Washington University

NIH Research Projects · FY 2025 · 2025-09

We propose to evaluate scale-up and sustainment strategies to promote tobacco use treatment (TUT) in cancer survivors. In a landmark study of 28 cancer centers, we learned that scale-up success is a function of both implementation strategies and clinical context. Clinic selection of implementation strategies varies, and the same strategies do not yield consistent outcomes across variable contexts. We need a rigorous comparison of commonly used strategies, knowledge on how context (and context-strategy fit) impacts scale-up and sustainment, and how to enhance scale-up and sustainment with additional strategies. In the UG3 phase, we will leverage the Practical, Robust Implementation and Sustainability Model (PRISM), a context-based extension of the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework, to adapt/refine strategies, harmonize outcomes, and establish trial feasibility across a range of clinic settings. UG3 Phase: Aim 1: Engage clinics using multilevel PRISM to identify contextual needs, core functions, and forms of strategies to scale-up and sustain TUT in a common protocol for use in the UH3. Aim 2: Establish the feasibility of a multi-stage RCT by demonstrating fidelity of strategy components, harmonized outcome availability, and refined thresholds for the successful reach of TUT. Go/no-go Threshold: To proceed to the UH3 phase, we must achieve >80% strategy fidelity, >80% outcome availability, and >15% TUT reach (based on empirical C3I data). UH3 Phase: Using a Type 3 effectiveness-implementation hybrid design, we will test strategies in a 2-stage cluster-randomized SMART trial of 72 clinics across 4 regional hubs. Stage 1 is a 4-arm cluster RCT to assess scale-up strategies. In Stage 2, non-responder clinics will proceed to a 2-arm cluster RCT to compare scale enhancement strategies. Responder clinics will undergo a 2-arm cluster RCT to compare sustainment strategies. Aim 3: Assess the effect of scale-up strategies on TUT reach and effectiveness. We hypothesize that Referral to Specialist, Point of Care, and combination will result in higher reach and effectiveness, compared to usual care. In a sub-aim, we will evaluate scale enhancement in non-responder clinics and hypothesize Precision Implementation (PI)+Biological Precision Treatment (BPT) will result in higher TUT reach, compared to PI alone. Aim 4: Test the effect of sustainment strategies on the maintenance of strategy component delivery, TUT reach, and effectiveness. We hypothesize that a clinic data-driven facilitation strategy (Precision Facilitation) will result in higher maintenance outcomes than General Facilitation. Aim 5. Examine implementation outcomes and determinants associated with comparative strategies. This proposal will develop a contextually-informed algorithm for cancer clinics in selecting optimal implementation strategies for TUT and advance implementation science in refining the strategy-context fit and metrics to inform precision efforts to scale-up and sustain TUT for cancer survivors.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are clinically proven drugs for weight loss and diabetes, yet their mechanisms of action are incompletely understood. Notably, in pancreatic β cells, how does the incretin hormone glucagon-like peptide-1 (GLP-1) amplify glucose-stimulated insulin secretion is still an open question. We know that GLP-1 signals through a class B GPCR, the GLP-1 receptor (GLP-1R), that is expressed abundantly in β cells. Little is known, however, about the subcellular compartmentalization of GLP-1R signaling in β cells, and how these organellar compartments cooperatively bring about GLP-1 signaling effects on insulin secretion. My preliminary data shows that the primary cilium, a sensory organelle of the β cell, contains a distinct pool of GLP-1R that may mediate early responses to GLP-1 and trigger downstream cytosolic second- messenger cascades that lead to insulin secretion. These findings build on prior work by my mentors’ labs and others that demonstrated a role for primary cilia in regulating glucose-stimulated Ca2+ signaling and insulin secretion in the β cell, while mice lacking cilia on β cells develop glucose intolerance and diet-induced diabetes. My project tests the hypothesis that β-cell primary cilium acts as a unique GLP-1-sensing domain that determines whole-cell responses to GLP-1. To dissect the subcellular mechanisms of GLP-1 signaling, I will utilize recently developed imaging tools and genetic models to quantitatively measure GLP-1-dependent Ca2+ and cAMP signaling in the β-cell primary cilium and cell body (Aim 1). In parallel, I will examine mechanisms of GLP-1R trafficking to the primary cilium and test the effect of ciliary de-localization of GLP-1R using genetic deletion of Tulp3, a ciliary GPCR adaptor protein (Aim 2). Completion of these studies will provide a detailed molecular understanding of how primary cilia regulate GLP-1 signaling in β cells and may identify new cilia signaling pathways that have the potential to improve diabetes and human metabolic health. Through this fellowship application, I will develop 1) a novel understanding of the regulation and compartmentalization of GLP- 1 signaling and 2) my potential as an independent investigator focused on endocrine cell function and diabetes. These training goals will be facilitated by the detailed research plan, a team of remarkably qualified mentors with expertise in the proposed study design, and exceptional facilities and training environment through Washington University.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Non-traumatic lower extremity amputation is on the rise in young adults (18-44 years old), which is likely due to the 95% increase in childhood-onset type 2 diabetes (T2D) in the United States. Forefoot and midfoot deformities are common diabetic foot complications that initiate the cascade of events leading to increased dynamic pressure, a precursor of ulceration, leading to amputation. In adult-onset T2D, we found that bone mineral density and motion are significantly related to deformity and plantar pressure. However, we do not know if people with childhood-onset T2D present with forefoot or midfoot deformity pathways to ulceration and amputation. We suspect that childhood-onset T2D will primarily follow a midfoot deformity pathway because of the increased presence of midfoot deformity in children with T2D, likely a result of early and severe onset of obesity. Thus, this application will address the gap of knowledge by investigating the deformity pathway in childhood-onset T2D. K99 Phase: Aim 1.1. Determine the effects of T2D, obesity, bone mineral density, and motion on foot deformity and plantar pressure in adults (18-45 years old, N=36), which will provide the foundation for understanding the foot deformity and plantar pressure in adults with childhood-onset T2D. Aim 1.2. Test feasibility and methodological application of imaging measures for the R00 phase in children with T2D and obesity (age 14- <18 years old, N=5), which will assist in adapting methods to pediatrics and provide pilot data for the R00 phase. R00 Phase: Aim 2.1. Determine the effects of T2D, obesity, bone mineral density, and motion on foot deformity and plantar pressure in children (14-<18 years old, N=54), which will provide the first-ever dataset of foot-specific bone mineral density, motion, and deformity in children. Aim 2.2. Explore candidate contributing factors to foot deformity in children (age 14-<18 years old; R00 N=54, K99 N=5, total N=59), which will identify contributors to foot deformity, informing interventional targets for amputation prevention. In both K99 and R00 phases, we will use unsupervised machine learning algorithms to understand the relationships between all variables and participants. Then, we will use multivariable regression models to test specific hypothesized relationships. The K99 project will provide me with multi-disciplinary training in (1) foot specific-imaging, (2) childhood-onset T2D, (3) statistical modeling, (4) writing and managing NIH R01 grants, and (5) improving science communication, teaching, and mentoring skills. My long-term goal is to become a leading clinical researcher investigating diabetic foot complications in childhood-onset T2D over the lifespan and preventing ulceration and amputation impacted by early-onset diabetic foot complications. This K99/R00 award will provide the foundational knowledge required to support future NIH R01 grants investigating longitudinal and interventional trials and prevent foot deformity to reduce the risks of amputation in individuals with childhood-onset T2D.

