Washington University

NSF Awards · FY 2025 · 2025-10

The growing use of artificial intelligence in healthcare and medical research has created a difficult challenge: researchers need to share their computer models to advance scientific discovery, but these models can reveal private information about the patients whose data was used to create them. Organizations are often reluctant to share their computer models because of privacy risks, even though withholding these models prevents broader societal benefits from medical research. This creates a barrier to scientific collaboration that could otherwise lead to better treatments, improved public health outcomes, and medical breakthroughs. This project addresses this challenge by developing methods that allow organizations to safely share models trained on sensitive patient data without compromising individual privacy. Proposed research will result in new techniques for auditing models, certifying their privacy guarantees, and providing actionable tools to fix any identified issues. This work serves the national interest by advancing medical research and scientific discovery, enhancing national health and prosperity through improved healthcare technologies, supporting American competitiveness in artificial intelligence innovation, and enabling secure collaboration while protecting personal privacy rights. This project develops an end-to-end framework for privacy-preserving sharing of machine learning models trained on sensitive data. Despite growing interest in sharing models rather than raw data, machine learning models remain vulnerable to privacy attacks, such as membership inference attacks, which can reveal whether an individual's data was used during training. The research activities include four technical components. First, the project will evaluate the privacy properties of shared models by subjecting them to existing and newly tailored privacy attacks, establishing a foundational understanding of their vulnerabilities. Second, the team will develop formal privacy guarantees using methods like differential privacy and establish privacy-utility tradeoffs, creating privacy certificates for machine learning models that may include legal and usage constraints. Third, the project will design explainable auditing tools and privacy patching mechanisms such as machine unlearning to help developers mitigate risks without compromising model utility. Fourth, the research will build user-friendly tools to deploy these methods, focusing on real-world applicability in healthcare and biomedical research. The project will introduce a novel privacy-risk scoring system, enabling developers and regulators to assess the privacy risks associated with a given model. Unlike existing point solutions, this comprehensive framework integrates auditing, certification, and remediation into a unified system. Results will be disseminated through tools, publications, and educational modules to support broad adoption and training. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-10

This research aims to develop statistical tools to improve the reliability of artificial intelligence (AI) that is widely used in real-world systems such as automated decision-making, financial forecasting, and neuroscience research. Modern AI often relies on efficient machine learning algorithms to process large-scale, sequentially arriving datasets. While these algorithms are powerful, understanding their behavior and measuring their uncertainty remains a major scientific challenge. To bridge this gap, the investigators will focus on establishing mathematically rigorous methods for uncertainty quantification to build trustworthy AI. Applications will include enhancing theoretical guarantees and interpretability of neural networks, providing robust estimation and inference for econometric and biomedical studies, and detecting real-time change-points in high-dimensional time series data. The projects will promote the progress of science through open-source software and graduate education, and will support the national interest by contributing to reliable, data-driven decision-making in fields important to economic resilience, public health and national security. This research will provide a comprehensive theoretical framework for online statistical inference in machine learning, focusing on constant learning-rate stochastic gradient descent (SGD) algorithms. It addresses fundamental challenges such as non-stationarity caused by arbitrarily fixed initialization and complex dependency structures arising in recursive estimation. The investigators will derive the limiting distributions of SGD-type estimators and construct confidence regions with guaranteed asymptotic coverage. Specific efforts will include (1) establishing Gaussian approximations for high-dimensional dropout regularization, (2) deriving limiting distributions for SGD under non-smooth quantile loss functions using characteristic function techniques, and (3) developing online inference procedures for quantile change-point detection in high-dimensional time series using a novel Bahadur representation. These methods will be supported by numerical experiments and implemented in publicly available software. The results shall provide foundational advances for statistical inference in modern machine learning, bridging theoretical developments with practical applications in dynamic, high-dimensional environments. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-10

Non-technical description The field of optical engineering has reached such maturity that light scattering through a carefully design medium can replicate almost any function that a digital computer can perform, blurring the boundary between computational imaging and physical optics. However, nonlinearity – the seed of complexity in weather patterns, ecosystems, the human brain, and of course artificial neural networks – represents a key missing ingredient in all-optical image processing hardware. Intensity dependent light transport is well known, but it typically requires unreasonably bright light sources that are not found in everyday settings. By developing nanostructured pixels capable of trapping both heat and light, and efficiently generating heat from light, this project will produce nonlinear image processors that respond to the low power levels found in everyday light sources, such as LEDs and cheap laser diodes. This work will provide a big step towards economical object sensors capable of performing medical diagnostics, surveillance, and safety/security monitoring without needing a camera, computer chip, or even a battery. Inspired by creative individuals with no formal education in computer science or electrical engineering that solve interesting and important problems using high level programming languages and microelectronics kits, this project will also produce an “optical devices” apprenticeship. Developed in collaboration with industry experts, the course will train non-science students in the skills and techniques needed to realize useful nanophotonic systems via a guided-play based experience. Devices produced in the research portion of the project will be used within exhibits and workshops on all-optical image processing, targeting high school students to both inspire and empower them to enter the photonics workforce. Beyond science dissemination, these events will break misconceptions about scientific careers, highlighting creative expression and play rather than technical detail and mathematical rigor. Technical description In pursuit of nanomaterials that exhibit intensity dependence with exceedingly weak illumination, we will simultaneously optimize the contributions to nonlinear enhancement from both nano-structural resonances and intrinsic nonlinearities. This will allow us to discover and approach the upper-bound on nonlinear refractive index strength. Specifically, we will develop a new class of visible and infrared meta-atoms, referred to as dipolar guided mode resonators, that support extremely long-lived resonances while coupling efficiently to free space. These resonances will be optically and thermally tailored to amplify photothermal effects through a careful balance between radiation loss, thermal decay, and absorption. Addressing a crucial performance metric for any image filter – resolution – we will explore the fundamental limit for how densely an array of individually free space addressable high quality factor cavities can be arranged. The project will culminate in prototype demonstrations of one- and two-dimensional image thresholding filters with light sources ranging from picosecond pulses, amplified tunable diode lasers, and cheap fixed wavelength laser diodes and LEDs. As well as being a launch pad for all-optical machine vision research, we expect the devices we build to be directly applicable to low overhead commercial image sensors. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-10

