University Of Michigan At Ann Arbor

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Over the past 14 years, the Nephrotic Syndrome Study Network (NEPTUNE) has established a cohort of more than 850 pediatric and adult patients with proteinuric glomerular diseases characterized with deep clinical, histological, genetic, and molecular profiles, and with long term outcomes under standard of care. The multi- scalar datasets from these patients have been combined into the NEPTUNE Knowledge Network (NKN) and have been enriched by more than 220 ancillary studies that have investigated disease mechanisms in discrete patient subgroups as starting points to stratify patients for targeted therapies. The NEPTUNE infrastructure has matured sufficiently so that multi-scalar information can be rapidly generated by the NEPTUNE analytical units along the genotype-phenotype continuum. These data allow for the rapid definition of an individual participant’s molecular disease processes at the time of presentation exposing the mechanistic heterogeneity of glomerular disease for targeted treatment intervention. With these key pre-requisites in place, NEPTUNE is now able to test the precision medicine concept in glomerular disease with the goal of identifying the right treatment for the right patient at the right time. This precision medicine study will utilize the NKN to develop and deploy two treatment response prediction models: (1) Predicting response to current Kidney Disease Improving Global Outcomes (KDIGO) recommended standard of care treatments of glomerular diseases with the aim of answering patients’ questions about which currently available treatment is optimal for them; (2) Predicting in the NEPTUNE Match study framework whether molecular pathways underlying an individual patient's glomerular disease are likely to be targeted by a specific clinical trial intervention The trial recommendations are provided to study participants and site investigators to facilitate selection of a molecular matched trial. Impact of NEPTUNE Match on patients and trial outcomes is prospectively ascertained. NEPTUNE Match has established partnerships with academic and industry lead clinical trials supporting the patient stratification for targeted NS trials in a precompetitive manner across diverse trials in glomerular disease and will continue to expand capacity and breath in response to the rapidly evolving trial space in glomerular diseases.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Level 2 hypoglycemia (i.e., low blood glucose) can affect one’s daily life; generate fear and psychological distress; and lead to brain dysfunction, heart complications, and even death. People living with type 1 diabetes (T1D) are particularly susceptible to developing Level 2 hypoglycemia due to the obligatory use of exogenous insulin to manage diabetes. Advanced diabetes technologies (ADTs), such as continuous glucose monitoring and closed- loop insulin pumps, have become the standard of care to improve diabetes control and reduce hypoglycemia. Yet roughly one in three adults living with diabetes continue to develop Level 2 hypoglycemia despite using ADTs, and no strategies have demonstrated effectiveness in alleviating hypoglycemia beyond these standard-of-care technologies. Training to improve hypoglycemia symptom detection and psychoeducation for addressing unhelpful hypoglycemia beliefs have shown promise in reducing Level 2 hypoglycemia. However, these approaches’ effectiveness requires confirmation in ADT users. A scalable intervention with low patient burden is especially needed to expand access to these strategies. We have developed and feasibility-tested two automated real-time patient glucose data–guided digital intervention components delivered via SMS messages: digital hypoglycemia symptom detection training and digital hypoglycemia psychoeducation. In the proposed project, we will conduct a clinical trial to determine the individual and combined contributions of these two components to reducing Level 2 hypoglycemia in T1D adults who continue to develop Level 2 hypoglycemia despite using ADTs. We will then select the intervention that best balances effectiveness with recipient burden as the optimized program for future implementation. We will recruit 208 participants across the U.S. to achieve this objective. Under a 2×2 factorial design, participants will be randomly assigned to one of four experimental conditions: (1) digital hypoglycemia symptom detection training; (2) digital hypoglycemia psychoeducation; (3) both; or (4) usual care only; all participants will be followed up for 1 year. We will determine the individual and combined effects of the digital hypoglycemia symptom detection training and hypoglycemia psychoeducation on reducing Level 2 hypoglycemia (Aim 1). Then, we will identify and select the intervention that best balances effectiveness with recipient burden as the final program (Aim 2). Finally, we will investigate the intervention mechanisms of action and explore potential factors moderating the intervention effectiveness (Aim 3) based on our trial and qualitative interview data. We hypothesize that each digital component (i.e., hypoglycemia symptom detection training and hypoglycemia psychoeducation) will have an effect in reducing Level 2 hypoglycemia in adult ADT users. By the end of this study, we will (1) inform the strategies necessary to address Level 2 hypoglycemia beyond the current standard of care and (2) provide an effective, scalable solution to alleviate this devastating and even life-threatening complication.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT How do tissues acquire their intricate shapes and functions, and how do disruptions in these processes lead to congenital disorders? Understanding the principles that drive tissue morphogenesis is essential for tackling challenges in developmental disorders, regenerative medicine, and synthetic biology. This project centers on the concept of modularity—the idea that tissue formation relies on a finite set of cellular behaviors, such as division, migration, and shape change, which are reused and adapted to build diverse tissue architectures. By leveraging modularity as a unifying framework, this research seeks to uncover how cells organize into functional modules during early brain and epidermal development in the Drosophila embryo. We focus on two complementary systems: the brain and the epidermis. In the brain, we aim to identify patterns of cell division, migration, and differentiation that coordinate neurodevelopment. These patterns will illuminate universal principles of brain morphogenesis and provide a foundation for understanding how disruptions in these processes contribute to congenital disorders. In the epidermis, we will analyze modularity by investigating how morphogenetic cell activities are reused, combined, or specialized to drive tissue diversity. By addressing how a finite repertoire of cellular modules balances conservation and innovation, we aim to uncover the principles that enable diverse tissue architectures. Central to this effort is the development of a machine learning-based algorithm for cell segmentation and tracking from 3D live-imaging datasets generated using light-sheet microscopy. This novel tool is critical for overcoming longstanding technical challenges in tracking cell lineages over time, enabling us to reconstruct dynamic cellular behaviors across entire embryos. These reconstructions will provide the foundation for identifying and analyzing cellular modules in unprecedented detail, directly supporting our modularity-focused investigations. Aligned with the MIRA mechanism’s emphasis on flexibility and innovation, this work integrates expertise in live imaging, computational biology, and developmental genetics to pioneer a modularity-based framework for understanding morphogenesis. By addressing foundational questions in developmental biology, this research has the potential to transform our understanding of tissue formation and its disruptions in disease, while enabling new applications in synthetic biology and medicine.

