVID Clinic in order to reduce wait times; and 2) removing patient requirements for clinic evaluation that disproportionately affect underserved populations. Aim 2 is to improve the Long COVID care experience by: 1) streamlining care that crosses multiple disciplines and physical care sites, and 2) supporting patients’ social needs. This will be accomplished by: 1) supporting a clinical case manager to directly assist patients with coordinating medical care and connecting with community resources, and 2) iteratively assessing and addressing referral challenges between clinics. Aim 3 is to support primary care teams as they care for patients with Long COVID by co-creating: 1) educational resources for PCPs, and 2) streamlined communication and referral pathways between PCPs and specialty clinicians. This will be accomplished by engaging multiple key stakeholders to: 1) develop multi- modality educational materials related to Long COVID patient assessment and management; 2) disseminate materials via culturally and logistically preferred approaches (including via established, trusted community intermediaries and via an established ECHO (Enhanced for Community Healthcare Outcomes) virtual educational infrastructure); and 3) refine existing handoff processes to minimize the administrative workload on PCP teams and facilitate their ability to meet patients’ needs. Continuous stakeholder input, comprehensive data tracking, and iterative needs assessments using mixed methods approaches will facilitate ongoing project evaluation and adaptation in order to respond to the community’s evolving needs.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract The overall goal of the proposed study is to identify long-term neurobehavioral consequences of childhood mild traumatic brain injury (mTBI) for the developing brain and examine their contribution to addiction risk using a rigorous cotwin-control design, longitudinal follow-up, and multimodal and innovative neuroimaging tools and neurobehavioral assessments. mTBI sustained during childhood or adolescence, periods of continuing brain development and reorganization, is a major public health problem due to its high prevalence and long-lasting neurobehavioral consequences associated with increased risk for addictive behaviors. However, progress in understanding long-term sequelae of mTBI and their role in addiction is hindered by a number of significant methodological challenges: a) case-control studies are correlative and do not allow to distinguish consequences of TBI from pre-existing neurocognitive deficits potentially increasing the risk for TBI; b) matching cases and controls is very problematic due to substantial (and largely heritable) individual variability in brain structure and function and heterogeneity of brain damage; c) single neuroimaging modalities provide only a limited insight into the consequences of mTBI; d) in cross-sectional studies, the effects of mTBI may be confounded with the effects of substance use. The proposed study will address these critical barriers to progress using a combination of rigorous and innovative approaches: (i) the co-twin control design that will provide the best-possible controls for mTBI cases - their monozygotic co-twins without TBI history, (ii) multimodal neuroimaging assessments leveraging high spatial resolution of MRI and high temporal resolution of brain electrophysiology, and (iii) a longitudinal follow-up assessment of changes in substance use behaviors (onset, regular use, substance use disorder symptoms). Assessment will include structural, functional, and diffusion MRI, quantitative Gradient Recalled Echo (qGRE) MRI, a novel neuroimaging technique sensitive to cortical cellular microstructure, brain neurophysiology including resting-state EEG, and event-related brain potentials (ERP), methods that are sensitive to abnormal timing and synchrony of neuronal dynamics. The following Specific Aims will be pursued: Aim 1: To identify long-term consequences of mTBI in early adolescence and distinguish them from pre-existing factors potentially associated with risk for mTBI using a cotwin control design. We hypothesize that, in mTBI- discordant monozygotic pairs, twins with lifetime history of mTBI will show alterations in brain structure and function and deficits in neuropsychological performance compared with their cotwins without mTBI history; Aim 2: To determine, both cross-sectionally and prospectively, whether mTBI is associated with elevated risk for addictive behaviors. A better understanding of the mechanisms by which long-lasting neurobehavioral consequences of childhood and adolescent mTBI contribute to addiction risk will inform the development of more efficient treatment and rehabilitation approaches, as well as prevention of substance use and abuse and mental illness in youth with a history of mTBI.