NON-TECHNICAL SUMMARY: Nucleic acids and proteins are both incredibly powerful in their ability to encode information and perform specific functions, yet they each benefit from unique advantages with regard to designability and breadth of function. To date, synthetic polymers seeking to mimic these natural biopolymers only take advantage of a single code – either nucleic acid or protein. The proposed work explores "bilingual biopolymers" as a novel class of biomolecules that are able to simultaneously encode both nucleic acid and protein information, in turn providing greater control over structure and function. Specifically, the research will explore modification of the protein code to control – in both time and space – the chemical properties of these functionalities, which will in turn provide control over assembly and other activities. We will explore methods that enable both rapid quantitative switching of the protein code as well as time-released activation. This will in turn expand the capabilities of these molecules toward applications in drug delivery and sensing. The ability to modify the protein code while also harnessing the nucleic acid code will be used to modulate the location of RNA in cells, enabling control over cellular function and potential therapeutic applications. This research project will span the fields of materials science, chemistry, and molecular biology, providing undergraduate and graduate students with a highly interdisciplinary training experience involving the use of cutting-edge techniques. This project will also contribute to public access to science through a science communication project implemented in a course taught by the PI, as well as through the PI’s participation in outreach activities including serving as a judge for both science fair and an online scientific poster session. TECHNICAL SUMMARY: "Bilingual biopolymers" are a novel class of programmable materials capable of interpreting both peptide and nucleic acid information codes to direct assembly, disassembly, and guest release. Peptide nucleic acid (PNA) serves as an ideal scaffold for these polymers, as it has a peptide-like backbone that can be functionalized with amino acid side chains and is able to bind sequence-specifically to DNA and RNA. In preliminary work, amphiphilic PNA sequences have been developed in which the amino acid code directs assembly and the nucleic acid code is targeted for stimuli-responsive disassembly. The current project is focused on controlling the assembly state through chemical modification of the amino acid side chains, which will enable exploration of applications for the peptide code beyond micelle assembly. Specifically, the proposed experiments will: (1) Establish the relationship between side chain modification and disassembly using photocleavable caging groups. (2) Develop tunable time-released control of assembly state using thermally-responsive 1,2-dicarbonyl amino acid caging groups. (3) Explore the use of bilingual PNA oligomers to direct RNA localization to biomolecular condensates in a sequence-specific way. Together, this work will enable the dual coding nature of these biopolymers to be harnessed to develop materials with potential for use in probing important biomedical questions as well as for therapeutics and cellular delivery. Additional broader impacts of the proposed research include activities aimed at improving undergraduate education and universal access to STEM research and scientific knowledge. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2024 · 2025-09

Amyotrophic lateral sclerosis (ALS) is a rapidly fatal progressive neurological disorder characterized by the degeneration of motor neurons in the brain and spinal cord. Environmental exposures likely play an important role in ALS pathogenesis. However, due to difficulty recruiting large, representative samples of newly diagnosed ALS cases, these environmental risk factors remain largely unidentified. The proposed work will address this knowledge gap by comprehensively searching for new candidate environmental risk factors and then formally testing their association with ALS risk using a large population-based administrative dataset with >70,000 incident ALS cases from the U.S. We will systematically assess the nationwide relationship between ALS in 2002-2019 and nearly 200 air pollutants at the census tract level. Specifically, we will consider all “air toxics” and “criteria pollutants” as estimated by the U.S. Environmental Protection Agency, as well as fine particulate matter (PM2.5) and ultrafine diesel and jet aircraft emissions. In addition, we will agnostically search for geographic clusters of ALS to identify novel environmental risk factors for further examination in our study. We will prioritize candidates that might underlie the known association between military service and ALS. Based on our pilot statistical analyses we anticipate examining estuarine exposures using geographic indicators of naturally-derived volatiles, ultrafine particulate, and biotoxins, along with several disease vectors. Throughout our work we will account for correlated environmental exposures, demographics, and tobacco and alcohol use. Our pilot dataset that we constructed using the methods proposed here demonstrates the expected associations for these factors, medical risk factors, and lead. We will leverage our large nationwide dataset to test for interaction between the set of top exposures including lead. This will allow us to cross multi- exposure associations with the NIEHS-funded Comparative Toxicogenomics Database to identify potential biological mechanisms underlying ALS. We will enhance our screening of this database through in vitro experimental studies in which we compare the toxicity of selected chemicals on motor neuron subtypes, which recapitulate aspects of ALS-relevant neuronal vulnerability. We will develop regression models with summed concentrations of chemicals weighted by effects on relevant genes. We will attempt to replicate findings in a dataset with >50,000 additional incident ALS cases. For the most recent cases of all ages we will examine the above exposures in relation to ALS progression while also accounting for medical risk factors and treatment from a specialist or multidisciplinary ALS center.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Sequencing human genomes, especially those from individuals with Mendelian disorders, has yielded discovery of thousands of new disease genes and has led to personalized treatments, improving the lives of patients and their families. Unfortunately, less than half of this population is able to reap these benefits because, despite continued advances in sequencing technology and data analysis, many patients remain without a molecular diagnosis. A major barrier to increasing the diagnostic yield is the abundance of variants of uncertain significance (VUS), and in particular missense VUS, which are found in more than half of all patients. As more individuals are sequenced, the number and proportion of patients with missense VUS continues to grow, much faster than the field is currently able to interpret the functional significance of these variants. Therefore, it is critical to both scale up existing methods and develop new approaches to determine the pathogenicity of these VUS in as many genes as possible to help patients and families in need. One such method that offers hope for solving this VUS problem is Deep Mutational Scanning (DMS), which uses cell-based assays to simultaneously test thousands of missense variants by changing each residue in a protein of interest to all 19 other possible amino acids. However, it is currently very challenging to generate a cell-based assay that reliably reports the activity of a given gene of interest. Fortunately, combining DMS with a multiplexed fluorescence-based approach, SortSeq, gives an accurate assessment of deleteriousness and pathogenicity for variants in the GLI2 gene, which operates in the Sonic Hedgehog (SHH) signaling pathway. This proposed work will use this same well-validated assay to interrogate multiple genes involved in SHH signaling in order to determine the feasibility of a pathway-based approach for efficiently conducting DMS in many genes with the same molecular read-out. The scope of work is expanded to include a second pathway, the retinal development pathway, including DMS of CRX and OTX2, and leverages identical assays for paralogous families of transcription factors to further scale up the approach. This proposal also tests and validates an innovative computational pipeline that includes de novo biophysical predictions to understand the effects of variants in intrinsically disordered regions (IDRs), which is particularly synergistic with the focus on transcription factors, which typically contain large stretches of IDRs. Successful completion of these aims will establish multiple strategies for pathway-based and paralog-based scaling that can be quickly and easily adapted across many disease-causing genes, resulting in improved genome-based diagnostics and future therapeutics.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY This proposal describes a five-year training program to support the development of an academic, physician- scientist with a focus on advancing the understanding of cutaneous inflammatory diseases. The principal investigator has a strong track record of basic science research in the areas of molecular virology, immunology, and cell biology and seeks to enhance her expertise in centrosome, cytoskeletal, and keratinocyte biology. Central to her further training is a proposed mentored research project focusing on the role of centrosomal protein CEP43 in the maintenance of epidermal integrity and its link to immune activation. Keratinocytes prevent epidermal disruption and promote epidermal homeostasis by the formation of a highly organized network supported by specialized cell junctions and adhesion molecules that are supported by the cytoskeleton and organized by the centrosome. The PI presents preliminary data showing that targeted deletion of Cep43 in the epidermis leads to dysregulation of the keratinocyte cytoskeleton and robust psoriasiform rash. These data strongly suggest that the research plan will define new mechanisms linking keratinocyte and epidermal integrity to immune activation by focusing on the centrosome and the centrosomal protein CEP43 in particular, and that this approach will ultimately lead to the identification of novel pathways contributing to epidermal homeostasis that could serve as therapeutic targets for the treatment of inflammatory skin disease. The specific aims are: (1) Define mechanisms by which CEP43 loss leads to keratinocyte stress and p53 activation, (2) Define mechanisms by which CEP43 loss leads to inflammation and psoriasiform dermatitis. The research design employs cutting- edge techniques and novel animal models. Ultra-expansion microscopy (UExM) will be used for super-resolution imaging of centrosomal and cytoskeletal structures in keratinocytes. Newly created conditional knockout mice enable Cep43 deletion specifically in keratinocytes, followed by phenotypic analyses using histology, transmission electron microscopy, and transcriptomic profiling to assess cellular stress responses and inflammatory pathways. The candidate’s career development plan includes hands-on training in UExM and participation in leadership, mentorship, and grant-writing workshops. Regular mentorship meetings with Dr. Marco Colonna, a world expert in innate immunity, and Dr. Moe R. Mahjoub, a leader in centrosomal and cytoskeletal biology, will provide robust guidance. Washington University in St. Louis provides a supportive environment with state-of-the-art facilities, a collaborative research community, and guaranteed protected research time. This environment, combined with strong mentorship and advanced resources, will enable the candidate to successfully transition to an independent investigator and significantly advance our understanding of cutaneous inflammatory diseases.