NIH Research Projects · FY 2025 · 2026-02

PROJECT SUMMARY/ABSTRACT The preservation of organ functions, such as eyesight and mobility, is a significant health concern in the elderly population. Organ frailty and disease progression are associated with the dysregulation of tissue homeostasis, which is typically regulated by regenerative units, consisting of adult stem cells (ASCs) and neighboring niche cells that regulate ASC function. Therefore, to better understand why regenerative functions decrease in aged individuals, uncovering how aging alters niche cell types and expression (mRNA) is critical for discovering regenerative therapeutical approaches. The potential to uncover molecular mechanisms to reverse age-related disorders prompted me to spatially profile microenvironmental niches in young, old, and regenerated tissues. I have recently developed Ex-Scope, which integrates Expansion Microscopy and Seq-Scope, a submicrometer-resolution ST (spatial transcriptomic) technology, to obtain a high-resolution multi-Omic method that represents an order of magnitude improvements over Seq-Scope. With the assistance of Dr. Guo, who has extensively worked on planarian tissues, we optimized Ex-Scope to spatially profile planarian tissue. Planarians are capable of regenerating any lost body part, but most importantly, regenerated tissues have a youthful tissue architecture; thus, making them ideal to study tissue homeostasis and rejuvenation. Using mRNA single-cell data on young, old, and regenerated planarians, as a reference dataset (obtained by Dr. Guo), we will provide spatial insight into rejuvenating mechanisms between microenvironmental niches and stem cells. Concurrent, we will demonstrate the advantageous resolution of Ex-Scope by profiling RNA granules in planarian stem cells and oocytes (young, old, and regenerated), which are compartmentalized biomolecules that regulate transcription in stem cells and the establishment of pluripotency. In aim 1) we propose to characterize RNA granules and soluble transcriptomes in planarian stem cells and oocytes, with a hypothesis that the granular structures in oocytes and ASCs would have transcriptome contents distinct from soluble cytoplasm, and 2) we propose to profile microenvironmental niches and their changes during aging and rejuvenation, with a hypothesis that aging and rejuvenation will affect cellular (single cell), tissue-level (microenvironment) and subcellular level (RNA granule) transcriptome, each of which is important for tissue function and homeostasis. We expect that the current work will give us a systematic understanding of how aging deteriorates tissue function by altering transcriptomic structure at both microscopic and macroscopic levels, and how regeneration can reverse it and rejuvenate tissue homeostasis.

NIH Research Projects · FY 2026 · 2026-02

Abstract Cholinergic brain activity plays a crucial role in regulating sleep, particularly Rapid Eye Movement (REM) sleep, as demonstrated in animal studies. How these findings translate to humans remains insufficiently explored. Understanding the neurobiology of sleep in humans is critical, as sleep dysregulation is closely linked to neurodegeneration, making sleep a promising therapeutic target. REM sleep behavior disorder (RBD), an early sign of Parkinson’s disease (PD) and Dementia with Lewy Bodies—collectively known as Lewy Body Disorders (LBD) —often appears decades before diagnosis, where it is referred to as isolated RBD. Cholinergic changes also emerge early in LBD, possibly starting in isolated RBD phase. These changes extend beyond the typical decline in cholinergic activity and can include compensatory mechanisms, such as increased activity of the vesicular acetylcholine transporter. We hypothesize that changes in cholinergic neurotransmission, whether increases or decreases, can affect the tonic and phasic availability of acetylcholine. Changes in tonic and phasic availability of acetylcholine, in turn, may disrupt the sleep-wake cycle, leading to REM sleep disturbances such as RBD among others. Our preliminary findings in patients with PD support this hypothesis. We observed cholinergic changes using the selective brain PET radiotracer [18F]-FEOBV, which binds to the vesicular acetylcholine transporter, and self-reported measures of RBD symptoms and excessive daytime sleepiness. Wearable at-home sleep recording devices, such as the Sleep Profiler™, provide a patient-friendly method for quantifying sleep architecture and its alterations with performance comparable to traditional in-lab polysomnography. These technologies enable more ecological investigations of sleep biomarkers. The main aim of this study is to investigate the relationship between cholinergic brain changes and sleep, moving beyond qualitative, questionnaire-based measures in patients with PD (K99) and isolated RBD (R00). We will do that by using advanced imaging techniques ([18F]-FEOBV PET) and wearable sleep recording devices (Sleep Profiler™). During the K99 phase, we will focus on patients with PD, examining the association between cholinergic changes and REM (Aim 1) and non-REM sleep alterations (Aim 2). Building on the skills acquired during the K99 (sleep recording analyses and neurobiology of sleep), I will transition to the independent R00 phase to investigate cholinergic changes in a newly recruited cohort of patients with isolated RBD. I will explore how these changes relate to sleep architecture and clinical progression (one-year follow-up). This research can provide valuable insights into how the cholinergic system contributes to sleep disturbances, potentially paving the way for novel cholinergic modulation treatments that target sleep to protect brain health in isolated RBD and LBD. It may also validate the use of wearable sleep devices for at-home monitoring of cholinergic system changes. The findings in this study will inform the design of future research on molecular mechanisms linked to sleep disturbances and neurodegeneration.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Sjögren’s disease (SjD) is a chronic autoimmune disease characterized by immune cell infiltration of the exocrine glands, which mainly comprise the salivary glands (SGs) and lacrimal glands (LGs). An accumulating number of studies show a significant association between the prevalence of autoimmune diseases and abnormal lipid metabolic conditions and wherein changes in lipid metabolism contribute to disease development. However, how abnormal lipid/cholesterol metabolic conditions contribute to SjD development is unclear. Currently, most patients are diagnosed at later stages of the disease. Therefore, understanding the earlier events in disease development prior to clinical manifestations is essential to identify novel targets for therapeutics and new diagnostic tools for early detection of SjD in at-risk populations, such as those with changes in lipid/cholesterol metabolism. Our preliminary studies found that the expression of INSIG1 and INSIG2, negative regulators of cholesterol synthesis, was significantly downregulated in SjD patients, thus resulting in high cholesterol levels. In agreement with these findings, we found that mice with a deficiency for Insig1/2 in the SGs (Insig1/2 cKO mice) exhibited SjD-like phenotypes with complete penetrance. Interestingly, our preliminary study shows that defects in exocytosis, a system for salivary protein secretion, and elevation of oxidative stress are detectable prior to SjD-like phenotypes (acinar cell death/hyposalivation and autoantibodies detection/inflammation) appear in Insig1/2 cKO mice. Therefore, this study aims to determine how cholesterol metabolic abnormalities in the SGs lead to exocytosis dysregulation and acinar cell death (Aim 1), and how cholesterol metabolic aberrations induce oxidative stress-inflammation (Aim 2) in SjD. In Aim 1, we will track exocytosis under a live-imaging system using newly developed Gate16-eGFP reporter mice, allowing us to visualize the dysregulated exocytosis process in Insig1/2 cKO mice. In addition, we will identify the underlying mechanism that leads to dysregulated exocytosis by genomics and proteomics approaches. In Aim 2, we will determine how oxidated cholesterol (a.k.a. oxycholesterol), a harmful cholesterol linked to inflammation, is induced and contributes to SjD pathogenesis and characterize the immune response to defects in local tissue homeostasis. A detailed understanding of the mechanism(s) by which cholesterol metabolism links to exocytosis and inflammation and how these cascades and loops contribute to SjD will provide new knowledge of the pathogenesis of SjD, advancing our understanding of autoimmune diseases.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the leading cause of dementia, with women twice as likely to develop AD than men. Recent research has highlighted the critical role for gonadal hormones, and specifically lifetime exposure to estradiol, in decreasing risk for AD in women. This sex-specific factor encompasses age of first menstrual period, pregnancies, hormone contraceptive exposure, age of menopause, and hormone therapy, with factors that increase the amount of estrogen exposure decreasing risk for AD. Emerging epidemiological data suggests that hormone contraceptives protect against cognitive decline and dementias even decades after hormone contraceptive use. The main goal of this project is to identify how HC exposure interacts with genetic risk and stress to modify progression of AD-related pathology and behavioral changes. Our overall hypothesis is that HC exposure protects against AD progression via both increased cumulative lifetime estrogen exposure, and via progestin-modulation of stress-related signaling. We will use a mouse model of hormonal contraceptive exposure recently characterized in my laboratory, together with the APP/PS1 mouse model of Alzheimer's disease with behavioral, pharmacological, and molecular tools to address this question. We will focus on both estradiol-mediated protection, and interactions between hormone contraceptives with stress as a modifiable risk factor for Alzheimer's disease. Based on previous findings that hormone contraceptives decrease corticosterone responses to stress, we hypothesize that hormone contraceptives mitigate progression of cognitive impairments and AD-like pathology, including amyloid β accumulation. We further anticipate that hormone contraceptive exposure will decrease stress-induced neuroimmune activation in the hippocampus and prefrontal cortex, thereby protecting against Alzheimer's disease progression. Finally, we hypothesize that whereas ethinyl estradiol exerts protection against ongoing disease progression in part via estrogen receptor β, progestin components of hormonal contraceptives mediate the amelioration of stress-exaggerated disease processes. This project is at the frontier of knowledge on how hormonal contraceptive exposure impacts the brain and exerts long-term protection against Alzheimer's disease. Further, this project will open broad opportunities for future research that extending towards new sex-specific targets for preventive interventions in Alzheimer's disease, related dementias, and age-related cognitive decline. Overall, this project will be an important contribution to understanding sex-specific factors in the development of Alzheimer's disease, and as such, will be an important contribution towards women's health research.