NIH Research Projects · FY 2025 · 2023-09

Expanding evidence-based blood pressure/stroke prevention interventions for youth and their older adult caregivers (parents, grandparents, etc.) is critical to achieving the World Health Organization (WHO) and Nigerian goals for reducing the hypertension and stroke burden. Innovative strategies that engage local communities, link younger and older generations, and decrease health disparities are urgently needed. Music is a positive social determinant of health that is inclusive and can allow people to achieve healthy outcomes. It is also a non-invasive, safe, inexpensive, evidence-based implementation strategy, that can be used to engage youth in intervention design and evaluation tailored to their specific needs and those of their older adult caregivers. The effectiveness of music as an implementation strategy has been documented in various randomized control trials, including blood pressure and stroke prevention interventions. Nigeria also has a rich music culture that can be leveraged to increase uptake of evidence-based BP/stroke interventions. We propose “Innovative Tools to Expand Music-Inspired Strategies for Blood Pressure and Stroke Prevention (I- TEST BP/Stroke)” to accelerate behavioral BP/stroke campaigns in Nigeria inspired by music. I-TEST- BP/stroke will use participatory crowdsourcing methods to drive BP/stroke prevention among youth/caregiver dyads in Nigeria. Crowdsourcing open calls will allow us to identify locally relevant music-inspired campaigns to increase uptake of BP/stroke prevention. Then, apprenticeships with music and public-health professionals will build capacity for implementing these campaigns using common music elements (i.e., rhythms, beats, lyrics) known to impact cardiovascular health. Our preliminary data from Nigeria demonstrate that youth can develop effective public health interventions using these participatory methods. Our partnership with the Nigerian Institute of Medical Research provides extensive experience in implementation research, participatory methods, and pragmatic trials. Building on this strong foundation, our multi-disciplinary research team proposes a hybrid type II implementation trial with these specific aims: (1) to develop a new, combined, music- inspired BP/stroke campaigns for youth/caregiver dyads using crowdsourcing open calls and apprenticeships; (2) to determine whether the final music-inspired campaign increases uptake of BP/stroke prevention interventions among youth and their caregivers using a stepped-wedge, pragmatic randomized controlled trial (RCT) in 30 geographic areas; (3) to use mixed-methods approach to explore multi-level factors that influence the uptake of the music-inspired strategy. Our primary outcomes will be the uptake of strategy and BP/stroke preventive measures defined here as maintenance of normal BP rates for youth, systolic blood pressure reduction for caregivers, and increase in stroke preparedness knowledge. Secondary outcomes are reach, fidelity, acceptability, and sustainment. Our study is responsive to the strategic priorities of the United States National Institutes of Health, Sound Health, the WHO, the Nigerian Ministry of Health and PAR-22-132.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Mutations in genes that glycosylate alpha-dystroglycan (α-DG) are frequent causes of a spectrum of muscle disease ranging from congenital muscular dystrophy (CMD) to childhood and adult onset limb-girdle muscular dystrophy (LGMD). These devasting myopathies are deemed dystroglycanopathies and cause muscle wasting, progressive weakness, and degeneration of skeletal muscle leading to loss of ambulation, difficulties in breathing and premature death. The α-DG glycosyltransferase genes include, among others, FKTN, FKRP, POMT1, POMT2, and POMGNT1 and together account for >50% of genetically diagnosed CMD/LGMD. Accurately diagnosing patients with CMD or LGMD before symptom onset or early in the course of the disease has the potential to enable the use of preventative gene therapy or other therapeutics and in most cases can only be done through genetic testing in pre-symptomatic individuals or prenatally. When a new DNA variant in one of these genes is observed in a patient, however, there is often insufficient evidence to classify it as pathogenic. Within this study, we will use a new approach to express and characterize every possible missense variant in the assessed genes to advance our understanding of dystroglycan biology, improve the interpretation of genetic variation in dystroglycanopathy genes, and advance CMD/LGMD care and treatments. We will employ deep mutational scanning, a method for measuring the effects of massive numbers of missense variants of a protein simultaneously. Further, as only a subset of CMD and LGMD patients have potentially pathogenic variants in known muscular dystrophy genes, we will perform CRISPR screens in different cellular contexts to identify genes contributing to abnormal alpha-dystroglycan function. Our two aims are: 1) Quantifying the effect of nearly every possible missense variant in FKTN, FKRP, POMT1, POMT2, and POMGNT1 on protein stability, alpha-dystroglycan glycosylation and cellular adhesion and 2) Perform in-depth analysis of dystroglycanopathy patient variants integrating multiple in vitro assays, clinical information and patient specimen biochemical analysis to validate our DMS approach and disseminate pathogenicity predictions. The functional data we generate, the analyses we propose, and tools we build will transform the characterization of dystroglycanopathy gene variants. They will also serve as a resource to better understand muscle biology, improve the clinical translation of dystroglycanopathies and CMD/LGMD using genetic information, and inform new treatments.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY / ABSTRACT BACKGROUND: Socioeconomic differentials and their influence on health of older adults is disproportionately documented in high-income countries. Given socioeconomic, cultural and historical differences between these countries and low- and middle-income countries (LMICs), findings could be biased or even invalid for a universal generalization. Thus, aging studies on socioeconomic characteristics and health must be examined contextually. Among older adults, such investigations are rare and just published in the last twenty years. The hypothesis central to the socioeconomic status-health association is the negative relationship between socioeconomic characteristics and health outcomes, but the extent to which this association exists within a low-resource setting is not known among older adults of LMICs in Southeast Asia, particularly Cambodia. Considering individual nations' cultural and historical differences may impact how socioeconomic characteristics are conceptualized and measured, a precise examination of the topic is required. From the life course perspective, the older population with histories of violence and psychological distress must be studied within their cultural and historical context. Using survey data collected by this investigator in 2019, this study proposes to examine physical and psychological health of older Cambodians residing in a rural and low-resource setting in the northwestern Cambodia, using contextually sensitive measures and a rigorous theoretical framework. AIMS: This project aims 1) to characterize older Cambodians in terms of demographic characteristics, social support, socioeconomic characteristics, and physical and psychological health, 2) to examine associations of socioeconomic characteristics with physical health and psychological health among older Cambodians, and 3) to investigate potential mediating roles of social support and welfare support in the associations. METHODS: This study will use the most recent aging data of 220 older adults living in a rural setting of three Cambodian provinces. Dependent variables include the number of health complaints and psychological well-being index. Independent variables are household wealth index and a latent variable derived from three subjective self-perceived economic circumstances. Social support and welfare support are operationalized using Social Support and Social Network scale and status of welfare assistance, respectively. Descriptive analysis will be used to achieve Aim 1. Structural equation modeling will be used to examined Aim 2 and Aim 3. IMPLICATION: Findings will reduce disparity in social aging research in LMICs and have practical significance for development of programs and policies targeting older adults living in rural and low-resource settings. This investigation will further our understanding of the contextual socioeconomic characteristics and social support that may be modifiable to influence health for older adults in low-resource communities. This project is in direct response to Objective F-3 of the NIA 2020-2025 Strategic Direction to develop and implement strategies to increase inclusion of underrepresented populations in aging research. 1