NIH Research Projects · FY 2025 · 2025-09

Depression is the leading cause of mental-health related morbidity worldwide and approximately 19.4 million US adults and 3.8 million US adolescents are affected annually. Emerging evidence suggests that prenatal exposure to legacy (polybrominated diphenyl ethers, PBDEs) and replacement (organophosphate esters, OPEs) flame retardant chemicals increase the risk of maternal postpartum depression and symptoms of depression in young children. Despite widespread evidence of their neurotoxic effects and endocrine disrupting potential, there are limited studies investigating impacts of PBDEs/OPEs on mental health outcomes, and there have been no studies that have investigated effects of PBDE/OPE mixtures on depression. We hypothesize that higher prenatal exposure to OPEs and PBDEs is associated with altered maternal depression trajectories in the first eight postpartum years and with greater symptoms of depression in childhood (age 6-8). We also hypothesize that childhood adversities, resilience and familism may be important modifying factors for PBDE/OPE exposure effects on maternal depression trajectories and childhood depressive symptoms. We propose to investigate the following specific aims in 500 mother-child pairs participating in the MADRES cohort in Los Angeles. Aim 1 will investigate individual and joint effects of prenatal exposure to PBDEs and OPEs with maternal depression trajectories from pregnancy through eight years postpartum. Aim 2 will investigate individual and joint effects of prenatal exposure to PBDEs and OPEs and early childhood OPEs with parent- and child-reported depressive symptoms at ages 6-8 and will examine whether these relationships differ by child sex and maternal depression. Aim 3 will examine the modifying roles of maternal and child exposure to adversities, maternal resilience and maternal-reported familism on the associations between OPE/PBDEs and maternal depression trajectories and child depressive symptoms at ages 6-8. As exposures to environmental chemicals and mental health outcomes disproportionately impact pregnant women, it is an urgent priority to understand the contribution of modifiable risk factors to develop effective public health intervention and prevention strategies.

NIH Research Projects · FY 2025 · 2025-09

Abstract Since natural killer (NK) cells can kill tumor cells that also stimulate NK cell production of cytokines, there is intense current interest on how to harness NK cells to advance immunotherapy of cancer. Most strategies guiding such work focus on markedly enhancing NK cell responses to tumors. However, our understanding of NK cell biology in the context of immune checkpoint therapy (ICT) of cancer is poorly understood. Contrary to expectations, here the applicant’s laboratory presents preliminary data indicating that antibody-mediated NK cell depletion or genetic absence of NK cells enhanced ICT in mice, suggesting NK cells subvert ICT. Moreover, transfer of NK cells into the tumor itself in mice genetically lacking NK cells restored subversion of ICT. Furthermore, anti-NKG2D also enhanced ICT. Finally, the applicant provides evidence from human tumor databases that a similar process may be occurring in patients. Thus, NK cells subvert ICT and NKG2D appears to be involved in this process. Therefore, the Specific Aims of this proposal are to: 1) Elucidate effector mechanism(s) by which NK cells constrain ICT; 2) Evaluate contribution of NKG2D; and 3) Translate mouse findings to human tumors. Taken together, this proposal will lead to increased insight on the role of NK cells in ICT and will help guide new strategies to modulate NK cells for improved cancer immunotherapy.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT The gut microbiome is a complex ecosystem of microorganisms that live in the gastrointestinal tract. The gut microbiome and alterations to the gut microbiome, or dysbiosis, are linked to a number of human diseases. Variation in the gut microbiome plays a key role in microbiome-associated disease, but the rules governing microbial community dynamics are still being discovered. The composition and function of gut microbial communities change in response to variation in the host’s internal and external environment. While changes in response to antibiotics, disease, and diet are profound, gut microbiome changes associated with normal variation in host physiology or differences in host genetics are more subtle. Research in my lab focuses on understanding drivers of gut microbial community dynamics, particularly those related to changes in the environment or variation host physiology. Both environmental and host influences on the gut microbiome have been studied, but the relative contributions of each are still unclear and the mechanisms underlying these interactions have not been fully explored. My research program will focus on three main themes over the next five years: 1) examining how environmental and host factors interact to shape microbial community development and variation across an individual’s lifespan; 2) developing a more complete understanding of how normal variation in host physiology influences the gut microbiome; and 3) revealing the mechanisms by which host physiology contributes to variation in the gut microbiome. My lab uses metagenomics coupled with behavioral observations and non-invasive and minimally invasive methods to track hormones and immune activity to detect associations between environmental change, host physiological variation, and the gut microbiome in both wild animal systems and humans. Additionally, we pair this approach with cutting-edge computational tools and in vitro fermentation methods to determine the directionality and causality of relationships between the gut microbiome and host factors. This approach will allow us to understand the fundamental rules governing host-associate microbial community assembly and dynamics. This project will significantly contribute to our understanding of the range of normal variation in host-microbe interactions. The results of this project are key to predicting drivers of gut microbial dysbiosis and designing effect microbiome- targeted interventions and treatments.