NIH Research Projects · FY 2026 · 2026-02

Infection-induced cell cycle diversion promotes macrophage inflammatory biogenesis Project Summary Infection of macrophages by bacterial pathogens triggers a profound structural and biochemical remodeling process that drives the inflammatory response. A productive macrophage inflammatory response is characterized by altered mitochondrial metabolism and increased cytokine secretion, yet the mechanisms that reshape cellular infrastructure to support these key functions are not well understood. Studies from our laboratory and others clearly demonstrate that mitochondrial morphology, metabolism and signaling are central to host defense and inflammation. Our preliminary data show that macrophage infection by the bacterial pathogen methicillin-resistant Staphylococcus aureus (MRSA) stimulates mitochondrial biogenesis, without concomitant DNA synthesis or cell division. Using a chemogenomics approach to probe the connections between mitochondrial form and function, we find that inhibition of specific cell cycle regulators in infected macrophages prevents organelle biogenesis and limits production of inflammatory cytokines, despite the lack of cell division. Indeed, MRSA induction of mitochondrial biogenesis in primary or immortalized macrophages appears comparable to compounds that induce mitotic blockade. Notably, infection-induced mitochondrial biogenesis appears to be refractory to perturbation of canonical regulators of biogenesis such as PGC-1α. Together, these observations lead to our central hypothesis that macrophage sensing of bacterial infection initiates a specialized inflammatory biogenesis program by stimulating entry of macrophages into G1 for organelle expansion, while blocking commitment to S phase to prevent DNA synthesis during this period of acute oxidative stress. We reason that organelle expansion supports acute metabolic remodeling and cytokine secretion, and blocking S phase entry prevents partitioning of newly expanded cellular infrastructure and protects genome fidelity by limiting synthesis during the oxidative stress associated with robust host defense. We will test this hypothesis by (1) identifying the critical regulatory steps that distinguish the canonical cell cycle from inflammatory biogenesis, and (2) defining how inflammatory mitochondrial biogenesis differs from the canonical biogenesis program to enable host defense and inflammation. These studies will yield mechanistic insight into the blueprint for macrophage innate immune defense and elucidate therapeutic opportunities to modulate inflammation and infection.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT Pancreatic insulin mass (a combination of ß-cell mass and function in the production and storage of insulin) is linked to blood glucose regulation. Normal islet ß-cells contain more than a billion insulin molecules per cell. To maintain this amount involves the synthesis of ≥ 6,000 new molecules per second. Insulin synthesis begins with the translocation of preproinsulin into the endoplasmic reticulum (ER) triggering the formation of proinsulin, which must fold in order to advance through the secretory pathway. Things get “tricky” because not all newly-made proinsulin folds properly. Improperly-folded proinsulin cannot pass ER quality control for export from the ER. Further, misfolded proinsulin has a propensity to associate with bystander proinsulin molecules, forming non-native protein complexes that can propagate the misfolding. Because failed proinsulin molecules do not undergo the forward trafficking needed to become mature insulin, these unsuccessful molecules must be degraded to limit the amount of proinsulin misfolding that can predispose to diabetes. In the last cycle of this grant, our laboratories provided incontrovertible evidence that misfolded proinsulin molecules are targeted for intracellular degradation, and this function is essential for both normal insulin production and the health and survival of pancreatic ß-cells. This competing continuation provides a deeper dive, at the molecular level, to explore three essential secretory pathway quality control mechanisms: ER-Associated Degradation (ERAD); ER-autophagy (ER-to-lysosome, known as ER-phagy); and delivery of (pre)proinsulin into the ER. The three tightly collaborative investigators (Qi, Tsai, Arvan) are experts in these processes and they share highly successful interactions. Specifically, in recent years, the Arvan lab identified the contribution of proteasomal degradation to the maintenance of steady state proinsulin levels in ß-cells, while the Qi lab identified the importance of Sel1L-HRD1 ERAD in maintenance of pancreatic insulin mass [and crucially in additional studies, identified that the ER-based Sigma-1 Receptor (product of the SIGMAR1 / ΣR1 gene) is an endogenous ERAD substrate — upon diminished ERAD, ΣR1 (and other key gene products) are impacted to regulate ER homeostasis]. Curiously, we find that when ERAD capacity or proteasomal clearance is insufficient, proinsulin levels in ß-cells do not rise even though proinsulin is also an ERAD substrate — rather, these levels actually fall, and enhanced ER-phagy is one of the key contributors to this phenotype. Further, our preliminary data (and research plan) highlight perturbed preproinsulin translocation in addition to ΣR1-dependent upregulation of ER-phagy — demonstrating that ERAD crosstalk intersects with several key elements of ß-cell ER function. Thus, we offer a strong rationale for studying ER quality control mechanisms that are linked to development/progression, and possible treatment, of pancreatic ß-cell failure.