NIH Research Projects · FY 2025 · 2025-09

Project summary Microbial ecosystems play a major role in human health. An ability to quantitatively predict their function and dynamics, and design communities with desired properties, would be transformative for microbiome-based diagnostics and treatments of diseases. However, natural systems are highly complex, harboring hundreds of species. Recently, an important theoretical development was the realization that high-diversity ecosystems are subject to different emergent laws, arising from diversity. These emergent behaviors limit our ability to obtain generalizable insight from simplified examples in the lab. Understanding the behavior and properties of complex communities requires ecological theory and computational tools specific to the high-diversity regime, considering microbiomes in their natural complex context. The solution is to simplify the description, not the system. Recent advancements in my group have demonstrated that increasing community diversity can enhance the predictive power of simple ecological models, a phenomenon we refer to as “emergent simplicity.” This breaks from traditional perspectives, opening the door to new methodologies that work because of diversity, not despite it. Over the next five years, my group will: (1) Build computational tools to identify functionally significant taxa groupings, applicable to diverse ecosystems like marine, soil, and gut microbiomes; (2) Create statistical methods to design microbial communities with desired functions, with initial validations focused on synthetic communities suppressing pathogens such as K. pneumoniae; (3) Test the power and limitations of coarse-grained modeling in a complex natural community (soil); and (4) Systematize the insights from these empirical examples into a theory of ecosystem coarse-graining, classifying ecosystem properties by their “coarse-grainability,” and guiding data collection by identifying the most informative perturbations for predictive coarse models to be learned. The research will yield (A) statistical and computational tools of broad applicability to fundamental biology, such as de novo discovery of relevant dynamical variables; (B) new statistical methodologies to discover bacterial interactions from community-level observations; and (C) a systematic methodology for developing interpretable coarse-grained models trainable on minimal data, enabling prediction in clinical contexts where obtaining millions of training examples is infeasible.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Early human development generates thousands of precise cell fates from a single zygote with extreme fidelity. This is largely accomplished via the coordinated regulation of gene expression in cell type- specific patterns. Extensive observation of these patterns has nominated candidate genes that can be exogenously expressed in non-target originating cell types to generate desired cell types through a process called cellular reprogramming. For instance, the overexpression of defined transcription factors (TFs) in human fibroblasts can be convert them directly into a variety of therapeutically useful cell types, including neurons and cardiomyocytes. However, most reprogramming schemes produce heterogeneously differentiated cells that do not faithfully adopt the gene regulatory programs of the target cell types, and consequently are unsuited for therapeutic applications. It is increasingly appreciated that epigenetic factors, including the structure and composition of chromatin, might influence the efficiency of reprogramming in a given cell. For instance, nucleosomal wrapping of DNA and compaction in heterochromatin can silence natively active genes to promote cell type conversion. Therefore, epigenetic events represent unobserved variables that can confer differential competence for reprogramming. Here we propose to observe these variables directly using a novel time-lapse epigenome profiling method, in which multiple snapshots of heterochromatin protein enrichment and how they change over time are captured in the same single cells. We will use time-lapse information to identify key spatiotemporal changes in chromatin-mediatedgene regulation that are associated with successful reprogramming and use catalytically inactivated Cas9 fused to chromatin regulatory domains to functionally test whether these events can lead to more efficient iEP outcomes. We further will produce rich, standardized datasets from time-lapse profiling of common reprogramming trajectories for public use, with a focus on their utility for deep learning approaches to discover new modulators of reprogramming efficiency In the long term, we anticipate that these improved methods we introduce will improve the rational design of efficient cell type conversion schemes for tissue regeneration and other important therapeutic purposes.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Spinal cord injury (SCI) is a life-altering event that leads to long-lasting motor impairment. Currently, there is no cure for paralysis. Transcutaneous spinal cord stimulation (tSCS) combined with exercise training can restore posture control, voluntary walking, and arm/hand function in people with SCI. However, its low selectivity in activating specific muscles compared to invasive approaches limits the rehabilitation exercises that can be practiced and help with recovery. This project will generate evidence-based knowledge of the neural mechanisms underlying spatial, frequency, and amplitude control of tSCS in generating different types of leg movements. Participants with SCI will perform leg movements using different stimulation parameter configurations in non-invasive tSCS. We will quantify changes in muscle recruitment, torque generation, and pain enabled by the different stimulation parameters. A clear understanding of the mechanisms by which these different parameters in non-invasive tSCS can be used to selectively target different muscle groups will promote the development of personalized therapies that directly target only those muscles that need assistance while respecting individuals' residual motor function.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT The gut microbiome and immune system develop in concert, influenced by environment, diet, infections, and antibiotics. Secretory immunoglobulin A (sIgA) in breastmilk is the primary mediator of coordinated immune and microbiome development, modulating host-bacterial interactions. Breastmilk sIgA is the main source of IgA be- fore the first month of life, and formula-fed infants lack sIgA exposure during this critical period. Antibiotics ad- ministered during infancy lead to dramatic changes in microbiome composition during a critical period for regu- lation of gut inflammation. Preterm infants are more likely to be exposed to antibiotics, are more susceptible to bacterial infection, have less mature gut microbiomes, and have persistent alterations in immune development relative to their term counterparts. Animal models are essential to precisely control the complexity and variables of human immune and microbiome development. Gnotobiotic mouse models have been used to determine how individual strains impact immune development in adults. However, <25% of species tested in these models have >5% prevalence among infants. Therefore, new models are necessary to determine the impacts of microbes that colonize human infants on the developing immune system. We have developed a gnotobiotic mouse model of colonizing germ-free mating pairs with bacterial isolates or fecal samples from human infants. Pups are born microbiome-humanized, avoiding the negative immune consequences of lack of microbial exposure. Just as in human neonates, the gut microbiome of these mice matures over time, and we find that microbiome similarity correlates with cellular and secreted markers of immune response. The rationale for our proposal is to use this model to understand how human-associated microbes impact immune development, sIgA bacterial binding, and susceptibility to antibiotic-mediated disruption and bacterial pathogen colonization. In Aim 1, we colonize gnoto- biotic dams with the most abundant and prevalent bacterial isolates or combinations colonizing human infants from two clinical cohorts of 80,000 fecal samples from over 1,050 hospitalized preterm or community term infants. By using germ free breeding pairs homozygous or heterozygous IgA knockout mice, we will evaluate how ma- ternal or infant sIgA impacts immune development. In Aim 2, we colonize wild-type germ-free mice with preterm or term fecal samples and evaluate immune disruption relative to antibiotic treatment. In Aim 3, we evaluate immune tolerance and susceptibility to E. coli challenge with rescue with IgA supplementation. Our proposal is innovative because our interdisciplinary research team will complement data from unique human cohorts in a gnotobiotic mouse model that recapitulates microbiome and immune development and disruption by antibiotics and infectious challenge. This proposal is significant because we will use sophisticated multivariate analyses to precisely determine how prevalent infant-associated microbes differentially affect immune development. Our work is impactful because we will advance understanding of the co-development of the gut microbiome and immune system and establish a predictive framework for promoting healthy microbiome-immune interactions.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Trophoblast is the major epithelial cell type in the placenta and provides an essential maternal-fetal interface during pregnancy. Understanding the specification and differentiation of the trophoblast lineage is vital for improved diagnosis and treatment of placental complications, including implantation failure, preeclampsia, and preterm birth. Trophoblast has historically been difficult to study in humans due to limited access to first-trimester placental tissue and the inability of animal models to fully recapitulate human placental development. To enable dissection of early mechanisms of human trophoblast development, we will leverage “naïve” human pluripotent stem cells (hPSCs), which exhibit molecular signatures of pluripotent cells in pre-implantation embryos. We recently showed that naïve hPSCs readily differentiate into human trophoblast stem cells (hTSCs), which can in turn differentiate into specialized extravillous trophoblasts (EVTs) and syncytiotrophoblasts (STBs) or self- organize into 3D organoids that encompass a diversity of trophoblast cell types. Here, we will combine these 2D and 3D models of trophoblast development with epigenomic and single cell approaches to dissect the mechanisms of human trophoblast differentiation and function. Importantly, we have already validated key preliminary findings in human first-trimester placental tissues and will extend this in vivo validation to all the major findings of this project. Aim 1 will establish an epigenome roadmap during the transition from naïve hPSCs into hTSCs and their subsequent differentiation into specialized trophoblast fates. This work will identify functional cis-regulatory elements (CREs) and test the hypothesis that trophoblast specification from naïve hPSCs is primary mediated by transitions between unmarked and actively marked CREs. Aim 2 will define a core transcriptional circuitry governing human trophoblast specification, starting from the results of a genome-wide CRISPR/Cas9 knockout screen in hTSCs. We will test the hypothesis that transcription factors (TFs) enriched at enhancers and promoters of hTSC-specific essential genes constitute an upstream circuitry of trophoblast inducers and integrate these trophoblast inducers and their target CREs into a dynamic gene regulatory network during trophoblast specification. Aim 3 will investigate candidate regulators of trophoblast differentiation into EVT and STB lineages, which perform specialized functions during pregnancy. We hypothesize that the G protein- coupled receptor CCR7 and the TF TEAD1 are required for EVT differentiation. By generating trophoblast organoids from CCR7 and TEAD1 knockout hPSC lines, we will delineate a genetic hierarchy of factors regulating EVT differentiation and invasion. We will also investigate novel regulators of STB differentiation based on their ability to promote cell cycle exit in hTSCs and their enrichment at STB-specific open chromatin. In summary, this project will provide conceptual and experimental advances in understanding the genetic and epigenetic mechanisms regulating specification of the human trophoblast lineage. Our work will also define the action and significance of CREs and TFs in regulating the differentiation of hTSCs into specialized trophoblast cell types.