NIH Research Projects · FY 2025 · 2025-09

Muscular dystrophies and myopathies encompass a large group of genetic diseases characterized by overlapping and indistinguishable clinical features but are caused by sequence variants in more than 200 genes. Accurate diagnosis and prevalence estimates for these disorders are essential for timely therapeutic development and high-quality patient care, yet up to 50% of patients do not receive a definitive molecular diagnosis despite increasing access to next-generation sequencing tests. This proposal aims to bridge the gap between genetic testing and patient care by defining the clinical relevance of genes and genetic sequence variants asserted to cause muscular dystrophies and myopathies. Using the frameworks and infrastructure of the NIH-funded Clinical Genome Resource, we will evaluate the clinical validity of the relationships between genes and muscular dystrophies and myopathies and assess the pathogenicity of individual variants in these genes. The outcomes of these efforts will support the development of more focused, consistent, and comprehensive multi-gene panels and clarify the diagnosis of patients to ensure their eligibility for impending therapies and clinical trials. These efforts will be iterative and build over time: The accumulation of variants with confirmed, FDA-approved classifications of pathogenicity will be used to further refine the criteria used to evaluate pathogenicity and to clinically validate large-scale functional assays, potentially replacing invasive muscle biopsy as a means of diagnostic clarification. In addition, proven assertions of gene-disease validity will lay the groundwork to assess the pathogenicity of variants in an increasing number of genes. This rigorous curation effort will provide the necessary foundation of comprehensive, standardized clinical genetic knowledge to advance therapy development and improve patient care.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY: Obesity is a complex disease that greatly increases the risk of developing insulin resistance, type 2 diabe- tes, and other cardiometabolic diseases. Obesity is also associated with chronic low-grade inflammation and a dramatic increase in the number of adipose tissue macrophages. Macrophages are the predominant immune cell within adipose tissue, and in obesity, these macrophages become activated and elicit an inflammatory re- sponse that has been associated with insulin resistance. Importantly, macrophage activation is tightly linked with metabolic reprogramming. Specifically, inflammatory macrophages exhibit high rates of anaerobic glycoly- sis while pro-resolving macrophages rely more on oxidative phosphorylation. However, very little is known about macrophage branched chain amino acid (BCAA; leucine, isoleucine, and valine) metabolism. This is a critical gap in knowledge since obesity is linked with elevated plasma BCAA concentrations, which are predic- tive of the future development of type 2 diabetes. Since elevated BCAA levels and adipose tissue macro- phages are both correlated with obesity and insulin resistance, there is a critical need to understand how mac- rophages process BCAAs in metabolic disease and to determine whether BCAA metabolism influences macro- phage activation and tissue insulin resistance. Our long-term goal is to define the pathways controlling macrophage function to develop novel therapeutic options that improve the health of people affected by metabolic disease. The overall objective of this applica- tion is to determine how macrophage BCAA metabolism contributes to the development of obesity-related met- abolic dysfunction. The rate-limiting step of BCAA catabolism is catalyzed by branched chain keto acid dehy- drogenase (BCKDH). BCKDH activity is negatively regulated via phosphorylation by the BCKDH kinase. In contrast, protein phosphatase 1K (PPM1K) activates BCKDH by removing the inhibitory phosphate group to increase BCAA catabolism. This proposal seeks to test the novel hypothesis that macrophage Ppm1k in- creases BCAA catabolism to reduce mTOR signaling and limit inflammatory cytokine production to prevent adi- pocyte insulin resistance. Our studies are designed to identify how PPM1K affects macrophage metabolism and activation, and determine how macrophage Ppm1k influences adipocyte function. Completion of our re- search proposal will uncover a novel aspect of macrophage metabolism and provide further clarity to uncover the role of BCAAs in the development and progression of metabolic dysfunction, which may provide insights into innovative targets to decrease the burden of metabolic disease.

NIH Research Projects · FY 2025 · 2025-09

Title: PET Imaging of Chemotherapy-Induced Cardiotoxicity Abstract. Cardiovascular disease is now the second leading cause of long‐term morbidity and mortality among cancer survivors. Both conventional chemotherapy and targeted therapies are associated with an increased risk of myocardial damage, resulting in left ventricular dysfunction and heart failure. Overall, cardiotoxicity from chemotherapeutic agents have been observed with drugs encompassing wide range of structural domains, including anthracyclines (Doxorubicin), alkylating agents (Cisplatin), taxanes (Paclitaxel), and monoclonal antibodies (Herceptin etc). Therefore, noninvasive detection strategies capable of providing a very early and specific readout prior to development of decreased cardiac function could significantly impact patient care, allowing for early treatments of cardioprotective therapies and modification of chemotherapeutic regimens. To accomplish this objective, our team has developed 68Ga-Galmydar, a novel PET tracer which gives a highly sensitive and specific functional readout of mitochondria status within the myocardium. Deploying the fluorescent traits of this molecular imaging probe, we have performed live-cell fluorescence imaging which has shown a gradual decrease in uptake and retention of Galmydar within mitochondria of H9c2 cells following DOX-treatment. Data show uptake profiles that are both dose- and time-dependent. 68Ga-Galmydar micro-PET/CT imaging demonstrates a 1.91-fold lower uptake and retention in hearts of DOX-treated rats compared to their vehicle treated control counterparts. Biodistribution studies performed post-imaging also confirm these imaging derived- SUV data. These data strongly indicate that 68Ga-Galmydar PET imaging has the potential to serve as a noninvasive strategy for the detection of DOX-induced cardiotoxicity at earliest stages. Armed with this provocative preliminary data, the specific aims of this RO1 proposal are: 1) A. Assess the potential of 68Ga- Galmydar to monitor chemotherapy (DOX, Paclitaxel, Herceptin)-induced cardiotoxicity with or without cardio- protectants and perform comparative analysis with 2 reference standards (13N-Ammonia; perfusion and cell viability marker) and fasting 18F-FDG (inflammation marker) in rabbit models in vivo. B. Validate the potential of 68Ga-Galmydar PET imaging to provide early detection of cardiotoxicity prior to other imaging-demonstrable functional and structural myocardial abnormalities. Specifically, PET findings will be compared to MRI-determined myocardial strain, and native myocardial T1 values, T2 values, extracellular volume (ECV), and late gadolinium enhanced (LGE) imaging, under identical conditions. Rabbit models will be imaged with PET/MRI. 2) Evaluate 68Ga-Galmydar potential for noninvasive detection of chemotherapy-induced cardiotoxicity in breast cancer (n=10) and lymphoma patients (n=20, 15 males and 5 females) and perform comparative analysis with 18F-FDG to evaluate concurrent myocardial inflammation (as positive contrast to expected 68Ga-Galmydar signal decrease) in same participants. Successful completion of the proposed aims will deliver a versatile molecular PET imaging tracer for monitoring earliest stages of myocyte impairment in patients undergoing chemotherapy, thus steering the field towards imaging-guided stratification of treatment plans within medical oncology and benefiting the management of cancer patients.