NIH Research Projects · FY 2026 · 2026-02

1 PROJECT SUMMARY 2 3 Apicomplexan parasites are a major cause of mortality and morbidity in humans and animals. As a 4 model apicomplexan parasite, Toxoplasma gondii is highlighted by the CDC as the 2nd leading cause of 5 foodborne illness in the US and is classified as an NIAID Emerging/Re-emerging Pathogen. While life- 6 threatening diseases can occur in immunocompromised individuals and fetuses, infections caused by clonal 7 strains frequently found in Europe and North America are mostly benign in healthy humans. However, severe 8 toxoplasmosis outbreaks with fatal consequences among healthy individuals have been documented in South 9 America, where a variety of non-clonal genetically heterogeneous Toxoplasma strains with distinct virulent 10 features are prevalent. To date, the virulence characteristics and parasite genes responsible for the 11 pathogenicity of such Toxoplasma strains in humans remain largely unknown. 12 This project focuses on the virulence traits of human-pathogenic, atypical Toxoplasma strains in the 13 laboratory rat model and aims to understand the genomic basis of pathogenicity and identify genes 14 determining the parasite virulence. The proposal is organized into two specific aims: 1) to elucidate the 15 pathogenic potential of these atypical Toxoplasma strains in the rat model in vivo enabling downstream 16 phylogenetic analysis of known virulence factor and facilitating comparastive genome analysis to detect 17 additional virulence determinants; 2) to utilize a CRISPR/Cas9-based functional genomic screening approach, 18 both in vivo and in vitro, to uncover novel virulence factors in one atypical Toxoplasma strain associated with 19 human fatality. Collectively, the completion of this project will provide novel insight into the molecular basis of 20 high-pathogenic Toxoplasma outbreaks in the human population and contribute to building the scientific 21 framework for the development of therapeutic strategies against acute toxoplasmosis.

NIH Research Projects · FY 2025 · 2026-02

Health system resilience has emerged as a crucial objective for health systems globally, yet the critical role of the nursing workforce in achieving these targets remains insufficiently understood. Bridging this knowledge gap is essential to harness the full potential of nurses in strengthening health system resilience. The purpose of this F31 application is to prepare the applicant for a career as an independent investigator focused on expanding collective knowledge of key predictors and evidence- informed strategies for developing health system resilience. The proposed fellowship consists of two complementary components: 1) a training plan aimed at developing quantitative and qualitative methods proficiency, substantive disaster and health system resilience expertise, and role attainment of a nurse scientist; and 2) a research plan that will further understanding of the relationships between the nursing workforce, health system resilience, and disasters. A strong mentorship team that includes sponsors and collaborators from the University of Michigan Schools of Nursing, and Public Health will provide interdisciplinary expertise in the nursing workforce, global health, disasters, statistical analyses, and qualitative methodologies. Through formal coursework and mentorship, the training plan will allow the applicant to build upon early experience in qualitative methodologies, as well as substantially increase knowledge and experience in quantitative methodologies and data management. The applicant will be supported through intensive mentorship by an expert and personally committed team of mentors, advanced coursework, participation in the national and global scientific community, and progressively independent research. The proposed research project will utilize data from reputable open access sources including World Health Organization National Healthcare Workforce Statistics, country-level health data from the World Bank, country level disaster data from the Emergency Events Database (EM-DAT), and country-level health statistics from the World Health Organization. The specific aims are to 1) examine the relationship between the global nursing workforce, and population health outcomes during declared disasters, and 2) identify the facilitators, barriers, and key adaptations of the role of the nursing workforce in contributing to health system resilience during disasters. This study aligns with the National Institute of Nursing Research’s strategic plan by examining mechanisms to address health outcomes as well as population and community health by investigating approaches to mitigate negative outcomes at the macro level. Findings from this study are critical for shaping future policy and research agendas, and to better identify key predictors of health system resilience.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT The long-term goal of this project is to identify molecular and genetic mechanisms that determine and maintain kidney epithelial cell states in normal physiology and in response to injury. Acute kidney injury (AKI) is a common and costly clinical syndrome and contributes to the development of chronic kidney disease (CKD). Epithelial cells in proximal tubules are highly vulnerable to ischemic damage, which contributes to most severe cases of AKI. After injury, surviving epithelial cells can regenerate the epithelia of damaged proximal tubules, but the extent of recovery varies widely between patients. Successful regeneration requires coordinated transformations in gene expression. As regenerating cells repopulate the nephron, they can regain normal gene expression patterns or become stuck in a failed repair state that leads to CKD. Computational approaches to infer gene regulatory networks involved in cell-state decisions after AKI have consistently identified the tissue-specific transcription factor Pax8. Despite the evidence supporting a critical role for Pax8, the genome-wide targets and functions of Pax8 in regeneration remain largely unknown. For this proposal, we have developed novel in vivo and in vitro models to study Pax8 in normal and regenerating kidney epithelial cells. Our preliminary data indicate that Pax8 maintains differentiated proximal tubule gene expression patterns. After ischemic injury or genetic Pax8 inactivation, expression of Pax8 targets is lost, driving de- differentiation and inducing resilience to ischemic stress. Our data reveal altered chromatin modifications at enhancer elements where Pax8 can activate or repress target genes in concert with other key proximal-tubule- specific transcription factors. Our hypothesis is that Pax8 functions as a central cell-state switch in proximal tubule injury, toggling cells between a de-differentiated, resilient state and a differentiated, functionally mature state. The aims of the project are to 1) define proximal tubule Pax8 target genes before and after injury, 2) identify gene regulatory networks co-regulated by Pax8, and 3) identify mechanisms of altered Pax8 function during ischemic stress. The broader implications of this project address the mechanisms that determine and maintain differentiated cell stability. Ultimately, these insights will lead to new treatments for patients suffering from AKI and other diseases with impaired epithelial function.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY This proposal aims to develop advanced statistical and computational methods for analyzing immune data to enhance our understanding of the immune system’s role in aging and age-related diseases. Aging is accompanied by significant changes in the immune system, increasing susceptibility to infections, chronic inflammation, and other health challenges. Understanding the heterogeneity of immune profiles and their associations with aging outcomes holds great promise for predicting disease risk and identifying therapeutic targets. Large-scale studies such as the Health and Retirement Study (HRS) provide invaluable data on the elderly population. However, immune data obtained from flow cytometry present unique analytical challenges. These data are compositional, highly skewed, and prone to substantial measurement errors, rendering standard analyses unreliable. Existing methods for supervised and unsupervised analysis of immune data frequently fall short in adjusting for covariates, identifying key immune features, capturing nonlinear relationships, and integrating multiple data sources, resulting in significant gaps in our understanding of immune aging. This proposal addresses these challenges through innovative methodologies. In Aim 1, we will develop a robust nonparametric framework to denoise immune cell frequency data. This framework is free from distributional assumptions and adaptable to diverse data types, enhancing the accuracy of subsequent analyses. In Aim 2, we will create a model-based clustering framework to identify immune subgroups, with a special focus on adjusting for covariates and identifying key drivers of heterogeneity between clusters. In Aim 3, we will develop novel semi-parametric methods to integrate multiple sources of immune biomarkers and associate them with aging outcomes, emphasizing biological interpretability and feature selection. In Aim 4, we will build an open- source software package to ensure the accessibility and wide dissemination of these methods. Motivated by and applied to HRS data, these methods aim to uncover immune signatures in the elderly and clarify their relationship with age-related outcomes. The research will deliver powerful tools for immune data analysis and transformative insights into the interplay between immunity and aging.