NIH Research Projects · FY 2025 · 2023-09

Project Summary / Abstract My research program aims to understand cellular mechanisms underlying robust embryonic tissue patterning. Despite environmental fluctuations, tissues develop nearly identical patterns, shapes, and sizes among different stage-matched individuals. In contrast, artificial tissues grown in vitro are highly variable, limiting their value for disease modeling. How single cells can reliably sense and control tissue parameters remains an important open question in both developmental biology and tissue engineering. Departing from the traditional focus of patterning control by biochemical signaling, my research aims to understand how cells integrate biochemical and mechanical signals to detect and respond to changes in tissue pattern and shape. We are empowered by our expertise in in vivo live imaging, zebrafish genetics, computational modeling, and innovative approaches to manipulating tissues’ biochemical and mechanical environments. Using these multidisciplinary tools, we will test how cells incorporate mechanical information to detect tissue-scale changes that are challenging to detect by morphogen signaling alone. First, we will determine whether cells can sense the cell type identity of their neighbors through cadherin-based adhesion, and use this information to modify cell fate decisions and correct errors in tissue patterning. Second, we will identify mechano-responsive morphogen signaling pathways and investigate whether mechanochemical crosstalk allows the cells to infer their relative positions more accurately in tissues undergoing morphogenesis. By revealing how tissue parameters are encoded by biochemical and mechanical signals, and how cells decode mechanochemical signals to sense and control changes in tissue parameters, our research will elucidate the information flow from tissue-scale changes to cellular responses. Our work will establish cell adhesion and mechanical force as key channels of tissue information directing accurate cellular decisions in early tissue patterning events, a novel paradigm that will impact our understanding of development, mechanical consequences in diseases, and engineering strategies for artificial tissues.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract: More than 40,000 new rectal cancers occur annually in the US and the majority are locally advanced when diagnosed (LARC). Current total neoadjuvant therapy (TNT) with chemoradiation followed by surgery provides modest outcomes with a 20-25% pathologic complete response (pCR) rate and 5-year disease survival of only 65%. Therefore, there is an unmet need for new treatment approaches that improve LARC clinical outcomes and reduce morbidity. Using LARC patient samples and pre-clinical modeling, we recently identified a rationale for combining short course radiation therapy (SCRT) with inhibitors of the immuno-oncology target IDO1. Indoleamine 2,3 dioxygenase 1 (IDO1) metabolizes tryptophan along the kynurenine pathway and is recognized as a potent suppressor of tumor reactive immunity. Our robust findings identify IDO1 overexpression as a pathologic response in LARC therapy leading to immune-independent treatment resistance and an immunosuppressive TME. We found that: 1) Radiation induces IDO1 overexpression universally across LARC patients and in colorectal cancer (CRC) models regardless of MSI status. 2) IDO1 activity directly promotes critical mediators of CRC growth and treatment resistance (β-catenin and PI3K/AKT; 3) In mice, the potent IDO1 inhibitor epacadostat (EPA) sensitizes CRC to simulated SCRT radiation by relieving immune suppression and augmenting radiation induced CRC apoptosis. We have conducted a Phase I dose escalation study of epacadostat in combination with SCRT/chemotherapy, and identified EPA 400mg BID to be safe and shows preliminary evidence of efficacy. These findings lead us to conclude with following central hypothesis: IDO1 inhibition is a rationally selected adjunctive immunotherapy in CRC that enhances anti-tumor immunity, synergizes with DNA damaging therapy, and protects the normal small intestine. Project goals include: Defining efficacy of EPA/SCRT/chemotherapy as TNT for LARC and a pharmacodynamic basis for EPA in a biospecimen accruing Phase II trial with a randomized biomarker cohort (Aim 1). Defining biomarkers and identifying precision medicine approaches to support the further clinical study of this combination (Aim 2). We will leverage institutional experience and expertise, our established clinical trial infrastructure (NCT03516708), and a standard-of-care cohort, to address this central hypothesis Impact: If successful, we will take this approach to a potentially practice-changing, randomized phase III clinical trial using precision medicine approaches to address the unmet need to improve LARC patient outcomes. As IDO1 is also upregulated in other solid tumors treated by RT (cervix, anal, etc), the approach of combining EPA with genotoxic therapies might be expanded to other solid tumor types.