NIH Research Projects · FY 2025 · 2025-09

Elucidating how lineage specification occurs at the top of the hematopoietic hierarchy has tremendous implications for treating impaired blood production. The critical contribution of lineage-biased multipotent progenitors (MPPs) to steady-state hematopoiesis emphasizes the importance of uncovering the mechanisms underlying lineage-biased MPP production from hematopoietic stem cells (HSCs) and the lineage specification mechanisms at the MPP population. Despite its potential clinical significance to efficiently modulate myeloid cell production, how initial myeloid lineage specification occurs at the adult HSCs and MPP populations remain poorly understood. Our recent discoveries of distinct subsets within a granulocyte/macrophage (G/M)-biased MPP, MPP3 and their differential lineage potentials indicate the bifurcation point for G/M versus erythroid lineage at the MPP3. Based on those findings, this proposal aims to establish signaling pathways that control G/M versus erythroid cell production at the HSC and MPP levels. In Aim 1, we will investigate the role of Notch2 signaling in the production of erythroid lineage cells using old mice and Notch2 gain-of-function mice. In Aim 2, we will interrogate the function of unfolded protein response (UPR) signaling in the production of myeloid cells in vivo using chemical activators and inhibitors. Collectively, these studies will verify the function of Notch2 and UPR signaling in the production of erythroid and myeloid cell production in vivo, respectively.

NIH Research Projects · FY 2025 · 2025-09

This proposal aims to quantify the link between social determinants of health (SDoH) and psychopathology in adolescence. As social and environmental factors are robust predictors of positive life outcomes, it is important to understand the variable ways in which they affect development. Factors such as low socioeconomic status and environmental adversity have been linked to increased risk for psychopathology, but individual responses to these challenges differ, suggesting that the effect is not immutable. Here, I propose to identify factors associated with deviations in expected psychopathology using childhood behavioral problems as a metric. To this end, I will apply machine learning models to an existing large and longitudinal dataset of children, the Adolescent Brain and Cognitive Development (ABCD) Study, to estimate expected psychopathology based on SDoH. Next, I will use the difference between predicted and reported psychopathology to generate a psychological resilience/susceptibility estimate, which is the extent to which one’s actual psychopathology deviates, for better or worse, from their model prediction. Estimating this gap will allow for the identification of neural and genetic factors associated with better- than-expected and worse-than-expected psychopathology. Aim 1 involves generating an individualized framework for accurately estimating psychological resilience/susceptibility. I will train and optimize a machine learning model to predict a behavioral problems score based on broad SDoH data, encompassing prenatal, interpersonal, and community-wide factors. Once a model of sufficient accuracy is achieved, model predictions for each individual can be compared to actual psychopathology, and the difference in scores will comprise psychological resilience/susceptibility (RS-Gap). The RS-Gap will be validated using psychiatric diagnoses at a follow-up timepoint, and associations with longitudinal quality of life measures (e.g., sports participation, grades, and substance use) will also be assessed. The goal of Aim 2 is to identify genetic correlations between RS-Gap and traits of interest such as impulsivity and neuroticism within the ABCD cohort. I anticipate a shared genetic basis between RS-Gap and predisposition to psychiatric disorders. Finally, Aim 3 concerns neuroimaging measures associated with psychological resilience/susceptibility. I hypothesize that the RS-Gap will be associated with structural and functional differences in brain areas associated with stress reactivity and emotion circuits. Together, these results will identify risk factors for the development of psychopathology and serve as a new avenue to study the pre- onset stages of neuropsychiatric disease. The activities in this proposal will be conducted in an exceptional training environment to help my development into a productive and independent researcher. I will learn to conduct science that is rigorous, reproducible, and statistically sound, to effectively communicate my findings to a range of audiences, and to mentor young scientists to do the same.