NIH Research Projects · FY 2025 · 2025-09

Project Abstract / Summary Alzheimer’s disease (AD) is the leading cause of dementia and has significant medical and public health concerns. Despite extensive efforts, the exact relationships between in-vivo amyloid-beta (A), tau (T), and neurodegeneration (N), neuropsychiatric symptoms (NPS), vascular risk factors, and genetic risks for NPS in AD are poorly understood. Patients with AD pathology exhibit neurobiological and NPS heterogeneity characteristics. The central goals have been to better understand AD’s underlying neurobiological heterogeneity mechanisms and improve outcomes. This study plans to leverage in-vivo ATN markers from amyloid PET, tau PET, and MRI to investigate the multivariate relationships between these markers and neuropsychiatric phenotypes and genotypes. This project will utilize large-sample data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Washington University’s Knight Alzheimer’s Disease Research Center (Knight ADRC), Baltimore Longitudinal Study of Aging (BLSA), and National Alzheimer’s Coordinating Center (NACC) cohorts. This study will be the first to systematically investigate the multivariate relationships between ATN biomarkers, NPS, vascular risks, and genetic risks for NPS via machine learning predictive modeling and heterogeneity analytics in AD. In all cohorts, the project will consistently and optimally quantify PET as regional distribution volume ratio (DVR) and standard uptake value ratio (SUVR), as well as MRI as regional volume measures. We will integrate these cohorts and generate harmonized data resources for machine learning method developments and their applications. Aim 1 will develop and optimize machine learning/artificial intelligence methods in the context of regional ATN biomarkers and identify their multivariate predictive relationships with global NPS and highly prevalent domain-specific NPS features. This aim will identify dominant ATN regional hubs collectively involved in NPS processes. Aim 2 will identify the regional heterogeneity of ATN biomarkers via semi-supervised machine learning and reproducibility analytical methods. This aim will correlate the ATN profiles and NPS prevalence and severity between identified subgroups of patients or controls and each subgroup of patients to test the hypothesis of whether ATN and NPS phenotypes differ between subgroups of patients. Aim 3 will examine the relationships of individualized ATN heterogeneity signatures with baseline NPS and longitudinal trajectories in NPS. Aim 4 will study vascular risk and genetics for NPS to test whether ATN and NPS heterogeneity signatures have differential genetic etiologies. In summary, this innovative project will provide critical information on neuropsychiatric aspects of AD mechanisms and significantly contribute to precision medicine in the diagnosis and treatment of AD patients with NPS.

NIH Research Projects · FY 2025 · 2025-09

Project summary The research program in our laboratory is centered on understanding how immunity and defense are optimized. Using plants as model systems, we focus on how defense processes are regulated by dynamic factors such as tissue type, development, ontogeny and importantly, the interplay between circadian rhythms and immune responses. In this research program, we aim to unravel how natural variations in circadian rhythms—referred to as chronotypes—influence the timing and effectiveness of immune responses against a range of pathogens. This proposal will exploit the natural variability in the genus Solanum to rapidly advance our understanding of how circadian defense mechanisms have evolved as a function of different local environments. Our work is built on the premise that, much like in humans, the circadian clock in plants is a crucial regulator of immune function. Solanum species offer a rich diversity in circadian traits that remain largely unexplored. Research from our lab shows that the timing of immune optimization in Solanum differs from that of the classic model plant Arabidopsis, suggesting that alternate regulatory mechanisms have evolved for this important trait. These findings indicate that Solanum species have developed unique circadian adaptations to their environments, optimizing their immune responses according to their specific chronotypes and environmental cues. This diversity provides a valuable opportunity to deepen our understanding of how various environmental factors, such as light, temperature, and humidity, influence biological rhythms and circadian mediated immunity. Our laboratory will leverage the genetic and phenotypic diversity within Solanum to develop a powerful system to study these interactions and to identify key genetic variants and regulatory networks that govern circadian-mediated immune responses. Using a multimethod approach, including genome-wide association studies (GWAS), CRISPR gene editing, transcriptomics, and epigenomics, we will elucidate the genetic and molecular mechanisms underlying these processes. We will explore how these genetic differences translate into variations in disease resistance, uncovering fundamental principles of how biological rhythms modulate immunity. More importantly, the findings from our studies will advance our understanding of the mechanisms by which circadian rhythms regulate immune function, offering potential parallels to similar processes in humans. By shedding light on how timing influences immune responses across different organisms, our work has significant implications for optimizing immune-related treatments, improving vaccine efficacy, and understanding disease susceptibility in humans.