NIH Research Projects · FY 2024 · 2023-09

ABSTRACT Activation of immune cells plays a critical role in initiation and progression of multiple sclerosis (MS), leading to progressive neurodegeneration of the central nervous system (CNS). While glutamate imbalance has been described in MS brains and has been proposed to contribute to axonal damage and tissue destruction, the relationships between glutamate dynamics and immune activation during disease progression remain unclear. Presently, the lack of clinically available noninvasive imaging methods to detect immune cells and glutamate metabolism limits our understanding of MS pathogenesis and monitoring of responses to therapies. Recent development of radiotracers for positron emission tomography (PET) have shown great potential for detection of cells from the immune system and for imaging glutamate reuptake by astroglial excitatory amino acid transporter-2 (EAAT2). Specifically, 2'-deoxy-2'-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG) enables the detection of activated T-cells in inflammatory diseases and cancer models. [18F]Fluoro- fluorenylaspartyl amide ([18F]FFAA) has demonstrated the ability to measure EAAT2 activity in the CNS. Hyperpolarized 13C magnetic resonance spectroscopic imaging (HP 13C MRSI) is an emerging imaging technique which measures enzymatic reactions in vivo in real-time. HP 13C pyruvate has been shown to detect highly glycolytic cells from the innate immune system in peripheral and CNS inflammation models. Recently, pyruvate labelled on the second carbon position, [2-13C]pyruvate, provided a new way to monitor glutamate production in the human brain. This project proposes to validate these innovative noninvasive PET and MR methods to provide a new way to investigate the relationships between innate and adaptive immune responses and glutamate dynamics in preclinical MS models. The mentored phase of this project will develop and validate new neuroimaging technologies: Aim 1 will investigate the potential of [18F]F-AraG and [18F]FFAA PET imaging to visualize activated T-cells and glutamate reuptake during disease progression. Aim 2 will develop and validate HP [2-13C]pyruvate as a method to simultaneously detect pro-inflammatory innate immune cells and determine real-time brain glutamate production. The independent phase of this project will build on these initial results and Aim 3 will evaluate the potential of this multimodal PET and MRI approach to monitor immune responses, glutamate production, and astrocyte functions following therapy. Central to the success of this proposal, Dr. Guglielmetti will have the support and guidance from an established group of experts in neuroimaging, particularly HP 13C MR technology (Dr. Myriam Chaumeil and Dr. Peder Larson) and PET imaging (Dr. Henry VanBrocklin) as well as in neuroimmunology and MS (Dr. Ari Green and Dr. Zamvil), providing her with the necessary skillsets to embark on a career as an independent scientist.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY / ABSTRACT: Most forms of psychopathology have been increasingly recognized as brain disorders that emerge early in development and persist throughout the lifespan. Given the considerable costs of mental illness, it is imperative to develop ways of identifying adolescents who are the most vulnerable, which may lead to more precise and personalized interventions. Here, we propose using a novel predictive framework that may better capture the neurodevelopmental origins of psychopathology, thereby yielding more accurate predictions of psychopathology. Specifically, we plan to develop multi-task neural networks that are trained on spatial maps from three neuroimaging modalities and yield simultaneous predictions of an individual’s age (“brain age”) and psychopathology (“brain pathology”). By integrating predictions of brain age and brain pathology through this novel multi-task framework, we may derive models with improved predictive power, which would also be useful for uncovering the specific biomarkers that underlie each dimension of psychopathology. To investigate these research questions and replicate our findings, we will use multimodal neurodevelopmental data from two of the largest neuroimaging datasets that also contain three longitudinal timepoints – namely the Human Connectome in Development (HCD) and the Adolescent Brain Cognitive Developmental (ABCD) samples. In contrast to using single-task models, we hypothesize that the multi-task predictions of brain age and brain pathology would be better able at detect individual differences at any given point in time (Aim 1) and such predictions would best map onto within-subject changes throughout adolescence (Aim 2). Further, we will use multiple feature importance methods to identify which brain areas and neural properties added the largest predictive power to our most accurate models (Aim 3). This F31 proposal may prove useful in identifying adolescents who are most vulnerable to psychopathology (“personalization”) and accessing risk earlier in the course of development (“precision”). We will also make our deep learning models publicly available so that anyone could use them to yield out-of-sample predictions, which may have wide-spread applications for neuroimaging researchers and pediatric clinicians. Through the pursuit of these research objectives, the applicant will receive essential training in the following areas: 1) deep/machine learning methods, 2) multimodal neuroimaging, 3) advanced psychopathology, 4) conducting rigorous and reproducible research, 5) professional development as the applicant progresses toward a career as an independent, NIH-funded academic researcher. The assembled training team has substantial expertise in each of these subject domains. With their support, the applicant will develop the theoretical, analytical, and professional aptitude needed to foster his research and career ambitions. Altogether, this F31 proposal will be catalyst to help the applicant in his goal of becoming an independent principal investigator that uses multi-model approaches to delineate the most important determents of psychopathology and predict risk on an individual-basis.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract The prognosis for pancreatic ductal adenocarcinomas (PDAC) patients is dismal. Unfortunately, attempts at immunotherapy for PDAC to date using single agents have not achieved significant clinical benefits. This is likely due to the presence of a uniquely suppressive tumor microenvironment (TME). Our recent data suggest that immune priming by dendritic cells (cDCs) may ultimately a rate-liming barrier to productive anti-tumor immunity. While the focus of research in pancreatic cancer has been on the TME during primary disease, we are only now realizing how significant the differences in the TME are between primary and metastatic disease and/or metastatic lesions in different organs. These differences are critical, as the majority of immunotherapeutic approaches are being tested in refractory metastatic PDAC patients. We will address this shortcoming in understanding metastatic PDAC biology by determining the differential impact of metastatic disease site(s) on immune priming by cDCs. cDCs are central for generating tumor antigen-specific T-cell responses. In animal models and human correlative studies, cDCs are crucial for responsiveness to both cytotoxic and checkpoint immunotherapies. Our published data show that cDCs were severely dysfunctional in PDAC patients and that this dysfunction was driven by two distinct mechanisms. First, we reported that PDAC patients had impaired cDC development in their bone marrow, which led to a functional depletion of circulating pre-DCs, impaired cross-presentation of tumor antigens, and poor responses to checkpoint inhibitors. Even when DC development is not fully impaired, we've shown cDCs are dysfunctional and excluded from the PDAC TME. Overall, these mechanisms impair the ability of conventional therapies to prime tumor antigen-specific T-cell responses and checkpoint immunotherapy to drive efficacy. Together these data support our hypothesis that metastatic organ site-specific drivers lead to divergent effects on local and systemic tumor immunities. We will directly address this hypothesis with the following aims: Aim 1. Determine the impacts of the site of metastatic disease on immune priming by cDCs. Aim 2. Determine the impacts of the site of metastatic disease on systemic immunity and cDC development. Aim 3. Determine how therapy differentially shapes the TME at different metastatic sites to impact immune priming. Significance: These understandings are critical for the treatment of mPDAC patients.