NIH Research Projects · FY 2025 · 2025-09

Abstract The intestinal epithelium acts as a physical barrier to separate the luminal contents from the underlying tissue compartment of the organ. Typically, any damage caused by medications or environmental toxins is promptly repaired to maintain homeostasis. However, in chronic inflammatory conditions such as inflammatory bowel diseases (IBD), ability to heal wounds is dysregulated perpetuating chronic inflammation. Healthy endogenous microbiota is being increasingly recognized to promote repair, yet the specific mechanisms by which microbes guide repair remains elusive. Moreover, majority of the studies have focussed on bacteria, how nonbacterial members such as fungi modulate wound repair remains unknown. Using murine models of injury and repair and human isolates of fungi, we discovered that endogenous fungi are critical for crypt regeneration post injury. Importantly, the repair promoting effects were specific to the fungal strains that are depleted in IBD. Our preliminary data suggests that endogenous fungi engage epithelial cells to induce Palmitoylethanolamide (PEA), a lipid metabolite, which in turn inhibits inflammatory activation of fibroblasts to promote wound repair. Here we will use conditional knockout mice, single cell RNA sequencing, primary epithelial and fibroblast cultures, and metabolomics to investigate how endogenous fungi alter epithelial transcriptome to induce PEA (Aim 1) and the specific mechanisms by which PEA inhibits inflammatory activation of fibroblasts to promote repair. Successful completion of these aims will give a mechanistic understanding of a previously unappreciated role of endogenous fungi in modulating epithelial cells and fibroblasts to enhance intestinal wound repair. Additionally, it will uncover novel targets for stimulating crypt regeneration in inflammatory conditions of the gastrointestinal tract.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Sleep loss is frequently reported early in tauopathies, which are neurodegenerative diseases such as Alzheimer's disease (AD), where abnormally hyperphosphorylated tau protein accumulates in the brain. Extensive evidence suggests a reciprocal relationship between sleep-wake disruption and enhanced tau aggregation, with the accumulation of tau aggregates further disrupting the sleep-wake cycle in both animal models and humans. How sleep loss mechanistically contributes to neurodegeneration remains unknown, which is important as targeting early sleep dysfunction could be the key to combating neurodegenerative diseases. My recent publication demonstrated that subjecting healthy mice to sleep deprivation (SD) results in substantial inflammatory microglial reactivity and metabolic impairments in the brain, similar to those observed in disease mouse models. Furthermore, numerous publications from our lab have emphasized the importance of microglial reactivity in influencing neuronal damage and brain atrophy using the P301S mouse model of tauopathy. This is exemplified by the dramatic reduction in neuroinflammation and tau-mediated neurodegeneration in mice lacking expression of triggering receptor expressed on myeloid cells type 2 (TREM2), a gene selectively expressed in microglia in the brain. This led me to hypothesize that changes in sleep could epigenetically alter microglial responses to intraneuronal tau aggregates, thereby directly influencing the progression to neurodegeneration. To address this hypothesis, I used P301S mice lacking TREM2 or expressing the AD-associated R47H variant, or the common variant as a genetic means to identify distinct microglial responses influenced by SD. My preliminary data showed that chronic SD during early life followed by sleep recovery was neuroprotective and reduced TREM2-dependent microglial reactivity. This finding raises the intriguing possibility that sleep architecture can be re-trained to potentiate long-term transcriptional changes in microglia, reducing inflammatory damage and ultimately promoting neuroprotection by acting as an ‘epigenetic memory’ that determine disease outcomes. I will test this hypothesis in Aim 1. My pilot study also revealed that SD after onset of pathological tau overrides the neuroprotective effects of lack of TREM2 in P301S mice, leading to increased microglial reactivity and brain atrophy. This suggests that SD has the potential to exacerbate neuronal damage by epigenetically overriding the homeostatic restrictions on persistent inflammatory cascades typically maintained by the absence of TREM2 signaling in microglia. I will address this hypothesis in Aim 2. These aims will investigate the mechanistic impact of sleep on genetic regulatory processes within microglia, revealing its functional consequences in the context of tau-mediated neurodegeneration. A K99/R00 Award will provide me the opportunity to be trained in chromatin and methylation profiling as well as enhance my expertise in sleep and neurodegeneration research in the Wang and Holtzman labs at Washington University. These experiences will build the foundation of my future independent research in sleep and epigenetic mechanisms in neurodegenerative diseases.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY This proposal for a K01 Mentored Career Development Award details a Career Development Training Plan and Research Strategy to facilitate the candidate’s transition to an independent investigator role in diabetes research. In particular, the candidate’s long-term research goal is to make impactful discoveries that will enable a cell-based therapy to become a viable and widely-used treatment option for type 1 diabetes (T1D), alleviating the hardships and complications associated with this disease. To guide the candidate’s transition to independence, the Career Development Training Plan integrates a scientific research proposal investigating new aspects of β cell development and maturation, a mentoring team of experts in stem cell and β cell biology, and the world-class research environment at Washington University in St. Louis. T1D results from the selective autoimmune destruction of the insulin-producing β cells in pancreatic islets. Studies have shown that transplanting human cadaveric pancreatic islets into T1D patients reduces or eliminates the need for exogenous insulin injections, indicating that replacing the destroyed β cells can serve as a functional cure for insulin-dependent diabetes. However, issues with human donor islet supply, quality, and immunogenicity have limited the widespread use of this approach. In an effort to generate an unlimited supply of highly functional islets for cell therapy, excellent progress has been made in the generation of stem cell-derived islets (SC-islets) via direct differentiation protocols. In particular, these cells are able to replicate the first and second phase insulin secretion kinetics of primary β cells, the ability to cure severely diabetic mice within two weeks of transplantation, and further maturation after long-term transplantation. Despite these remarkable advancements, current generation SC-islets still lag behind primary human islets in terms of insulin secretion and overall islet composition. Emerging evidence has demonstrated that microenvironmental cues (e.g., substrate composition and mechanical properties) sensed by cells through their actin cytoskeleton play important signaling roles in cell behavior and fate selection in several model systems, but actin’s role in the directed differentiation of hPSCs to endodermal cell types has been very limited. To further enhance the specification to and maturation of SC- islets using these principles, this proposal seeks to leverage microenvironmental cues transduced through the actin cytoskeleton and its downstream pathways to improve pancreatic specification during gut tube organogenesis as well as during endocrine cell maturation. These studies aim to improve specification to pancreatic β cells, eliminate other undesired cell types (e.g., enterochromaffin cells), as well as enhance the functional maturation and identity of these β cells. Successful completion of these objectives will not only improve the clinical effectiveness of SC-islets but will also uncover fundamental insights into the biology of how cytoskeletal state influences endodermal cell development.