NSF Awards · FY 2025 · 2025-09

This project uses machine learning to create a database of State of the State (SOTS) addresses from 1800 to 2016 and state-level agendas. The data collection involves collecting and cleaning the full set of speeches from governors over time. SOTS data are stored at publicly available data repositories and a website developed by the PIs. Methodologically, the project advances the study of unstructured data and the use of artificial intelligence and machine learning. The data support knowledge and scholarship related to public decision and provide a web resource for educators and journalists. This project extends the SOTS dataset that covers state-of-the-state addresses from 1800 to 2016. The PIs collect, process, and analyze SOTS speeches from years prior to 1960, using techniques developed to overcome poor quality documents implemented through software created by one of the PIs. The software applies machine learning to isolate, enhance, and extract text from hard-to-read documents, correcting document layout problems with a novel statistical approach before it runs optical character recognition (OCR). This results in a significantly higher level of accuracy than other current approaches. 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 2025 · 2025-09

PROJECT SUMMARY Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), the disease responsible for the most deaths by an infectious pathogen worldwide. The host immune response plays a critical role in determining infection outcome, however the factors contributing to a protective response versus progression to active disease are incompletely understood. During Mtb infection, alveolar macrophages (AMs) are the first cells to confront the bacteria. AMs phagocytose Mtb but cannot control the bacteria, ultimately dying and spreading Mtb to recruited immune cells. Among these recruited cells are bone marrow (BM)-derived monocytes that can differentiate into lung interstitial macrophages or pre-AMs, with the latter migrating into the alveoli and maturing to replenish the AM population. Recent work identified that SPTLC2, an enzymatic subunit required for de novo sphingolipid synthesis, is required in innate immune cells during Mtb infection. Mice deleting Sptlc2 in innate immune cells (Sptlc2fl/fl-LysM-Cre) or lung macrophages and dendritic cells specifically (Sptlc2fl/fl-CD11c-Cre) fail to replenish the AM population during Mtb infection, have increased susceptibility to infection relative to Sptlc2fl/fl control mice, and develop a Pulmonary Alveolar Proteinosis (PAP)-like pathology. We determined by single-cell RNA sequencing that monocyte-derived AM precursors that delete Sptlc2 fail to become AMs, instead differentiating into interstitial and other monocyte-derived macrophages, however preliminary data suggests these cells do not have impaired capacity to differentiate into AMs. Investigation of potential causes for failed AM repopulation identified that LPL-/- mice, which lack actin bundling protein L-plastin, also fail to maintain the AM population during Mtb infection. L-plastin is essential for perinatal pre-AM alveolar localization, so these data implicate a role for actin in AM population maintenance during Mtb infection. Sphingolipid species produced downstream of SPTLC2 include membrane lipid raft components upon which actin nucleates and polymerizes, but it is not understood how Sptlc2 deletion alters the sphingolipid profile of CD11c-expressing cells during Mtb infection or by what mechanism this impairs AM repopulation. This proposal will test the hypothesis that SPTLC2-deficiency limits the sphingolipid profile of monocyte-derived AM precursors during Mtb infection, impairing actin polymerization and preventing their migration into the alveolar space. Aim 1 will establish if actin-mediated migration of monocyte-derived AM precursors into the alveoli is Sptlc2-dependent by investigating migration capacity and recruited cell fate, and by determining if SPTLC2 is required for actin polymerization at sphingolipid- containing rafts in AM precursor membranes. Aim 2 will identify the functional role of Sptlc2 in AM repopulation by profiling how loss of SPTLC2 and Mtb infection alters AM and AM-precursor sphingolipid profiles and identifying if sphingolipids can be reconstituted by supplementation in Sptlc2-deleting cells. These studies will elucidate fundamental aspects of immune homeostasis during Mtb infection.

NIH Research Projects · FY 2025 · 2025-09

Abstract Text The Artificial Intelligence Ready and Exploratory Atlas for Diabetes Insights (AI-READI) project is one of the data generation projects in the NIH Common Fund’s Bridge2AI program. The project seeks to create a flagship ethically-sourced dataset to enable future generations of artificial intelligence/machine learning (AI/ML) research to provide critical insights into type 2 diabetes mellitus (T2DM), including salutogenic pathways to return to health. The ability to understand and affect the course of complex, multi-organ diseases such as T2DM has been limited by a lack of well-designed, high quality, and large multimodal datasets. The team of investigators will aim to collect a cross-sectional dataset of 4,000+ people and longitudinal data from 10% of the study cohort across the US. The study cohort will be balanced for diabetes disease stage. Data collection will be specifically designed to permit downstream pseudotime manifold analysis, an approach used to predict disease trajectories by collecting and learning from complex, multimodal data from participants with differing disease severity (normal to insulin-dependent T2DM). The long-term objective for this project is to develop a foundational dataset in diabetes, agnostic to existing classification criteria, which can be used to reconstruct a temporal atlas of T2DM development and reversal towards health (i.e., salutogenesis). Six cross-disciplinary project modules involving teams located across eight institutions will work together to develop this flagship dataset. All data will be optimized for downstream AI/ML research and made publicly available. . The AI-READI project will also engage in a tribal consultation to address barriers and facilitators of participation with the goal of collecting similar data within a Native American cohort in an ethical and respectful manner. Specific aims include 1) Collect and share the dataset for AI/ML research according to the Findable, Accessible, Interoperable, Reusable (FAIR) data principles, 2) Create a model for developing large scalable datasets, and 3) Increase access to and quality of AI/ML research by recruiting and training personnel.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT The exact process of episodic memory loss in aging and Alzheimer’s disease (AD) is not understood. The long- term goal is to refine our understanding of this process, and its links to pathology in the brain. Critically, our current ways of assessing memory decline are sufficient to detect frank dementia, but are largely insufficient to identify those at risk before significant pathology has already accumulated. In part, this lack of sensitivity stems from the fact that laboratory tests use simplistic, arbitrary stimuli that do not reflect the complexity of the real world. That is, existing cognitive evaluations are limited due to a failure to capture a central feature of human memories: they are not unitary, but rather feature representations of specific content in a structured fashion. These components of memories rely on different brain networks. The objective of this proposal is to determine the way aging distinctly affects the content (Aim 1) and structure (Aim 2) of memory representations, and how this relates to dysfunction in different brain networks based on their susceptibility to AD pathology (via plasma biomarker status, Aim 3). The central hypothesis is that aging will be associated with distinct profiles of memory deficits for event content and structure, linked to unique brain networks. The rationale underlying this proposal is that completion of the project will identify two distinct cognitive and neural targets for characterizing, clinically assessing, and eventually treating AD in at-risk older adults. Our specific aims will test the following hypotheses: (Aim 1) Aging disproportionately affects memory for local perceptual information, such as people and objects, which will coincide with dysfunction in an anterior-temporal brain network. (Aim 2) Older adults will show a shift in brain networks involved in representing event memories and poor differentiation between events compared to younger adults, leading to a bias toward remembering information at a gist-level and a susceptibility to confusion. (Aim 3) Plasma biomarkers will predict the extent of age-related dysfunction in memory networks. Specifically, tau burden will relate to anterior-temporal network dysfunction and memory loss for local perceptual content in memories, whereas amyloid burden will relate to dysfunction in a posterior-medial brain network and more widespread memory deficits related to context and structure. This work uses an innovative combination of novel behavioral testing techniques, as well as cutting-edge brain imaging and plasma proteomic tools. The proposed research makes a significant contribution, because it will provide foundational evidence that memory loss is not a monolith, but rather a nuanced process with different components that are uniquely vulnerable to the presence of pathological biomarkers in AD. Results of this project will have a positive impact on basic research in memory and aging in that they will provide important evidence for the way the human brain supports the content and structure of memories, and how this changes across the lifespan. Moreover, this work will inform future clinical investigations and interventions by refining their targets for understanding and treating specific memory deficits.