NIH Research Projects · FY 2025 · 2023-09

Nigeria has a substantial number of preventable cancer deaths each year. The human papillomavirus (HPV) vaccine and hepatitis B (HBV) vaccine are both evidence-based strategies to prevent cancer, but they have not been widely scaled up in Nigeria. This suggests the need for innovative strategies that leverage implementation science and tap the collective wisdom of Nigeria, Africa’s most populous country. We propose the “US-Nigerian Cancer Control Center for Research on Implementation Science Excellence (C3-RISE).” Our overall mission is two part: (a) use participatory implementation science strategies (i.e. crowdsourcing open calls and apprenticeships) to expand uptake of HPV and HBV vaccines for cancer prevention; and (b) serve as a hub for excellence and capacity building in implementation science to advance the understanding of intervention uptake and sustainment of evidence-based interventions to prevent cancer. This project brings together an exceptional group of multi-disciplinary researchers from the Nigerian Institute of Medical Research (the apex federal health research organization, similar to the US NIH), Washington University in St. Louis, and the University of North Carolina at Chapel Hill. We propose the following aims: (1) To accelerate cancer control by developing, testing, and refining participatory implementation strategies to decentralize vaccines to prevent cancer in community settings; (2) To enhance the scientific productivity of C3-RISE by providing overarching operational and scientific oversight; (3) To support innovative research and the development of scholars trained to accelerate the uptake and sustainment of evidence-based cancer control interventions in Nigeria. These aims will be accomplished by a nurturing hub of two cores (Administrative, Capacity Building) alongside two research studies (Study 1 focused on HPV vaccination, Study 2 on HBV vaccination). Our three partner institutions launched a participatory implementation science project four years ago that directly informed national Nigerian health guidelines, trained 231 students, provided mentorship opportunities to 43 faculty, and culminated in a WHO/TDR practical guide on crowdsourcing for health (UH3HD096929). This led to a recently awarded NCI R01 grant (R01-CA271033) that uses participatory implementation science to develop innovative strategies to enhance HPV services in Nigeria. C3-RISE will leverage this momentum to catalyze cutting-edge cancer research, training, community engagement, and policy translation. Our project will increase excellence with implementation science, as it aligns with the Nigerian National Cancer Control Plan by focusing on participation, capacity building, and sustainment. This U54 grant application directly responds to NIH, NCI, and NIMH strategic priorities.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Interpretation of the clinical significance of somatic variants in cancer remains a major challenge in cancer diagnosis, prognosis and treatment prediction. The Clinical Genome Resource (ClinGen) has established extensive infrastructure including tools, web resources, procedures, and expert panel templates to help communities of experts establish the clinical relevance of genes and variants. However, ClinGen’s effort is almost exclusively focused on the interpretation of germline variants and their role in heritable phenotypes, leaving a significant gap in clinical interpretation of somatic variants in cancer. Concurrently the Global Alliance for Genomics in Health (GA4GH) has begun to develop standards for genomic data interoperability. The Clinical Interpretation of Variants in Cancer (CIViC) resource provides a sophisticated variant knowledge curation interface. In this application, we propose to create a knowledgebase of high quality assertions of the clinical significance of somatic variants in cancer that utilizes the CIViC platform, adapts the procedures of ClinGen to somatic variant interpretation and implements the interoperability standards of the GA4GH. This effort is needed to broadly enable research and clinical translation involving the use of somatic cancer variant knowledge as it relates to oncogenicity, diagnosis, prognosis and therapeutic response. By adapting the ClinGen germline model, we will establish processes to engage the expert community and facilitate the creation of Somatic Cancer Variant Curation Expert Panels (SC-VCEPs). Formation of these SC-VCEPs will support creation of a ClinGen Somatic Knowledgebase of clinical cancer variant assertions curated and approved by experts. SC-VCEPs will be the primary drivers of curation and domain specific guideline creation. We will adopt and guide ongoing development of several emerging standards that enable the Findable, Accessible, Interoperable, and Reusable (FAIR) principles for genomic knowledge sharing. Specifically, we will adopt the GA4GH Variation Representation Specification (VRS) and associated genomic knowledge framework of the GA4GH Genomic Knowledge Standards (GKS) Work Stream. We will also use our expert-driven curation activities to inform and develop curation and minimal information standards. Finally, we will use natural language processing (NLP) to accelerate a set of defined human knowledge curation tasks that currently limit the rate of human curation. Specifically, NLP will be used to (1) streamline curator activities through integration of text-mined data directly into CIViC; (2) prioritize papers based on their likely evidence level such as clinical trials or case reports; (3) identify and match a larger variety of cancer variant types through a variant hierarchy system; and (4) automate simple but time-consuming tasks such as enforcing consistent synonym usage. Our ultimate goal is to support a large community of domain-specific expert panels working together to create a public knowledgebase of cancer variants and their clinical relevance.

NIH Research Projects · FY 2025 · 2023-09

This project is intended to support the applicant as a clinician-scientist in leukemia at Washington University School of Medicine / Siteman Cancer Center supporting NCI-funded clinical research. The applicant will support the implementation of clinical research at the institution by 1) improving operational efficiency, 2) expanding program capabilities, and 3) ensuring protocol compliance to achieve the highest quality conduct of clinical trials that can improve the lives of patients with cancer The applicant will also provide scientific leadership to NCI-funded research as co-chair of the Leukemia Committee of the Alliance for Clinical Trials in Oncology and the Older AML Clinical Basket for myeloMATCH, the NCI Precision Medicine Initiative in myeloid malignancies. The Leukemia Committee of the Alliance will continue to conduct practice-changing treatment trials and further our understanding of the biological basis of leukemia and its treatment. In older adults with AML, myeloMATCH will test the combination of targeted therapies with hypomethylating agents and venetoclax to improve remission rates and validate the prognostic significance of flow cytometry based measurable residual disease. A companion geriatric assessment will be implemented across treatment studies to validate measures that predict treatment tolerance and benefit.