NIH Research Projects · FY 2026 · 2025-09

PROJECT SUMMARY Advancements in antiretroviral therapies have helped people with HIV (PWH) achieve longer life expectancies. Unfortunately, PWH still experience earlier onset and increased rates of aging-associated comorbidities. Sleep disorders and chronic pain are underappreciated age-associated comorbidities that PWH report being especially detrimental to their quality of life. Our recent work demonstrated that insomnia is significantly associated with enhanced experimental pain sensitivity, greater severity of bodily pain, and poor quality of life in PWH. Insomnia severity was also associated with a faster pace of biological aging in PWH as demonstrated by the DunedinPACE DNA methylation biomarker. Chronological aging simply reflects the rate of time passed since birth and is the same for all people. Biological aging reflects the decline in physiologic function resulting from the deterioration of molecular and cellular functions, which can vary widely across people. PWH often experience a faster pace of biological aging that exceeds chronological aging, which may help explain the excess burden of age-associated health comorbidities in this highly affected population. We recently published the results of a pilot study demonstrating that a non-pharmacologic intervention for sleep known as Brief Behavioral Treatment for Insomnia (BBTI) delivered via telephone was not only feasible to implement but also reduced insomnia and pain severity in PWH. These preliminary findings await confirmation via an adequately resourced and powered clinical trial. Therefore, we propose a clinical trial titled, “Healthy Behaviors for Insomnia Prevention in People with HIV and Ongoing Pain (the HIP HOP study)”, to be conducted in PWH with comorbid insomnia and chronic pain. This study will test whether a four-week course of telephone-based BBTI can significantly 1) improve sleep quality, 2) decrease experimental pain sensitivity and clinical pain severity, 3) improve quality of life, and 4) slow the pace of biological aging by assessing these variables at baseline, upon treatment completion, and at 3 months follow-up. There is often substantial variability in treatment responses for clinical trials with a behavioral intervention, like BBTI. Social impacts on health may help explain this variability. Neighborhood social environments (disorder, safety, and social cohesion) and sleep environments (noise, light, and comfort) may influence how PWH respond to BBTI. Relatedly, neighborhood disorder is associated with poorer sleep quality, greater bodily pain severity, poor quality of life, and a faster pace of biological aging in PWH. The HIP HOP study will also determine whether social environmental factors assessed at baseline influence how PWH respond to BBTI. Brief Mindfulness Training (BMT) will be included as an active control condition against which to compare the effects of BBTI. This study is significant because results will help solidify telephone-based BBTI as an efficacious and scalable sleep intervention for PWH while also elucidating whether pain improves, and the pace of biological aging slows.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY / ABSTRACT Osteoarthritis (OA) is the most common type of arthritis and a frequent cause of pain and disability. Osteoarthritis annually affects ~595 million adults globally, with anticipated rises in incidence due to aging of the population. Treatment guidelines for symptomatic OA of the knee, hip, and shoulder recommend non- surgical intervention as first-line care to delay or avoid joint replacement surgery. Intra-articular corticosteroid (IACS) injections are routine outpatient procedures for OA to reduce pain, decrease reliance on oral analgesic medications, and improve function and quality of life. Patients often report weeks to months of benefit and often receive several injections per year. Yet, uncertainty remains about the safety of single and repeated IACS injections. Systemic corticosteroids (often delivered orally or intravenously) are associated with serious adverse effects, including impaired immune response, cardiovascular disease, and accelerated osteoporosis. These risks are tolerated for corticosteroid treatment of life-threatening conditions, but risk tolerances are typically lower for elective procedures such as IACS injection. However, even though IACS injections result in systemic corticosteroid absorption, there is a lack of rigorous evidence about their safety. Most evidence comes from randomized trials that exclude high-risk patients and are limited by small sample sizes and short follow-up. Small clinical studies of the effects of IACS injections have demonstrated elevations in blood pressure and blood glucose, reductions in bone density, and increased risk of infection, but larger studies are needed. There is no evidence-based consensus on the maximum safe exposure level with respect to modifiable IACS injection factors including dose, timing, or frequency. Consequently, treatment guidelines for OA are inadequate and fail to offer best practice recommendations regarding maximum safe doses, maximum number of injections per year, minimum time interval between injections, or considerations for high-risk patients. Overall, the lack of evidence may lead to potential unnecessary harm. Rigorous evidence is needed to guide optimal pain management strategies to treat OA and determine the maximum safe exposure level of IACS injections. To fill this knowledge gap, we propose a large, non-experimental study to examine the utilization and safety of IACS injections. We will use Medicare claims data with ~17.4 million older adult recipients of IACS injections for the treatment of symptomatic OA of the knee, hip, or shoulder. We will characterize patterns of use of IACS injections and examine whether more frequent, closely spaced, and higher dose exposure to IACS injections are associated with increased risk of an array of individual adverse events (e.g., infections, cardiovascular events, osteoporotic fractures). We will perform subgroup analyses in medically complex patients. This large study will generate evidence to address critical gaps in knowledge about how to optimize the safety of IACS injections to treat symptomatic OA. Results will inform shared clinical decision-making, prevent harms, and promote continued independence among older adults in the community.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Osteoarthritis (OA) is a worldwide chronic joint disease that causes pain and disability, and limits daily activity. Hip OA is the second most common disease after knee OA. Currently, total hip replacement (THR) is the treatment of choice for advanced hip OA. Given that life expectancy is longer, and we have not found a cure for OA, it is predicted that THR cases in the United States will increase to more than 1.4 million cases per year by 2040 resulting in a tremendous cost for the healthcare system. Hip Femoracetabular Impingement (FAI) is the leading cause of hip osteoarthritis in the young adult hip population. While the number of surgical procedures to treat hip FAI has grown exponentially in the past decade, there is still a 10-25% failure rate following surgical treatment, with progressive deterioration of the joint leading to OA. Surgeries have outpaced the true understanding of the disease resulting in failures rates around 15%, where patients still progress to OA following surgical intervention. Therefore, there is a need to study the mechanisms involved in initiating OA upon FAI and address this scientific gap. Without a validated animal model, our ability to discover the mechanisms of disease progression is limited. With the goal of having a low-cost and easy to reproduce translational animal model, our group has developed a small animal model of femoral head deformity that results in hip OA. Given 1) that FAI and its progression to hip OA stems from a mechanically induced repetitive injury and 2) the mechanical differences between quadrupedal and bipedal species, it is necessary to validate this model to human FAI mechanically and biologically. The goal of this proposal is to confirm that the experimentally induced femoral head hip deformity is a validated model to human FAI, both mechanically and biologically. For this we will: i) Determine differences in the mechanical behavior of the hip joint cartilage 1) before and after experimentally induced femoral head deformity in a rabbit model of hip FAI and 2) compare these changes to those seen in human hip FAI and ii) Investigate expression of proven human key molecular players in the progression of hip OA secondary to FAI in cartilage samples from the established rabbit femoral head deformity model. This project has the potential to tremendously impact the field, as it will allow, for the first time, to have a low cost, small translational animal model of hip FAI and hip OA. This model could be used as a platform to understand in-depth the mechanisms of hip OA, test interventions and translate our discoveries to patient care.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Acute kidney injury (AKI) has a rising incidence among hospitalized patients and the risk for progression to chronic kidney disease (CKD) has been established in both pre-clinical and clinical studies; however, there is still a knowledge gap on the molecular mechanisms driving the AKI to CKD transition. We previously identified Foxm1, a transcription factor considered to be a master regulator of the cell cycle, as having a role in tubular epithelial proliferation in a mouse model of acute ischemic renal injury, Subsequent studies using genetic deletion mouse models demonstrated that Foxm1 is involved in proximal tubular epithelial proliferation after injury in vivo. Furthermore, impaired tubular proliferation due to Foxm1 deletion led to an early AKl-to-CKD transition phenotype highlighting its pro-repair role; however, the exact mechanism for the profibrotic effect of Foxm1 deletion is unclear. Our recent in vitro work has identified a novel Foxm1 target mediating proliferation - the cyclin family membercyclin F (CCNF), CCNF is a gene with a role in cell cycle progression and genome stability, Induction of cell cycle arrest and genome instability have been described to promote the development of cellular senescence. In preliminary studies, we observed that expression of cell senescence markers and components of the senescence secretory phenotype (SASP) correlate with repression of Foxm1 induction after injury suggesting that Foxm1 deletion may be driving increased cellular senescence. This let us to hypothesize that (1) Tubular epithelial cells that failed to repair undergo cellular senescence which drives the AKI to CKD transition and (2) this process is mediated by downregulation of the Foxm1-CCNF axis inducing cell cycle arrest and genome instability, In Aim 1, we will characterize how Foxm1 repression during tubular epithelial repair leads to cellular senescence and in turn transition to CKD. In Aim 2, we will determine if CCNF repression triggers the transition to cellular senescence and identify potential downstream pathways, In this application we aim to understand how alterations in the pro-repair effects of Foxm1 lead to unsuccessful repair and development of cellular senescence with the goal of identifying areas for therapeutic interventions through senolytics (cell senescence removal) or senomorphics (suppress the SASP),