NSF Awards · FY 2025 · 2025-09

In recent years, there has been a tremendous surge in the availability of relational data in various scientific fields. For example, in biology, an abundance of data has been collected from metabolic networks, gene regulatory networks, brain networks, and ecological networks. Consequently, there is substantial interest from the scientific community in principled statistical procedures for drawing inferences from such array data. This project will develop broadly applicable statistical tools for such problems, enabling reliable inference across a range of applications, and will provide research training opportunities for graduate students. This project has three research aims. The first aim is to develop uncertainty quantification methods for array prediction problems that offer rigorous theoretical guarantees even when complex forms of missingness are present. The second aim is to develop an assumption-lean inference framework for regression problems involving network-linked data. The third aim of the project is to develop variants of the permutation test in various two-sample problems involving network data. Across all subproblems, we work under the framework of a jointly exchangeable array, which encompasses a vast range of data-generating processes and ensures that the developed methods will be widely applicable across different scientific domains. 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 · 2025-09

This project utilizes quantum spin defects hosted in diamond and atomically thin hexagonal boron nitride (hBN) to study how quantum systems behave when pushed away from equilibrium and how our everyday classical behavior emerges from underlying rules. These spin defects can be prepared and read out with optical light at room temperature, making them an ideal quantum platform without the need for complex cryogenic or vacuum hardware. Insights from these studies enable a better understanding of and prediction of the behavior of a complex quantum system and guide the design of improved quantum based simulators and sensors with important applications in science, technology, and national needs. The project also involves extensive education and outreach activities: developing an advanced undergraduate quantum laboratory, launching an annual “quantum open house” for regional colleges, and engaging secondary-school students and teachers across the greater St. Louis area through existing partnerships (e.g., the NSF NRT program in quantum sensing and the St. Louis Area Physics Teachers Association). Technically, the project will develop and employ two complementary room-temperature solid-state spin platforms: 3D ensembles of nitrogen vacancy (NV) centers in diamond and 2D spin defects in hBN. Both platforms offer unique advantages: a large number of quantum spins, optical initialization and readout at room temperature, long quantum coherence and lifetimes, strong and tunable long-range interaction, disorder, and dimensionality. Leveraging three distinct microscopic tuning knobs of the system Hamiltonian --- external driving, long-range interaction and dimensionality, the researchers will explore three exciting open questions in non-equilibrium quantum dynamics, (1) What novel phenomena can manifest when the constraint of time periodicity (Floquet) is relaxed for a driven system? (2) How do our everyday macroscopic classical phenomena emerge from microscopic quantum laws in the presence of different ranges of interaction? (3) Can distinct quantum phases and states be generated in lower dimensions? Expected outcomes include deeper understanding of out-of-equilibrium quantum phases, protocols for preserving quantum coherence relevant to quantum metrology, and benchmarks that connect controllable quantum platforms to complex real materials. 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 · 2025-09

Non-technical summary Chirality is the phenomenon where two objects, called enantiomers, can exist as non-superimposable mirror images of each other, such as one's left and right hands. Chirality is ubiquitous in organic molecules which are essential to life, including amino acids and carbohydrates. These are selectively found in nature as only one of the two mirror image forms. Some inorganic crystals such as quartz also possess chiral structures. While inorganic crystals that are both chiral and light-absorbing semiconductors are rare, they could enable new types of devices such as photodetectors. Photodetectors can be used in enhanced biomedical imaging devices and can be used to selectively produce chiral pharmaceutical agents. However, a significant challenge in realizing these devices is that the chiral semiconductor must be prepared with high excess of one of its two mirror image forms, known as enantiomeric excess. With support from the Solid State and Materials Chemistry Program in NSF's Division of Materials Research, Professors Bryce Sadtler and Rohan Mishra at Washington University in St. Louis combine experiments and theory to discover new types of chiral semiconductors and synthesize them with enantiomeric excess. By identifying new chiral semiconductors and synthesizing them with enantiomeric excess, Profs. Sadtler and Mishra tune their properties for applications of national interest including chiral electrodes for the electrochemical synthesis of chiral pharmaceutical compounds. Additionally, Profs Sadtler and Mishra are organizing a symposium at a national conference on the synthesis, characterization, theory, and applications of chiral materials. Technical summary Chiral semiconductors that absorb light to generate mobile charge carriers offer unique light-matter interactions and electron-transport properties including polarization-dependent photocurrents, chiral-induced spin selectivity for electron transport, and ability to discriminate between enantiomers of chiral molecules during photoinduced redox reactions. While several novel classes of chiral semiconductors have recently been developed, the current pool of inorganic compounds with chiral structures is still small, and the methods to produce these materials with enantiomeric excess are largely empirical and compound specific. The development of general strategies to identify and prepare new chiral semiconductors with control over enantioselectivity remains a fundamental scientific challenge. With support from the Solid State and Materials Chemistry Program in the NSF's Division of Materials Research, Prof. Sadtler is testing the hypothesis that the introduction of chiral ligands during solution-phase synthesis, such as chemical bath deposition and colloidal nanocrystal synthesis, can provide a general route to template the growth of chiral metal oxide and chalcogenide semiconductors with enantiomeric excess. Prof. Sadtler is first applying this method to known chiral semiconductors, including the metastable chiral phases of tin sulfide and tin selenide. Simultaneously, Prof. Mishra is employing calculations using density functional theory and group theoretical methods to screen for hidden metastable phases of metal oxides and chalcogenides that possess chiral crystal structures. Through iteration between theory and experiment, Profs. Sadtler and Mishra develop new insights into how chemical strain via alloying of the ions that comprise the compound semiconductor and epitaxial strain with the growth substrate can stabilize these metastable chiral phases. They perform structural, optical, and electrochemical characterization of the chiral semiconductors to elucidate how the crystal structure, the degree of enantiomeric excess of crystallites within the film, and the nanoscale morphology control the optical response and enantioselectivity for electrochemical transformations of chiral molecules. A general method for identifying and synthesizing chiral semiconductors with enantiomeric excess provides a broader palette to tailor the optical and electrochemical properties of these materials for applications in sensing, photonics, and enantioselective catalysis. 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 2025 · 2025-09