NIH Research Projects · FY 2024 · 2023-09

PROJECT ABSTRACT The prevalence of opioid use disorder (OUD) during pregnancy is rising, increasing the incidence of severe maternal, neonatal, and obstetrical morbidity and mortality. Although maternal OUD can be effectively treated with buprenorphine, leading to improved adherence to prenatal care and reduced obstetrical complications, fewer than 1 in 5 patients receive medication treatment for maternal OUD. In large part, so few pregnant women receive buprenorphine because it can be challenging to initiate effectively. Initiation (termed buprenorphine induction) must begin while a patient is in moderate withdrawal. If induction begins too early, buprenorphine will displace the other opioid from the μ receptor, precipitating severe withdrawal. Maternal withdrawal, both precipitated and anticipated, is associated with high relapse rates, non-adherence and lower treatment retention rates. Unsurprisingly, induction is a known critical time point for dropout in OUD treatment. Multiple alternative protocols for buprenorphine induction have been reported, including successful methods that do not require an opioid-free period or moderate withdrawal symptoms by using microdoses of buprenorphine, such as via a transdermal patch, as a bridge induction method to full sublingual doses. However, buprenorphine induction protocols have never been studied in pregnancy to determine the most effective type. We propose a prospective, mixed-methods study at two OUD-specific prenatal clinics to evaluate the feasibility of conducting an randomized controlled trial (RCT) comparing buprenorphine transdermal bridge induction versus standard sublingual induction in pregnant patients with OUD. In Aim 1, we will qualitatively assess feasibility domains using semi- structured interviews with 20 patients using buprenorphine to treat maternal OUD, 10 clinical team members who treats them, and 5 research team members. We will present the RCT protocol to interviewees, and ask for feedback on consensus-based criteria of recruitment capability, assessment procedures, and acceptability. We will solutions, ask interviewees to conduct a “premortem” exercise to predict potential etiologies of RCT failure, brainstorm and adapt the RCT protocol accordingly. In Aim 2, we will quantitatively assess intervention and research methods feasibility (eg, percentage of recruitment/retention goals, success of masking, intervention fidelity) and preliminary efficacy to minimize withdrawal symptoms by conducting a pilot RCT of bridge versus standard buprenorphine induction to treat maternal OUD (n=20 per arm). Results will provide preliminary data to aid in design of large, multi-site trial powered to rigorously assess the efficacy of induction methods on important obstetric and neonatal outcomes. If this larger trial shows that the bridge buprenorphine induction protocol is effective in multiple populations, this treatment protocol could be widely disseminated to improve outcomes for patients with maternal OUD and their infants.

NIH Research Projects · FY 2024 · 2023-09

Project Abstract Chronic pain is one of the most pressing public health burdens in the United States, affecting up to 20% of the population. Substance use disorders (SUDs) often co-occur with chronic pain. The relationship between chronic pain and opioid use disorder is often attributed to over-use in connection with post-operative pain, but the underlying mechanisms for chronic pain’s comorbidity with other SUDs (alcohol, tobacco, cannabis) are unknown. Depression often co-occurs with both chronic pain and SUDs and could be a mediator of the relationship between pain and SUDs. Socioenvironmental factors, including experiencing discrimination, may also play a role. Given the role of the brain’s reward system in both pain and SUDs, it is also plausible that some of the same genetic risk variants contribute to both chronic pain and SUDs. Both chronic pain and SUDs are moderately heritable and genome-wide association studies have identified loci contributing to their liability. However, these studies have focused on common variants in predominantly European ancestry individuals. This proposal, in response to RFA-PM-23-002, would leverage the multi-ancestral phenotypic and genomic data in All of Us to characterize the relationships between four of the most common SUDs (alcohol, tobacco, cannabis, and opioid use disorders) and chronic pain in a diverse sample. Our first aim will be to curate electronic health records to define a broad measure of chronic pain, as well as more detailed subtypes (e.g., neuropathic vs. nociceptive pain, musculoskeletal vs. visceral pain), and examine how these are related to SUDs. We will test whether a common risk factor, depression, partially mediates the relationship between chronic pain and SUDs. Further, we will estimate the extent to which social determinants of health (e.g., gender, socioeconomic background, experiencing discrimination) are associated with both chronic pain and SUDs. Our second aim will involve whole-genome analyses of chronic pain in multiple ancestries, identifying the genes and pathways that contribute to both chronic pain and SUDs, and employing genetically-informed causal inference models to identify reciprocal relationships. We will use the whole genome sequence data in All of Us to identify genomic factors – common genetic variants, as well as rare variants – that contribute to risk for chronic pain. Next, we will use genomic structural equation modeling and gene network analyses to identify genes and biological pathways that are shared (or distinct) between chronic pain and SUDs. Finally, we will apply multiple causal inference approaches to assess whether there is evidence for causal relationships between chronic pain and SUDs. This proposal will clarify the socioenvironmental and genetic mechanisms associated with chronic pain and SUDs through detailed phenotypic and large-scale genomic analyses on a diverse sample. The findings from these analyses will advance our understanding of why SUDs and chronic pain co-occur, leading to improved treatment and prevention efforts through the identification of shared biological pathways and modifiable psychosocial factors.

NIH Research Projects · FY 2025 · 2023-09

Neuronopathic lysosomal storage disorders (LSDs) are a group of fatal neurodegenerative diseases caused by genetic defects in components of the lysosome, which is the major site within the cell for the degradation and recycling of exhausted cellular components. Defective lysosomes accumulate undegraded storage material, which has classically been thought to be toxic for the cell and the driver of the pathogenic cascade of the dis- ease. Recent advances in the investigation of the lysosome, however, have shown that the storage burden it- self can be uncoupled from the most dramatic effects of the disease on the affected organs. Moreover, there are emerging roles of the lysosome as a central player in the regulation of cell metabolism which are distinct from its classical role as a cellular degradation site. The central hypothesis of this proposal is that are the changes in the communication between the lysosome and the rest of the cell, rather than the storage itself, that drive disease pathogenesis. Determining exactly which components of the lysosomal communication network mediate disease propagation, in which cell type, and how, is important because it could unveil the next generation of therapeutic targets. We propose to use innovative genetic tools and artificial intelligence-driven analytical pipelines to mechanistically investigate changes in lysosomal content and communication in the central nervous system of mouse models of two distinct LSDs. In Aim 1 we will catalogue LSD-associated changes in lysosomal content and composition and determine their relationship with LSD-specific cellular features based on the perturbation of components of the broad lysosomal gene metabolic network. In Aim 2 we will investigate the changes in the signaling network that mediates communication of the lysosome with the nucleus and determine the effectors of the cell’s response to lysosomal stress. In Aim 3 we will place the study of lysosomal content, signaling, and dysfunction in the context of specific cell types (neurons, astroglia, macrophages) to determine their role in the initiation and propagation of disease. Results from this study will provide the first atlas of changes in lysosomal content and signaling components in LSDs and will pioneer the integrative study of the lysosome as a multi-level network of causally associated components and pathways. Knowledge resulting from this study could lay the foundation for future translational investigation of treatments for neuronopathic LSDs.