NIH Research Projects · FY 2025 · 2026-02

Abstract Pre-diabetes (Pre-D) is characterized by elevated glycated hemoglobin and plasma glucose and is a clinical precursor to type 2 diabetes mellitus (T2D). Pre-D currently affects ~90 million Americans. Both Pre-D and T2D are highly associated with cardiovascular disease and among the top five causes of mortality worldwide. Exercise is the cornerstone of management and is most efficacious during the Pre-D stage when glycemia is below the diabetic threshold. However, excessive fatigability during exercise (i.e., exercise induced reductions in force or power of the limb muscles) limits exercise performance in people with Pre-D. Our laboratory demonstrated that (1) across the diabetic spectrum, people with Pre-D and T2D have greater fatigability of limb muscles than controls due to mechanisms within the muscle, and (2) fatigability in people with T2D was associated with a reduced blood flow to the exercising muscle. It is unknown, however, if people with Pre-D have impaired vascular function and oxygen delivery that leads to an increased fatigability. Our central hypothesis is that impaired vascular function impedes blood flow and blunts subsequent oxygen delivery to skeletal muscle during exercise, resulting in excessive fatigability of limb muscles in people with Pre-D. A unique and translational aspect of this proposal is the quantification of the vascular responses (macro- and micro-vasculature) to fatiguing exercise and exercising training at different sites along the vascular tree, including, in feed arteries (doppler ultrasonography), isolated skeletal muscle arterioles (extracted from muscle biopsy), capillary perfusion (near infrared spectroscopy, NIRS) and capillary density (from muscle biopsies). Aim 1 will determine if vascular dysfunction is a mechanism for excessive fatigability in people with Pre-D. Aim 1.1 will compare leg blood flow and skeletal muscle oxygenation in response to dynamic fatiguing exercise between people with Pre-D, healthy controls and T2D. Groups will be matched for age, sex, body mass index and physical activity levels to determine disease- related vascular function and fatigability rather than inactivity-related changes across the diabetic spectrum. Skeletal muscle blood flow through the femoral artery will be quantified with ultrasonography and skeletal muscle oxygenation with NIRS during a dynamic fatiguing knee extension exercise. Aim 1.2 will determine endothelial vascular function at macro- and micro-vascular levels in people with Pre-D and T2D. Flow-mediated dilation will be assessed in vivo in the femoral artery using ultrasonography and in isolated arterioles extracted from the vastus lateralis muscle biopsies. Aim 2 (a clinical trial) will assess the vascular mechanisms for improved blood flow and fatigability in response to dynamic exercise training with blood flow restriction in people with diabetes. People with Pre-D and T2D will perform 8 weeks of unilateral resistance training in which one leg is exercised with freely perfused conditions and the other leg with blood flow restriction. Thus, blood flow restriction and resistance training will be used as a probe to further understand the mechanisms of fatigability along the vascular tree in people with Pre-D and T2D, and test training strategies to improve fatigability in this population.

NIH Research Projects · FY 2026 · 2026-02

Cytomegalovirus (CMV) is a common beta herpesvirus with over half of adults in the US infected by age 40 and higher seroprevalence among women than men. Though most acute CMV infection in immunocompetent individuals is mild or asymptomatic, following acute infection the virus remains in a latent state with the potential for reactivation across the lifecourse increasing risk of the creation of a chronic inflammatory state, a well appreciated component of accelerated biological aging. Chronic inflammation from any cause can lead to deleterious effects across all organ systems, resulting particularly in later midlife increased risk of metabolic and cardiovascular disease (CVD) in women. There has been mixed evidence implicating CMV seropositivity (CMV+) in the development of CVD and CVD-related mortality. A major limitation of many studies of CMV+ and CVD risk are that such studies do not adequately capture the critical window of physiologic and inflammatory changes that occur in women during the midlife. In the proposed K01, I will obtain the necessary training in aging and field methods to address these research gaps and pursue an independent research career. My research objectives are to a) describe the midlife prevalence of CMV+ within the SWAN cohort and relate CMV+ to subclinical cardiovascular outcomes; b) examine the effect of midlife inflammation on the relationship between CMV+ and carotid intima media thickness; and c) explore changes in IgG antibody level of multiple herpesviruses across the midlife, and to examine the relationship between individual-level change in IgG level and subclinical CVD outcomes. I hypothesize that that individuals with prior CMV infection will have worse subclinical CVD outcomes than those without CMV, particularly in the absence of other common inflammatory conditions such as morbid obesity and type 2 diabetes. To test these hypotheses, I will utilize longitudinal data and banked specimens from the Study of Women’s Health Across the Nation (SWAN), a multi-site cohort of midlife women transitioning into late adulthood. I will conduct this work at the University of Michigan School of Public Health, supported by an interdisciplinary research team that will guide my training in 1) aging and cardiovascular disease epidemiology; 2) immunology and immune-related aging; and 3) practical skills in the development and implementation of prospective data collection methods. By thoroughly evaluating the connections between CMV, midlife inflammation, and CVD we can improve preventative care by identifying those who might be at increased risk for CVD regardless of the presence of other risk factors. This research will also underscore the importance of nontraditional risk factors for cardiovascular disease in women. This grant is critical to meeting the National Institute on Aging’s strategic goal of better understand the biology of aging and its impact on the prevention, progression, and prognosis of disease, and the NIH Initiative on Women’s Health Research goal of developing personalized prevention strategies for cardiovascular disease in women. This award will help launch my independent research career evaluating the etiologic intersections of chronic and infectious disease.