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Globally, undernutrition remains the largest source of mortality for children under five years of age. Stunting (impaired linear growth) and wasting (low weight-for-height) respectively affect 148 and 45 million children; both are associated with permanent sequelae, including impairments in immunity and neurodevelopment and susceptibility to infection. While undernutrition is preventable, existing interventions fail to prevent these long-term complications, highlighting the continuing need for treatment options. Microbiota-directed complementary food (MDCF) formulations are novel therapeutic foods that were designed to treat undernutrition by repairing delayed microbiota development observed in these children. A clinical trial of Bangladeshi children with moderate acute malnutrition demonstrated that one formulation, MDCF-2, improved weight gain compared to a standard nutritional intervention. Gnotobiotic animal studies have implicated Prevotella copri, an organism which is prevalent in non-Western populations and encodes diverse carbohydrate utilization machinery, in mediating beneficial effects of MDCF-2. In mice fed MDCF-2, P. copri colonization promotes weight gain and degradation of arabinan, an abundant glycan in MDCF-2, and shifted microbial community metabolism towards utilization of arabinose and amino acid synthesis. However, it remains unknown whether P. copri mediates MDCF-2’s growth-promoting effects through direct products of carbohydrate catabolism or other metabolic activities, and to what extent these effects depend on interactions with other organisms. The central hypothesis of this proposal is that the growth- promoting effects of MDCF-2 are mediated in part by other organisms which utilize arabinose liberated by P. copri to synthesize tryptophan and indole derivatives. To test this hypothesis, the first aim of this proposal will identify contributions of individual arabinose-utilizing organisms to differences in amino acid and microbial metabolite levels that are observed with P. copri colonization. This will involve analysis of existing metagenomic (MGX), metatranscriptomic (MTX), and mass-spectrometric datasets from mice colonized with and without P. copri, as well as validation of cross-feeding by co-culturing of P. copri and arabinose-utilizing organisms in vitro. Due to limitations of existing methods, this aim will also require development of new statistical methods for differential expression analysis of paired MGX and MTX sequencing data. To test whether dietary arabinan supplementation is sufficient to recapitulate the beneficial effects of MDCF-2, the second aim will utilize gnotobiotic mouse models to assess the effects of arabinan on host weight gain, intestinal gene expression, and microbial community composition and metabolism. Together, these studies will reveal mechanisms by which active ingredients in MDCF-2 mediate its effects, informing future therapeutics for undernutrition. They will also evolve methodology for deconvoluting functional activities of individual microbes from complex community dynamics with numerous applications beyond childhood undernutrition.

NIH Research Projects · FY 2026 · 2025-09

MODIFIED PROJECT SUMMARY/ABSTRACT Fetal growth restriction (FGR) is a leading cause of fetal and neonatal mortality among Black women, affecting 10-15% of pregnancies. Known risk factors like placental insufficiency or economic status do not fully explain disparities in FGR. However, by integrating evidence from maternal physiology with nutrition-obesity research, I have developed the hypothesis that low maternal serum triglycerides (TG) may be a key factor in FGR development among Black women. This is based on strong evidence that 1) FGR is a state of fetal nutrient deprivation, 2) high maternal TGs are required for fetal growth, and 3) on average, Black women have lower TG levels during pregnancy, possibly due to genetic variations in the lipoprotein lipase gene that are common among African ancestry and rare for other ancestries. Genetic variation may lead to higher TG uptake in maternal tissues, fewer TGs for fetal growth, and ultimately to FGR. Hence, in this proposal, I aim to define the role of genetics, maternal and placental lipids, and extrinsic exposures in FGR among Black women. I am seeking a K01 career development award to acquire the training, mentorship, and dedicated time to test my hypothesis and to launch a successful independent research career. I have a strong background in 1) obesity and metabolism, 2) precision nutrition, and 3) maternal-fetal medicine research. However, to perform the proposed research and future studies, I need to meet the following training objectives: (1) perform high-quality translational investigation of lipid metabolism in pregnancy, (2) acquire fundamental skills in the collection and analysis of genetic data, and (3) analyze and interpret fetal growth and placental development, and 4) enhance my professional and project management skills. In synergy with my training objectives, my research aims are: Aim 1. Identify genetic polymorphisms and metabolic pathways that associate with FGR among Black women, Aim 2. Determine the association of maternal TG with FGR, birthweight, and placental TG transfer, and Aim 3. Identify modifiable protective factors that are associated with adequate fetal growth in Black women. To meet these objectives, I have established a strong multi-site scientific and professional development committee across three highly collaborative institutions with strong research infrastructure and state-of-the-art facilities. My primary mentors are Sarah K. England, PhD (maternal physiology) and Clay F. Semenkovich, MD (lipid metabolism); my specialized mentors are Camille E. Powe, MD (pregnancy genomics) and Teri R. Hernandez, RD, PhD (pregnancy metabolism). Together, we have developed a training plan with hands-on experiences, didactic training, meetings, and seminar series to ensure my success. Overall, this award will provide me with the protected time and resources to develop the requisite expertise to rigorously test my hypothesis and prepare an innovative R01 grant application as I launch my independent career as a translational scientist who conducts well-executed, objective, and impactful research. Completion of the proposed aims will lay the foundation for novel precision medicine interventions to reduce FGR among Black women.

NIH Research Projects · FY 2025 · 2025-09

The major goal of this proposal is to define the mechanisms of a new pathway for genome stability, which we call RDIBs (RNA damage induced DNA breaks). It has been known for decades that many DNA damaging agents also damage RNA, due to their similar chemistries. However, outside of RNA quality control mechanisms related to translational control in the cytoplasm, the direct implications of RNA damage for genome stability in the nucleus are largely unknown. Our new data indicates that damage to nascent RNA through base methylation, if not promptly removed, results in DNA double-stranded breaks. Through a targeted screen for factors that recognize methylated RNA, we identify the RNA binding protein YTHDC1 as being critical for alkylation damage responses in conjunction with the THO complex (THOC). In the absence of YTHDC1 or THOC, alkylation base damage results in greater damage sensitivity and DNA breaks. This damage is fully attributable to RNA damage, since an RNA-specific demethylase can rescue these phenotypes. These breaks depend on R-loop formation, which are then processed by a structure-specific nuclease. We also show that in the absence of YTHDC1 or THOC, aberrant RNA methylation in the nucleus is sufficient to induce DNA breaks near the RNA methylation site. Our discovery of this pathway provides definitive evidence for how RNA damage can impact genomic integrity. Yet, several key questions about the RDIBs pathway remain, which we seek to answer in this proposal. We will define the causes and consequences of RNA damage induced breaks, by identifying the types of RNA modifications that activate RDIBs, the structure of the DNA break, the nucleases responsible for their formation, and the mechanism for the repair of the ensuing break (Aim 1). In parallel, we will use cell biological and biochemical reconstitution approaches to demonstrate how YTHDC1-THOC, along with an associated helicase and RNA endonuclease, help to resolve damage to nascent RNA in the context of R-loops (Aim 2). Together, these studies will shed light on an undiscovered pathway by which RNA damage can cause loss of genome integrity, as well as the mechanisms that suppress this form of damage.