NIH Research Projects · FY 2024 · 2023-09

Project Summary/Abstract Spinal cord injury (SCI) often results in reduced voluntary motor output, neuropathic pain, and autonomic dysfunction. Unfortunately, pre-clinical research and clinically available therapies alike have failed to adequately address the complex interrelationships amongst these changes in neural activity, despite widespread recognition that inappropriate neural transmission in overlapping spinal networks underpins them all. This mechanistic overlap suggests both that therapies intended to enhance recovery in one domain will likely impact multiple domains simultaneously and that it may be possible to leverage the dense interconnectivity of spinal networks to purposefully engineer multi-modal rehabilitation therapies – i.e., those specifically intended to address more than one consequence of SCI. The ultimate goal of this work is to enhance quality of life for people living with SCI by developing multi-modal therapies grounded in an integrative, neuro-mechanistic understanding of spinal cord function. Aim 1 (F99 Phase) will focus on neurotechnology-driven multi-modal therapies to simultaneously increase voluntary motor output while ameliorating neuropathic pain in a clinically relevant rat model of SCI. To do so, I will study potential contributions of neurons in the motor-dominant regions of the spinal gray matter to the spinal nociceptive process overall, which is traditionally only studied and characterized in the sensory- dominant regions of the spinal gray matter. We will test whether a latent pain-processing network is present in motor-dominant regions of the spinal gray matter, which becomes unmasked during periods of nociceptive transmission in rats with SCI. We predict that the emergence of this previously undetected network will be increasingly evident in rats with SCI-related neuropathic pain. If identified, this network could provide a new target for neuroprosthetic therapies to deliver multimodal rehabilitation benefits. This would address two critical unmet needs of the SCI population: non-opioid treatments for SCI-related neuropathic pain and multimodal rehabilitation. Aim 2 (K00 Phase) will focus on enhancing multi-modal rehabilitation intended to simultaneously improve bladder, bowel, and sexual dysfunction after SCI (i.e., pelvic floor dysfunction). Restoration of functions compromised by inappropriate neural control of pelvic floor muscles is a top rehabilitation priority for people living with SCI. Yet, despite its impact on physical and psychological health, the neural control of pelvic floor muscles is a comparatively understudied area of spinal physiology and neurorehabilitation. Thus, in the K00 Phase I will study the spinal neural control of pelvic floor muscles through the lends of somatic and autonomic integration, which is both essential for maintaining appropriate pelvic floor function and is disrupted by nearly every SCI. I will then be prepared to establish an independent research line developing multi-modal therapies that address the intersectional challenges faced by people living with SCI-related bowel, bladder, and sexual dysfunction.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Exceptional longevity (EL) is strongly correlated with exceptional health span, lower risk and delayed onset of age-related diseases. Moreover, EL is a complex genetic trait, like aging-related diseases, affected by polygenic targets, and other factors, like sex, ethnicity, lifestyle choices, social and environmental factors. Thus, in EL studies, single protective genetic targets usually have weaker effects upon survival to extreme age. Whereas, the right combination of genetic targets, as well as other factors, can have a stronger effect. Therefore, it is important to discover these protective factors, genetic targets and subsequent signaling pathways of EL, which are the critical basis to guide the development of novel medications and management for disease prevention/treatment to extend health and life span. Large-scale and multi-omics datasets, like genome, epigenome, transcriptome, proteome, metabolome, microbiome, phenome, of large-scale cohorts of centenarians and exceptional long-lived individuals, have been being generated in multiple EL projects. Whereas, it remains challenging to integrate and interpret complex multi-omics datasets. In response to the NIH RFA-AG-23-033, we propose to improve and develop novel artificial intelligence (AI) models that can efficiently integrate and interpret the EL multi-omics datasets, and identify risk and protective targets and medications to correct the disease risk signaling pathways for disease prevention and long and healthy life span extension. Deep learning (DL) and AI models have been widely used in the healthcare field and outperform traditional machine learning models, and thus offering solutions to this critical problem. We have rich experience in developing interpretable AI models of multi-omics data analysis for target ranking and core signaling network inference. In this study, we will (Aim 1) develop two (GNN) AI models, PathFormer and PathFinder, for unbiased core signaling pathways inference using multi-omics data (unbiased/unguided inference); (aim 2): develop a novel GNN AI model, modular k-Hop DeepNetFlow, for hypothesis guided core signaling pathway inference using multi-omics data (semi-guided inference); (Aim 4): develop novel DeepDrugMap knowledge graph, and Knowledge-driven, Multi-Module, Multi-Evidence (M3E) models to predict drugs that can boost protective signaling and inhibit the risk signaling pathways for disease prevention/treatment; develop a novel, open-source visual programming tool, LongevityOmicNet, to support the dissemination and reproducible analysis of the AI models with diverse supportive datasets, to the broader EL or aging study community. Also (Aim 3): collaborating with Dr. Michael Province (Co-PI), leading the LLFS project in WashU, we will apply these AI models to identify EL-associated protective factors, like the Sex, Genetics, Insulin resistance, Environment factors (SGIE-factors), and associated signaling pathways/biological processes, using large-scale multi-omics data of EL studies, i.e., LLFS, LG and ILO studies.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Pulmonary arterial hypertension (PAH) is characterized by a progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling that result in right heart hypertrophy, failure, and premature death. The underlying mechanisms of loss of capillary endothelial cells (ECs) and obliterative vascular lesion formation remain unclear. Our preliminary data showed that arterial programing was evident in human PAH patients and rodents. We hypothesize that general capillary ECs program to arterial ECs through HIF-2α-Cdk19/Sox17/Notch4 signaling which contributes to the pathogenesis of PAH. Completing our proposed study will provide a novel therapeutic strategy for the effective treatment of PAH in patients.