NIH Research Projects · FY 2026 · 2026-01

Alzheimer’s disease (AD) is the most prevalent neurodegenerative condition, with its effects becoming more pronounced with age, suggesting that aging is a critical factor in its development. Recent clinical observations have identified significant mechanical changes in the aging brain, including decreased stiffness, which reflects tissue rigidity, and increased viscoelasticity, which describes fluidic and time-dependent properties. These alterations primarily result from reduced tissue connectivity with age. However, their precise effects on brain cells remain unclear. This project focuses on microglia, the brain’s primary immune cells, which play a crucial role in maintaining brain health by responding to inflammation, clearing debris, and repairing damage. Their function is particularly important in AD, where they contribute to both inflammatory responses and disease progression. Despite growing recognition of the interplay between mechanics and cellular function, how aging-induced mechanical changes affect microglial behavior remains poorly understood. Investigating this relationship could provide valuable insights into AD pathogenesis and inform the development of targeted therapeutic strategies. The overarching goal of this project is to elucidate how matrix mechanics—specifically stiffness and viscoelasticity—shape microglial function and behavior, and to explore their implications for AD progression at the cellular and molecular levels. Our central hypothesis is that mechanical changes in the aging brain reshape microglial activity, promoting inflammatory characteristics that exacerbate AD pathology. To test this hypothesis, this research is structured around three specific aims: 1) engineer a 3D in vitro model that closely replicates the brain’s extracellular matrix (ECM) with independent control over stiffness and viscoelasticity, 2) investigate how variations in matrix mechanics influence microglial function, particularly their inflammatory response and ability to clear debris, and 3) decipher the mechanotransduction pathways through which mechanical properties regulate microglial activity, identifying key molecular mechanisms involved. By integrating a multidisciplinary approach, this project explores AD from a novel mechanobiological perspective. Successful completion of these aims will deepen our understanding of AD, advance research on brain aging and mechanobiology, and potentially lead to innovative diagnostic and therapeutic strategies, particularly by targeting mechanotransduction pathways.

NIH Research Projects · FY 2025 · 2026-01

Project Summary/Abstract Myocardial hemodynamic function is heavily influenced by intramyocardial pressure which increases during systole and is highest in the subendocardial region. The complex interaction between myocardial tissue and vasculature leads to unique hemodynamic phenomena in the myocardium including vascular compression during systole in the subendocardium, diastolic-dominant arterial blood flow, bouts of retrograde arterial flow during systole, and systolic dominant venous flow. Vasoregulation, adjusting the diameter of blood vessels through the constriction or relaxation of smooth muscle cells in vessel walls, can alter myocardial hemodynamics and help match oxygen delivery to myocardial oxygen demand. Currently, there exist numerous hypotheses regarding how the biomechanics of myocardial hemodynamics and physiological vasoregulatory responses must operate in order to supply sufficient oxygen to all areas of the myocardium. The overall goals of this project are to develop comprehensive computational models of myocardial hemodynamics and oxygen perfusion that incorporates vasoregulatory mechanisms and to use these models to test hypotheses on the mechanisms governing transmural variation of hemodynamics and oxygen perfusion. Key model constituents will include: 1) anatomically realistic arterial, capillary, and venous networks; 2) temporally varying inlet arterial pressure and temporally and spatially varying transmural pressures; 3) high- fidelity oxygen transport at the capillary scale. Models will be identified and validated based on data from in vivo and in vitro experiments through an ongoing collaboration between research groups at the University of Michigan and University of North Texas. The integrated model, in turn, will be used to analyze results, make novel predictions, develop and refine new hypotheses, and design new experiments.

NIH Research Projects · FY 2025 · 2026-01

Project Abstract Healthy aging may be a case of mind over matter. Experiments in systems ranging from worms to mice have established that neural states, which humans often associate with the feelings and motivations behind our behaviors, may be as influential as physical experiences in promoting a long and healthy life. One major motivational drive for animals is hunger, which promotes feeding. Feeding can be generated by the physiological need to consume nutrients as well as the hedonic properties of food. While brain circuits and mechanisms that regulate feeding have been described, it is unclear how they contribute to the generation of motive forces that drive feeding, and ultimately impact aging. Based on visually identified and quantified behaviors exhibited by hungry flies, we have found that flies exhibit distinct and measurable hunger drives that can be homeostatic (i.e., need-based) or hedonic (i.e., pleasure-based). These can be distinguished, at least in part, using sophisticated feeding behavior metrics that have shown homeostatic feeding is best represented by the number of feeding events on a protein rich food, while hedonic feeding is characterized by the duration of feeding events on a highly palatable food. We have discovered specific regions of the fly brain that influence feeding duration on palatable food but not the number of protein food events, suggesting that they are involved specifically in hedonic feeding. While the direct manipulation of homeostatic hunger has been shown to extend lifespan, preliminary data from our laboratory indicate that hedonic drive shortens fly lifespan. To understand how hedonic feeding is generated by the brain and manipulate this hedonic perception, we will determine how the identified hedonic neural circuitry encodes a hedonic hunger state in Aim 1. For Aim 2, we will identify how different levels of hedonic perception influences aging in Drosophila. The proposed study will provide key insight into how the brain weighs environmental cues to drive hedonic feeding behavior and how hedonic feeding impacts lifespan in various environmental contexts. Additionally, we will manipulate these cues to determine the cellular mechanisms through which feeding neural states can affect healthy aging.