PROJECT SUMMARY This project aims to explore mechanisms involving mu opioid receptor (MOR) signaling within the nucleus of the solitary tract (nTS) in mediating fentanyl-induced cardiorespiratory depression. Over the past decade, synthetic opioids, primarily fentanyl, have been the leading cause of the surge in opioid-related deaths. Fentanyl presents a significant treatment challenge due to its rapid onset of effects, which makes timely intervention strategies difficult to implement. Numerous studies have examined opioid-MOR mechanisms in ventral brainstem respiratory networks as key factors in the development of opioid-induced respiratory depression (OIRD). The nTS, located in the dorsal brainstem, contains robust mu opioid receptor expression, including vagal afferent fibers that terminate in this region as well as postsynaptic expression on nTS neurons themselves. Despite this abundance of MOR in the nTS, the extent to which the nTS mediates OIRD has not been thoroughly investigated. Therefore, the goal of this proposal is to examine mechanisms by which opioids impact neuronal activity within the nTS, and how this relates to the onset, severity, and duration of OIRD. We will employ various complementary techniques to evaluate opioid-MOR mechanisms within the nTS. Aim 1 will utilize a newly generated transgenic MOR-Cre rat line, combined with chemogenetics, optogenetics, and fiber photometry, to evaluate presynaptic and postsynaptic mechanisms of fentanyl-MOR signaling in the nTS. Aim 2 will use two additional transgenic rat lines to evaluate how vagal afferent fibers mediate the activity of catecholaminergic and GABAergic nTS neurons, and how fentanyl impacts this vagal signaling to these nTS neuronal subpopulations. This aim will employ fiber photometry, chemogenetics and immunohistochemistry to examine these peripheral-central circuits in the context of OIRD. Aim 3 will utilize transgenic rat lines to determine how opioids directly impact the activity of catecholaminergic and GABAergic nTS neurons whether they are necessary for the onset, severity, or duration of OIRD. Additionally, this aim will utilize a transgenic mouse line in which MOR has been knocked out of noradrenergic cells. Experiments using these mice will determine the extent to which MOR-expressing noradrenergic cell groups, including in the nTS, contribute to the induction and severity of OIRD. This research will be supported by primary mentor Dr. Jose Moron-Concepcion at Washington University in St. Louis and co- mentor Dr. Jordan McCall at Washington University in St. Louis and the University of Health Sciences & Pharmacy in St. Louis. Additional external support will come from Dr. Erica Levitt at the University of Michigan and Dr. Kevin Cummings at the University of Missouri. By investigating opioid mechanisms in the nTS, the overarching goal of this research is to advance our understanding of how opioids induce cardiorespiratory depression, potentially by preventing the engagement of reflex responses that would normally be engaged to facilitate a return to cardiorespiratory homeostasis. Data generated during this project period seeks to contribute to the development of new therapeutic strategies for managing OIRD in individuals with opioid use disorders.

NIH Research Projects · FY 2025 · 2025-09

Summary Abstract: How the Endocytic Network Mediates Specificity of Cell Signaling Receptor crosstalk – the cooperation between two or more receptors to modulate cell responses – is a key signaling mechanism. It enables cells to generate a large combinatorial repertoire of specific signaling with a limited variety of receptors. Receptor crosstalk plays an essential role in cell physiology. Consequently, dysfunctions in receptor crosstalk are associated with many human diseases, such as infectious diseases (including COVID-19), cancer, and cardiovascular diseases. To understand the physical mechanisms by which signals from different receptors are integrated in crosstalk, studies have exclusively focused on receptor interactions at the plasma membrane. In contrast, how the crosstalk signals are transduced with high fidelity from the plasma membrane to the nucleus is poorly understood and scarcely explored. The overall goal of this research is to establish the functional role of the endocytic network in transducing and regulating receptor crosstalk. During the past 6 years, our group has made pioneering discoveries in support of the central hypothesis that the endocytic network is where extracellular chemical and physical stimuli intertwine to regulate receptor crosstalk. Specifically, we reported a new model in which receptors can crosstalk by forming overlapping interfaces between discrete signaling clusters, challenging the prevailing view that receptors oligomerize to crosstalk. Importantly, such spatially organized interaction between receptors at endosomes and plasma membranes is modulated by extracellular physical cues, and directly regulates cell inflammatory responses. These prior discoveries and the plethora of new approaches we developed for studying endosome functions laid a critical and unique foundation for us to address the knowledge gap: how does the endocytic network mediate receptor crosstalk? We will address how the endocytic network orchestrates chemical cues from receptor crosstalk (Direction 1) and transduces extracellular physical cues to refine the specificity of crosstalk signaling (Direction 2). To address the first direction, we will define the physical mechanisms by which endocytic sorting, collective endosome-organelle interactions, and endosome-specific activation modulate crosstalk signaling originated from the plasma membrane. To address the second direction, we will integrate experiments with computational modeling to determine the feedback loop between the endocytic network and cell-matrix interactions that regulate receptor crosstalk. This project will establish a mechanistic and predictive understanding of how the endocytic network mediates the spatiotemporal specificity of receptor crosstalk and cell signaling in general; a topic that is poorly understood. It will also lower the technical barrier that has impeded research on this topic, by establishing novel quantitative toolsets for dissecting the dynamics and function of the endocytic network on multiple length scales. Ultimately, a better understanding of endosome functions in receptor crosstalk will facilitate the development of new therapeutic strategies for diseases.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Cardiovascular diseases such as coronary artery disease, heart failure, and arrhythmia contribute significantly to morbidity and mortality worldwide. Cardiac inflammation plays a significant role in disease pathogenesis, and cytokines like the interleukin-1 (IL-1) family contribute significantly to acute and chronic inflammation. Therapeutic approaches that inhibit IL-1β signaling have been shown to improve cardiovascular outcomes in patients with heart failure. However, the precise cellular targets of the IL-1 cytokine family in the heart remain poorly defined, limiting additional therapeutic development. The heart contains two main populations of macrophages: CCR2- resident macrophages and CCR2+ monocyte-derived macrophages, the latter being a significant source of IL-1β during cardiac injury. I have generated preliminary data indicating that IL-1β signaling modulates immune cell behavior and differentiation. The central hypothesis of this research is that IL-1 signaling to infiltrating monocytes and derived macrophages promotes myocardial inflammation by driving their differentiation towards pro-inflammatory cell states, leading to adverse cardiac remodeling. Aim 1 seeks to define the impact of IL-1β signaling to infiltrating CCR2+ monocytes and derived macrophages on cardiac remodeling and fibrosis. Using transgenic Ccr2CreERT2IL1rf/fRosa26tdTomato mice, I will conditionally knock out the IL-1 receptor in CCR2+ monocytes and macrophages and evaluate the effects on myocardial inflammation, fibrosis, and remodeling in two models of cardiac injury: pressure overload (Angiotensin II/Phenylephrine infusion) and ischemia-reperfusion (IRI). This aim will clarify whether IL-1 signaling to CCR2+ macrophages is a viable therapeutic target to mitigate adverse remodeling. Aim 2 investigates the mechanisms through which IL-1β signaling shapes the cardiac immune landscape and immune cell differentiation. By leveraging genetic lineage tracing (Arg1tdT-CreRosa26ZsGreen) and spatial transcriptomics, this aim will explore how IL-1 signaling influences the differentiation trajectories of infiltrating monocytes and their progeny. Computational analyses will be used to examine the regional organization and kinetics of immune cell differentiation during cardiac injury, with the goal of identifying reparative and pathological immune niches within the heart. Overall, this research will address critical gaps in understanding the contributions of IL-1 signaling in cardiac inflammation and remodeling. Defining how IL-1 signaling drives immune cell behavior and contributes to adverse cardiac outcomes will provide key insights into the potential mechanisms underlying IL-1-targeted therapies. Additionally, this work will help inform strategies to enhance the efficacy and safety of these therapies, with the ultimate goal of improving clinical outcomes for heart failure patients.