NIH Research Projects · FY 2025 · 2023-09

Washington University Post-Baccalaureate Research Education Program (WUP) is designed to provide rigorous research training and enrichment activities to recent college graduates in the biomedical sciences to better prepare them to apply, matriculate, and succeed in a PhD program. This program is based on the understanding that an in-depth mentored research experience supplemented with career enrichment activities will provide optimal preparation for graduate studies in the biomedical sciences. The research experience is complemented by a multi-tiered skill-enhancement program that integrates comprehensive scientific instruction and professional development to build self-efficacy, oral and written scientific communication skills, critical thinking and analysis, and ethical decision-making. Training in such skills is provided by a year-long WUP-specific journal club, numerous career development workshops, an ethics course, rigor and reproducibility training, academic courses, and other skill building activities. Although the training program is highly structured and logically organized, it is also personalized in that the Individual Development Plan (IDP) and the research interests of each participant are considered when selecting Mentors for one year of laboratory-based research. Scholars will choose from an array of mentors working in mechanobiology, biochemistry, cell biology, development biology, and regenerative medicine. WUP mentors have outstanding records of promoting the training, education, and career advancement of biomedical scientists and conduct rigorous, well-funded biomedical research. The WUP and its components will be assessed at specific intervals throughout the year, through participant, mentor, and director evaluations. The ultimate success will be measured by the matriculation of scholars into PhD programs, their completion of PhD programs, and their long-term success in biomedical science research and research-related careers.

NIH Research Projects · FY 2026 · 2023-09

Project Summary To improve our understanding of human disease in ancestrally diverse populations, we propose to establish the Washington University Omics Production Center (WU-omics PC). As part of the Multi-Omics of Health and Disease Consortium, the WU-omics PC will help design a collaborative plan to: (i) explore the use of multi- omics, environmental exposure data, and phenotypic information to assess disease states; (ii) develop methods for data harmonization, integration, and interpretation in multi-omics studies; and (iii) create a rich set of robust multi-dimensional data to share with the research community. In the first year of the award, the WU- omics PC will work closely with other members of the Consortium to design a project roadmap that details strategies for subject recruitment, the types of biospecimens to be collected, sample handling and shipping procedures, omics techniques to be performed, and best practices for transferring and integrating harmonized data. After year 1, we propose for the WU-omics PC to collect whole genome sequencing, whole genome bisulfite sequencing, ATAC-seq, RNA-seq, proteomics, and metabolomics data by using the agreed upon methods. The WU-omics PC will collect omics data by using well-established workflows that the same investigative team has already successfully applied to other multi-omics studies of similar scope and scale. Our omics workflows have been extensively benchmarked and we have detailed protocols for quality assurance, quality control, and correction of batch effects. The WU-omics PC is uniquely positioned to accomplish its goals because the infrastructure to perform large-scale, high-throughput omics assays is already in place. Moreover, the leadership of the WU-omics PC has a successful track record of participating in omics consortia and provides complementary and synergistic research expertise in genetics, biochemistry, analytical instrumentation, computational data processing, and multi-dimensional data integration.

NIH Research Projects · FY 2025 · 2023-09

Abstract Onchocerciasis (river blindness) is a major (vector-borne) neglected tropical disease caused by Onchocerca volvulus and proposed by the World Health Organization for elimination of transmission (EOT) by 2030. Currently, national control programs attempt to achieve EOT with mass drug administration (MDA) of ivermectin (IVM) to individuals aged ≥5 years over prolonged periods. IVM is microfilaricidal (kills the microfilariae, mf). By 2013, only a 31% reduction in mf prevalence was achieved since MDA with IVM began in the early 1990’s, making it clear that EOT using IVM alone would not be reached. The 2018 approval of moxidectin (MOX) for treatment of individuals aged ≥12 years was a significant milestone in enhancing the prospects of achieving EOT. However, as MOX is deemed to be mainly microfilaricidal (but see below), it will likely not be sufficient to meet EOT by 2030 in all endemic areas. Therefore, the development of new drugs and alternative treatment regimens to achieve onchocerciasis EOT is a pressing need. We propose to develop novel drugs and treatment regimens for facilitating sustained elimination of human onchocerciasis, based on our significant progress on: a) identification of filarial hit drugs with macrofilaricidal activity and their putative targets; b) demonstration that in vitro, MOX, a candidate MDA drug and emodepside (EMO), a macrofilaricidal repurposed drug under clinical development, target the early stages of worm development and could consequently prevent or reduce the establishment of adult worms (defined as having prophylactic potential); and c) transmission dynamics modelling incorporating prophylactic regimens with IVM or MOX that has already indicated that bi-annual or quarterly MOX MDA would greatly help accelerate WHO’s elimination goals compared to IVM. Our proposed aims build on the substantial progress we have thus far made and comprise: i) rationally designing novel macrofilaricidal drug candidates via medicinal chemistry optimization of known HIV-aspartic protease inhibitors (ritonavir, lopinavir, nelfinavir) that are active against 3 filarial species in vitro and in vivo; ii) evaluating in parallel, in vivo, the prophylactic potential of MOX and EMO (selected based on promising in vitro results and known PK and PD profiles in humans), and iii) evaluating innovative combination treatment approaches in vivo (using well-established filariasis animal models) as well as in silico by undertaking mathematical modelling to identify which suites of interventions would have the greatest potential to accelerate and protect onchocerciasis EOT in Africa. By the end of the project, we anticipate to have developed novel macrofilaricidal drug candidates which target one or more aspartic proteases for advanced preclinical studies and to have identified pioneering treatment regimens through prophylaxis that will augment the critically needed complementary tools for developing new integrated therapeutic strategies for facilitating sustained elimination of human onchocerciasis.