NIH Research Projects · FY 2025 · 2025-12

PROJECT ABSTRACT/SUMMARY Over two million Americans have a cardiac implantable electronic device (CIED) to manage arrhythmias, often secondary to cardiomyopathies, and prevent sudden cardiac death. Magnetic Resonance Imaging (MRI) is a powerful tool for non-invasive detection of myocardial tissue abnormalities—including inflammation, edema, and fibrosis—using late gadolinium enhancement (LGE) imaging and quantitative T1, T2, and extracellular volume fraction (ECV) mapping. However, MRI remains widely underutilized in patients with CIEDs, as metallic components in these devices distort the magnetic field and create off-resonance artifacts that severely degrade image quality. Although 16% of patients with CIEDs will develop a clinical indication for cardiac MRI at some point, they are 40% less likely to undergo an MRI exam than non-CIED patients, leaving clinicians to rely on alternative modalities that lack detailed tissue characterization capabilities. This project aims to address this unmet need by developing MRI technology for robust myocardial tissue characterization specifically tailored for CIED patients, providing quantitative tissue property maps (T1, T2, proton density, and ECV) and multi-contrast LGE images from a single imaging platform. Our solution is based on Magnetic Resonance Fingerprinting (MRF), an innovative framework that measures temporal changes in magnetization (“fingerprints”) to achieve rapid multiparametric mapping. We propose a novel cardiac MRF technique that is separately optimized for conventional 1.5T scanners, given that most CIED patients are currently imaged at this field strength, as well as emerging low-field 0.55T scanners, which offer inherent advantages for imaging near metallic implants, such as reduced off-resonance artifacts. In Aim 1, we will develop the proposed technique in parallel for 1.5T and 0.55T by integrating robust data collection strategies, such as center-out radial sampling and wideband excitation pulses, with a physics-informed deep learning reconstruction that further suppresses off-resonance artifacts and residual motion. We will evaluate accuracy, precision, and repeatability in phantoms and healthy subjects with an externally positioned CIED scanned at both field strengths compared to conventional cardiac mapping methods. In Aim 2, we will assess MRF for native and post-contrast mapping in cardiomyopathy patients with CIEDs at 0.55T and 1.5T and validate methods for detecting myocardial fibrosis, given its prognostic importance in many conditions. To this end, we will generate synthetic multi-contrast (bright- and dark-blood) LGE images from post-contrast MRF maps, which we expect to simplify the exam and enhance detection of fibrosis compared to conventional bright-blood wideband LGE scans. Furthermore, we will develop a clustering algorithm that directly analyzes tissue property maps to identify fibrosis, serving as a semi-automated and operator- independent alternative to LGE. This project has the potential to have a significant and immediate impact on public health by expanding access to advanced MRI techniques for myocardial tissue characterization in CIED patients, who are at high risk of adverse cardiovascular events yet are underserved by current MRI technology.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY / ABSTRACT Early childcare and education (ECE) centers are trusted institutions that engage with parents regularly, positioning them as key messengers for childhood immunization and respiratory health promotion. While ECE centers ensure compliance with mandated vaccines, their potential to support uptake of non-mandated immunizations—such as influenza vaccine, COVID-19 vaccine, maternal RSV vaccine, and nirsevimab antibody—remains underutilized. The BREATHE Well (Building Readiness, Engagement, and Trust for Healthy Environments) Toolkit is an evidence-based intervention designed to enhance ECE-originating vaccine communication, training ECE staff to effectively engage parents on immunization topics. This study will evaluate the feasibility, acceptability, and effectiveness of the BREATHE Well toolkit using a cluster- randomized controlled trial (RCT). The project will be guided by three specific aims: (1) Develop and refine the BREATHE Well toolkit through formative research, incorporating input from ECE staff, parents, and public health officials; (2) Assess the acceptability and feasibility of the toolkit through focus groups and surveys with ECE staff and parents in demonstration sites within Michigan; and (3) Evaluate the effectiveness of the toolkit in a cluster-randomized trial of ECE centers, measuring changes in parental vaccine confidence, intent to vaccinate, and staff capacity to serve as trusted messengers. The BREATHE Well toolkit will be designed as a scalable approach usable in different types of ECEs. Findings from this study will inform best practices for integrating vaccine-related education into ECE settings, with the goal of increasing parental vaccine confidence and improving uptake of recommended immunizations.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Social media (SM) use is associated with disengagement from school and poor mental health, and can facilitate inter-personal and community violence, including cyber-bullying which is highest among LGBTQ+ adolescents (25%) and female (21%) students. Digital apps have been used to document and share recordings of fights, create escalation of conflicts, and be used to create direct and indirect threats. Given these negative impacts, a number of school districts across the country have implemented policies that monitor, restrict, or ban cellphone use in schools. Policies vary greatly both in their objectives and enforcement. Despite the ubiquity of such policies, there are no studies that explore how effective cellphone bans are at reducing school- and community-based violence let alone their potential unintended consequences such as limiting the ability of students to report concerns about themselves or others. The proposed project will examine school cellphone policies in Michigan using a mixed method approach to assess both implementation and impact, with a particular focus on how such policies differentially impact communities of color across the state. This research falls under CDC Research Objective #1 (effectiveness research to evaluate innovative approaches for reducing community violence) and has direct policy implications for districts in Michigan and across the country seeking to restrict school cellphone use. Using a combination of interview, survey, and administrative data sources, researchers will describe state-level variability in district student cellphone policies, understand the barriers to and facilitators of implementation and estimate their impact on indicators of community violence, including fights in school, school discipline, and police incidents. The impact analysis will utilize several quasi-experimental methods including difference-in-difference and comparative interrupted time designs to estimate causal impacts of the policy. Leveraging rich administrative data on school- and community-based violence along with youth demographics and community characteristics from the Michigan Department of Education and the Michigan State Police will allow researchers to control for a variety of potentially confounding factors and study critical outcomes at the school level. Importantly, access to this type of individual-level outcome data will allow the researchers to convincingly assess if and how cellphone policies differentially affect racial/ethnic groups and other important subgroups (e.g., urban, suburban and rural schools). Moreover, this data will allow us to study how the cellphone policies impact mental health and academic outcomes and examine whether these effects mediate impacts on violence.