NIH Research Projects · FY 2025 · 2025-09

Project Summary: Malaria continues to pose a significant global health threat, with severe cases primarily caused by P. falciparum leading to diverse clinical complications. In the symptomatic stage of malaria, the parasite undergoes asexual replication within a parasitophorous vacuole (PV) formed inside the human Red Blood Cell (RBC). Hundreds of parasite-made proteins are secreted into the PV, and a subset of these proteins is further exported to the RBC through the Plasmodium Translocon of Exported Protein (PTEX) complex located at the PV membrane. These exported proteins play a crucial role in modifying the host cell, creating a conducive niche for parasite growth, and significantly influencing the severity of the disease. The process of how exported proteins are differentially sorted from PV-resident proteins and targeted to the PTEX complex remains to be determined. Recent findings indicate that mature N-terminal sequence (NTS) of secreted proteins, exposed after processing in the endoplasmic reticulum, encodes a promiscuous signal directing secreted proteins either to the export pathway or to retention within the PV. This proposal aims to unravel the mechanisms underlying this differential sorting and trafficking. Two proposed models are under consideration. The first involves accessory proteins recognizing and binding export-competent NTSs of export-destined proteins, guiding them to the PTEX complex. Conversely, accessory proteins in this model may bind to export-incompetent NTSs of PV-resident proteins, inhibiting further trafficking. The second model posits that the chaperone HSP101, a component of the PTEX complex, discerns between export-competent and -incompetent NTSs, thereby controlling selectivity. Given the diverse nature of mature NTSs in both varieties of secreted proteins, the central hypothesis of this proposal is that both models are partially correct; secreted proteins undergo differential sorting with the assistance of multiple sorting proteins and HSP101 in a stepwise manner. In Aim 1, sorting proteins in the PV will be identified through proximity labeling and co-immunoprecipitation, using exported-destined and PV-resident reporters. A refined cell fractionation strategy will be used to isolate the PV compartment, and global protein export will be blocked by genetically manipulating the parasite for the experiments. The top 5 hits will undergo rigorous characterization to understand their role in secreted protein trafficking pathways. Aim 2 focuses on investigating the role of HSP101 in secreted protein sorting. Reciprocal immunoprecipitations of secreted reporters and HSP101 will be conducted. Structure- guided modifications of HSP101 will be tested for their potential role in cargo sorting. The applicant aspires to be an expert in protein trafficking pathways of apicomplexan parasites. Elucidating the Plasmodium protein export pathway using cutting-edge methodologies under the mentorship of pioneering molecular parasitologist Dr. Dan Goldberg will greatly enhance the candidate's prospects for an impactful research career.