NIH Research Projects · FY 2025 · 2025-09

Each year, nearly $350 billion in Medicare spending is distributed across approximately 3,500 acute US hospitals based on a complex set of administrative technicalities. One important technicality is the hospital wage index, which standardizes hospital payments by local labor costs. However, hospitals can obtain exceptions to the wage index formula, resulting in ~$2 billion in additional hospital payments, which are considered by many to be economically unjustified. Compounding these distortionary effects is the wage index’s budget neutrality mandate, such that higher spending from increasing numbers of wage index exceptions is offset by lower payments to all hospitals. Together, the exceptions and offsets may either improve or erode some hospitals’ ability to hire staff and provide high-quality care, with implications for sicker and poorer patient populations who may receive poorer quality of care, thus making the wage index regressive and harmful. Moreover, hospitals receiving exceptions may use additional revenue to shift existing patients or admit new ones into higher-paying services, thereby shifting the composition of services and potentially restricting access to lower-paying services. We will explore the effects of Medicare’s hospital wage index, by examining (1) financial, (2) staffing and quality and health outcomes, and (3) access and costs (because of changes in the mix of hospital services) associated with exceptions and offsets, using 100% Medicare claims and wage index data. Innovation: While of equal or greater impact on hospital revenue, relative to other Medicare payment policies and reforms, the wage index has had limited study. Our econometric analyses can thus offer novel insights beyond current work that primarily consists of reports from contractors and agencies that have not assessed staffing, access, and health effects of the wage index exceptions and budget neutrality offsets. Impact: While theoretically a reasonable accounting tactic, when coupled with unjustified exceptions, budget neutrality may lead to undesirable and unintended effects related to hospital investments and quality, with important implications for older adults’ health. Fewer or lower-quality services, and lower nursing staffing ratios under these remediable payment distortions could diminish patient safety and increase adverse events. Given the push to address the adequacy of payments to ensure patient care access and quality, and growing understanding that Medicare policies may harm less resourced providers, our work can inform future wage index technical choices. Decision makers could use our findings to help understand and redirect reimbursements (without wage index exception distortions) to improve access to certain types of care.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with no cure, and although inflammation plays a significant role in the disease, gaps remain in leveraging this knowledge for personalized clinical outcome models and personalized therapeutics. Peripheral blood immune profiles—defined as the total numbers and activation states of specific peripheral immune cells—reflect overall inflammation, but methodologic gaps exist to characterize these immune profiles given limitations in conventional flow cytometry, hampering its widespread use for ALS. The long-term goal is to leverage immune profiles to identify dysregulated immune pathways that can be treated to slow or stop ALS progression. The overall objective in this proposal, being submitted in response to RFA-TS-25-036 Funding Option A, is to establish spectral flow cytometry as the state-of-the-art approach to characterize peripheral immune profiles in ALS. The central hypothesis is that spectral flow cytometry will yield rigor and reproducibility with fresh and frozen blood samples and will identify pro-inflammatory immune profiles for ALS clinical outcome prediction. The rationale is that establishing rigorous protocols for the widespread multicenter use of spectral flow cytometry in ALS will unlock the complex, but vast, potential of the immune system for improving diagnosis, prognosis, and drug development for all persons with ALS. The central hypothesis will be tested by pursuing two specific aims: 1) Utilize spectral flow cytometry to quantify inflammation in ALS peripheral blood biosamples and determine the consistency of immune markers between samples processed fresh versus frozen to inform multisite ALS studies; and 2) Determine the natural history, diagnostic, and prognostic significance of comprehensive longitudinal spectral flow cytometry immune profiles as an ALS inflammatory signature. Under the first Aim, spectral flow cytometry protocols will be optimized to characterize ALS inflammation in fresh and frozen samples, paving the way for its use in multisite ALS studies. Under the second Aim, immune profiles will be associated with important ALS clinical outcomes, such as case status and disease progression. The research proposed in this application is innovative, in the applicant’s opinion, because it moves the field in a new direction—bridging both mechanistic and knowledge gaps—by bringing the transformational potential of spectral flow cytometry to ALS, establishing the rigor needed to make the technology widely available to the ALS community, leveraging the resulting data to better understand the role of comprehensive immune profiles for ALS, and providing the foundation for future multisite studies. The proposed research is significant because peripheral blood immunophenotyping will enable improved ALS clinical outcome associations, and eventually therapeutic target identification, testing, and responder analysis.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Interpersonal community violence (ICV; e.g., assaults, homicides, violence between groups, and threats/use of weapons) is a public health crisis among American Indian/Alaska Native (AI/AN) peoples including youth in the U.S. Lakota youth who reside on the rural and impoverished Pine Ridge Reservation (PRR) are no exception. Despite research documenting contextual (e.g., structural racism, colonization and multiple historical traumas), risk (e.g., alcohol and drug use), and protective (e.g., cultural identity) factors for ICV among AI/AN youth, we know little about how to prevent ICV among AI/AN youth. A potentially promising approach to prevent ICV in tribal communities is crime prevention through environmental design CPTED. CPTED integrates physical (e.g., lighting) and, more recently social (e.g., community engagement) strategies to prevent crime, including ICV. Busy Streets Theory (BST) is a conceptualization of CPTED focused on local community engagement that fosters community ownership and allows for tailoring physical changes to community interests and culture, and creating positive social capital. BST aligns strongly with Lakota cultural teachings. In response to CDC RFA- CE-25-021 (Objectives 1, 2, and 3), the purpose of the current study is to examine how a place-based, community-led, and culturally CPTED activities may prevent and reduce ICV on the PRR. Using community- based participatory action research (CBPAR), we will develop (Aim 1) the CPTED project, preliminary entitled The Wancantognaka Project (The Generosity Project; TGP). In addition to culturally grounded CPTED projects (e.g., community gardens with traditional Lakota methods and foods, building inipis (sweat lodges) for ceremony), TGP will include program sessions for youth (ages 13 to 19) taught by Lakota adults, including Elders. Further, using the RE-AIM framework, we will collect implementation and community acceptance and perceived impact data and document costs (Aim 2). We will also assess youth outcomes (Aim 3) via surveys (baseline, immediate post, and 6- and 12- month follow-ups) that assess risk (e.g., 7 C’s of positive youth development, cultural identity, social support) and protective (e.g., alcohol and drug use, violent behaviors) factors. Finally, using police incident data, we will assess the impact of CPTED on rates of community violence (Aim 4). For Aims 3 and 4, we will utilize a longitudinal quasi-experimental design in which the community on the PRR implementing CPTED will be compared on youth (ages 13 to 19; N=320; 160 per community) and community outcomes (crime rates 48 bi-weekly intervals pre TGP and 24 bi-weekly intervals post TGP) to another community on the PRR (similar in terms of demographics and crime rates) not receiving CPTED. The proposed study is highly aligned with the Healthy People 2030 priority area of injury and violence prevention as well as the NCIPC’s goal to conduct rigorous research to expand and advance an understanding of approaches to prevent ICV and to eliminate racial inequities in risk for ICV.

NIH Research Projects · FY 2025 · 2025-09

Project Summary / Abstract Idiopathic Pulmonary Fibrosis (IPF) is a progressive fibrotic disease of the lungs that is more common in aging and men, with 1 in 200 adults over age of 70 diagnosed. Patients have an estimated 2-5 years mean survival time following diagnosis, and only lung transplant is considered curative. Understanding the causes and immunological environment of the fibrotic lung could provide new targets for therapeutic or prophylactic treatment. Tryptophan metabolism is associated with increased inflammation in the lungs of IPF patients, as well as in our bleomycin-induced murine lung fibrosis model, producing several metabolites, such as kynurenine (kyn) that are recognized by the Aryl-hydrocarbon receptor (AHR). AHR has been well-characterized as affecting the immune system through several mechanisms both pro- and anti-inflammatory. Preliminary data from our lab show that inhibiting one of the early enzymes in the kynurenine pathway (KP) of tryptophan metabolism, TDO, results in significant protection from fibrosis in our murine bleomycin (blm) model. Data from human IPF patients support that TDO is uniquely expressed in alveolar fibroblasts of IPF patients, but not healthy controls. Furthermore, AHR is mostly highly expressed in dendritic cells (DCs) which play a critical role in fibrosis. We hypothesize that KP metabolites from fibroblasts are activating AHR in DCs to stimulate pro-inflammatory signals which in turn drive pulmonary fibrosis. The long term goal of this proposal is to understand how tryptophan metabolism impacts lung fibrosis in order to identify novel therapies for IPF. The objectives of this project are to determine how TDO inhibition affects downstream metabolites, and whether those metabolites are signaling to relevant immune cells which are important for fibrosis, specifically DCs, in a pro-inflammatory way. The specific aims of my proposal are: 1) to determine the in vivo effects of TDO inhibition on the kyn pathway and dendritic cells, and 2) to evaluate the mechanism of fibroblast-dendritic cell cross talk through ex vivo co-culture and conditioned media experiments. Under the first aim, I will perform metabolomics on healthy mice and on mice with blm-induced fibrosis with or without treatment with a TDO inhibitor in order to understand how fibrosis alters the metabolome of the lung and to establish the effect of TDO inhibition on downstream immunomodulatory metabolites. I will also perform RNAseq on primary DCs from the same conditions to determine how their maturation and pro-inflammatory pathways are altered, as well as evaluate their functional capacity to polarize naïve T-cells. Under the second aim, I will test primary fibroblasts, DCs, and T-cells of both our murine blm model and human IPF patients to determine the specific mechanism of anti-fibrotic activity by both directly treating cells with TDO-inhibitors and Tryptophan metabolites of interest, as well as using conditioned media experiments to evaluate signaling.