NIH Research Projects · FY 2025 · 2025-09

Summary Multiciliated cells containing hundreds of motile cilia line the airway to generate directional fluid flow essential for mucociliary clearance. Despite stressful environmental conditions, the half-life of multiciliated cells is long, on the order of 6-12 months. This long lifespan dictates that there must be strict maintenance programs for preserving cilia ultrastructure, length, motility, and functions required to provide continuous airway clearance. We propose that loss of cilia maintenance results in acquired ciliopathies featuring short or absent cilia, slowed motility, and impaired airway clearance observed in lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and others. While much has been learned about genetic ciliary diseases, little is known about the cellular processes resulting in acquired airway ciliopathies. Our preliminary data shows that in airway tissues from patients with asthma and COPD, there is loss of cilia that surprising features uncoupling of BB proteins from their normal positions beneath cilia, and their translocation to the cytoplasm. We observed the same displacement of BB proteins to the cytoplasm suggesting loss of cilia maintenance in a mouse model of asthma, and in human airway epithelial cell cultures that were treated with inflammatory stimuli. To investigate the role of BB in regulation of cilia maintenance, we have conditionally deleted ciliopathy protein Cep120, which is essential for BB function during homeostasis, in multiciliated cells of adult mice with fully developed airways. Cep120 loss results in derangement of BB position and cilia structure similar to that observed in disease tissues. By tracking the loss of cilia in human tissues and mouse models, we identify that BB proteins accumulate in unique cytoplasmic degradation sites near the BB marked by autophagy and proteosome components. Collectively, our preliminary results suggest that acquired ciliopathies are due to disrupted BB function in mature multiciliated cells. Thus, we hypothesize that basal body functions are required for motile cilia maintenance in health, and that loss of BB proteins leads to cilia disassembly in acquired ciliopathies. This hypothesis will be tested in vitro and in vivo using a combination of genetic mouse models, multiciliated cell cultures of primary mouse and human cells, and airway disease patient-derived tissues. Our complementary Specific Aims will: (1) Identify changes in basal body proteins affecting cilia in acquired ciliopathies of chronic lung disease; and (2) Define the basal body mechanisms that maintain cilia during steady state in health. Loss of candidate BB proteins prior to cilia dysfunction in human diseased lung tissues and mouse models will support our hypothesis that cilia maintenance is dependent on BB, and that acquired ciliopathies are the result of failed BB functions. Our studies will define the novel role of the basal body in acquired ciliopathies, and provide new unique targets for maintenance of motile cilia and their functions in human lung diseases.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract The proposed three-year conference series entitled “Addressing the Complex Driving Continuum: Needs of an Aging Population” (ACDC: NAP), centered around aging, mobility, and transportation safety, aims to bring together leading experts from various fields such as geriatrics, neurology, public health, and transportation and mobility. This series is essential to address the needs of an aging population, particularly in integrating new technologies like Advanced Driver Assistance Systems and artificial intelligence to enhance mobility and driving safety for older adults. The conference series will provide a space for clinicians, policymakers, researchers, community organizations, and industry partners to assess the current state of research, investigate current clinical practices for evaluating crash risk, and examine national public policy/advocacy initiatives surrounding unsafe driving and resources for alternative transportation options with a special emphasis on involving underrepresented communities, rural populations, and low-income older adults. The conference will provide a platform for interdisciplinary collaboration, fostering new research and generating actionable strategies to bridge the current gaps in research and practice. The first conference to initiate this series will be held locally at Washington University School of Medicine in St. Louis in the fall of 2025, followed by national conferences in 2026 and 2027 in partnership with the Gerontological Society of America (GSA). The aims of this conference series will be to examine research that identifies age-related medical risk factors (e.g., visual impairments, Alzheimer’s disease, Parkinson’s, stroke) that increase crash risks and investigate evidence on assessment tools of driving-related abilities. It will also focus on interventions to enhance physical and cognitive skills and technologies to support the unique needs of older drivers and generate consensus on the decision-making process around driving cessation, its impact on older adults’ health and well-being, and alternative transportation options to sustain their independence. The conference will receive guidance and support from aging, transportation, and ADRD experts to ensure a comprehensive and impactful discussion. Dissemination strategies include peer-reviewed publications, webinars, podcasts, and community outreach efforts. By convening national experts from aging, allied health, transportation and mobility, neurology, geriatrics, gerontology, and public health fields, the conference is expected to foster new collaborations and generate actionable strategies to address current gaps.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Pathogenic mutations in the genes encoding Regulatory Factor X3 and X4 (RFX3/RFX4) transcription factors (TFs) were recently identified contributors to autism spectrum disorder and other neurodevelopmental disorders (NDDs). In preliminary work, I identified RFX4 as a TF that binds to cis-regulatory elements to control human cortical interneuron development, defining roles for RFX3 and RFX4 in regulating interneuron progenitor specification and differentiation. While prior work had demonstrated a role for RFX4 in ciliogenesis, its role in human brain development and contribution to NDDs remains undefined. Therefore, my proposed work will define the role that RFX4 plays in human cortical development to determine how pathogenic RFX4 mutations affect these processes. Toward that end, I derived human pluripotent stem cell (hPSC) models carrying pathogenic RFX4 heterozygous and homozygous loss of function (LOF) and patient-specific mutations. Using these models, I have demonstrated that RFX4 LOF causes dosage-dependent spontaneous differentiation of neural progenitors; likely due in part to a loss of RFX4-mediated repression of pro-neuronal genes. Furthermore, I have identified a regulatory relationship between RFX3 and RFX4, with RFX4 LOF resulting in loss many RFX3 binding sites, particularly at genes involved in synapse development. From these and other preliminary data, I hypothesize that RFX3 and RFX4 restrain neuronal differentiation in progenitors, with loss of either TF causing precocious neuronal differentiation resulting in altered maturation and function, likely major contributors to the NDD phenotypes found in human patients. In Aim 1, I will examine how RFX4 pathogenic mutations contribute to NDD etiology, defining temporal requirements for RFX4 and identifying consequences of RFX4 pathogenic mutation through a combination of cellular phenotyping and transcriptomic analyses across 2- and 3-diminsional models. I will also determine how pathogenic mutation affects RFX4 genome-wide occupancy and gene regulation by integrating RFX4 binding and transcriptomic data. Finally, I will define how RFX4 LOF mutation impacts neuronal maturation and neuronal network formation, providing a foundation for understanding the etiology of NDD pathogenesis resulting from RFX4 mutation which can be therapeutically targeted. In Aim 2, I will characterize the transcriptional interplay between RFX3 and RFX4, which is suggested from my preliminary data, examining the impact of RFX3 LOF upon RFX4 binding. This work will elucidate the basis of the proposed synergistic relationship between RFX3 and RFX4 in neuronal gene repression and will determine how transcriptional interplay between RFX3 and RFX4 regulates neuronal differentiation, maturation, and function, exploring convergent RFX3 and RFX4 LOF phenotypes that may contribute to NDD etiology. Together, my work under this proposal will provide novel insights into the etiology of RFX-associated NDDs and provides well characterized cellular phenotypes that can be used as a platform to develop gene targeted and pharmacological interventions to treat RFX mutation-associated NDDs. .

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT The long-term goal of this research is to reduce disability, improve quality of life, and delay dementia onset among people with Parkinson disease (PD) by enabling them to cope with cognitive decline so they can perform and participate in meaningful activities and roles. Cognitive impairment is one of the most common and disabling features of PD and is a major management challenge and area of unmet need. Surgical and pharmacological treatments have proven largely ineffective in addressing this pressing burden, so behavioral interventions that attenuate the negative functional consequences of PD-related cognitive decline are a top research and clinical priority. Unfortunately, the widely used cognitive training approach to cognitive intervention (repetitive practice of tasks designed to challenge and improve specific cognitive functions) has been unsuccessful in improving daily function and quality of life in people with PD. To overcome this limitation, the investigators take a strategy training approach, teaching targeted strategies that people can use in their everyday lives to circumvent cognitive deficits and accomplish daily tasks. Strategy training is a practice standard for cognitive rehabilitation in brain injury and stroke, but its application in PD is novel. Moreover, the strategy training intervention used in this study, the Multicontext (MC) Approach, explicitly focuses on generalization of training to daily function, an aspect that is critically lacking from PD-related cognitive intervention research to date. Through rigorous and systematic development and pilot testing, the investigators have fully specified and manualized the MC Approach, developed therapist training procedures, and shown that is acceptable to participants, feasible to administer with high fidelity in real-world treatment settings, and associated with clinically meaningful improvements in daily cognitive function. The primary objective of the current project is to determine the efficacy of the MC Approach for improving daily cognitive function in people with PD and mild cognitive decline. It is an assessor-blind randomized controlled trial comparing the short-term and long-term effects of the MC Approach to a traditional cognitive task training approach on personalized functional cognitive goals (Aim 1). Additional aims are to examine whether booster treatment enhances MC Approach treatment effects (Aim 2) and explore the cognitive-behavioral mechanisms of the MC Approach (Aim 3). This work will meet the pressing need for evidence-based and implementable interventions that reduce functional impairment associated with PD-related cognitive decline and potentially delay dementia onset in this population. Ultimately, it will improve clinical care for the growing number of people living with PD and reduce the socioeconomic burden of this disease.