University Of Michigan At Ann Arbor

NIH Research Projects · FY 2026 · 2026-05

Summary The gastrointestinal (GI) tract is the largest mucosal surface in the body. A single cell layer thick intestinal epi- thelium separates the host interior from luminal pathogens while at the same time a series of intercellular junc- tions, including tight junctions, allow for selective movement of nutrients, ions, and water. Maintenance of this barrier is critical for a healthy intestine and its disruption leads to diseases such as diarrhea, a common outcome of enteric viral infections. Notably, the GI tract is not uniform; it exhibits distinct anatomical and functional prop- erties between the small and large intestine, including variations in tight junction protein expression. Enteric pathogens evolved to overcome the intestinal barrier to infect the host. However, how intestinal regionalization impacts pathogenesis of human enteric viruses is largely unknown. Human astroviruses (HAstV) are a good model to address this fundamental question in viral pathogenesis. We have demonstrated that epithelium-only human intestinal organoids (HIO), which are “miniguts” derived from stem cells isolated from human intestinal biopsy tissues or surgical resections, support HAstV infections from all clades and in all segments of the intestine. HAstVs are highly prevalent viruses that infect the entire lengths of the GI tract causing mostly pediatric diarrhea but can also cause disseminated disease in the immunocompromised. They are genetically diverse and classi- fied into classical human astroviruses, serotypes 1 – 8 (HAstV 1- 8), and two non-classical clades, VA and MLB. In vitro work from polarized model colonic epithelial Caco-2 cells suggests that the pathogenic mechanism of classical HAstV-1, but not VA1, occurs when the enterotoxin function of the HAstV-1 capsid disrupts tight junc- tions by downregulating occludin. Our new findings demonstrate that VA1 alters electrical conductance of T84, another model human colonic epithelial cell line, (but not Caco-2) by modulating a different group of tight junction transmembrane proteins, the claudins. Some members of the claudin family but not occludin exhibit intestinal segment specific expression patterns. This raises the fundamental question whether HAstVs may interact with the intestinal epithelial barrier in a segment-specific manner and positions HIO as an ideal non-transformed and physiologically relevant model of the human intestinal epithelium for detailed mechanistic studies of HAstV inter- action with the small and large intestine. The goal of our research is to advance our understanding of HAstV pathogenesis by determining the interaction of HAstVs with the intestinal epithelial barrier. Towards that end, we will use a combination of virological, molecular, genetic, and imaging approaches to pursue the following aims: 1) Investigate barrier properties of the small and large intestinal epithelium infected with HAstVs, and 2) Deter- mine whether the VA1 spike changes claudins and paracellular permeability. These aims are in direct response to NIH Notice of Special Interest (NOSI) AI-23-048, as they will “improve understanding of basic virology of understudied viruses such as HAstV”. This research has high potential for transformative impacts on our under- standing of the pathogenesis of viral gastroenteritis and intestinal epithelial biology.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY The intersection of the opioid epidemic and widespread cannabis legalization has directed attention toward cannabis as a promising treatment for chronic pain, including knee osteoarthritis (OA). Cannabis compounds, particularly Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), act on the endogenous cannabinoid (eCB) system, which is involved in pain processing at peripheral, spinal, and supraspinal levels. Despite approximately 30% of individuals with chronic pain resorting to cannabis for relief, the contributions of eCBs and their interactions with exogenous cannabinoids, such as THC and CBD, remain poorly understood. We propose to conduct secondary analyses of an NIH-funded, 2x2 factorial, double-blind clinical trial involving knee OA patients randomized to receive CBD, THC, both, or placebo. This trial captures circulating eCB concentrations multiple times during treatment, as well as quantitative sensory testing (QST) data, patient- reported outcomes (PROs), and functional neuroimaging (fMRI) at baseline and after treatment. The goal of this F31 is to characterize the influence of exogenous cannabinoid treatment on the eCB system in patients with painful knee OA. In Aim 1, we will characterize the relationship between circulating eCB concentrations and clinical pain outcomes (e.g., pain intensity) over the course of cannabinoid treatment. We hypothesize that eCB concentrations will decrease following cannabinoid treatment compared to placebo, and these reductions will be associated with reductions in clinical pain outcomes after cannabinoid treatment relative to placebo. Aim 2 will utilize QST to characterize the relationship between circulating eCB concentrations and multimodal sensory responses. We hypothesize a positive baseline correlation between multimodal sensory sensitivity and eCB concentrations, and that decreases in eCB concentrations with cannabinoid treatment will predict corresponding reductions in sensory sensitivity. Lastly, Aim 3 will characterize the relationship between circulating eCB concentrations and pain neurobiology. We hypothesize that reductions in neural activation in pain-related areas (e.g., insula, primary somatosensory cortex, and thalamus) with exogenous cannabinoid treatment will be associated with a reduction in eCB concentrations. I will receive training in pain science, the eCB system in the context of chronic pain, neuroimaging techniques, cannabinoid therapeutics. This research, by clarifying the eCB system's role and its modulation through cannabinoid treatments, seeks to lay the groundwork for developing mechanism-based, individualized pain management strategies, significantly advancing chronic pain therapeutics and potentially improving patient outcomes. In addition, this study and training will facilitate my long-term career goal to become an independent researcher with a research program focused on investigating the neurobiological mechanisms of chronic pain and understanding the endocannabinoid system in the context of chronic pain.

NIH Research Projects · FY 2026 · 2026-05

Abstract/Project Summary The circadian rhythm has strong effects on cognition and memory. There is also strong evidence that the activities of neurons during sleep are important for the memory function of the brain. Until recently, little was known about why delaying these activities for a prolonged period of wakefulness (commonly known as “sleep loss”) should have an enduring negative impact on memory, especially given the brain’s general capacity to restore itself during an eventual “recovery sleep”. Recently, by recording from large populations of hippocampal neurons in behaving and sleeping rodents, we found that the reactivation and replay of neuronal ensembles in the hippocampus during sharp-wave ripple events were significantly diminished during recovery sleep compared to in sleep immediately following behavior on a maze, suggesting that prolonged waking during the inactive cycle, when animals normally sleep, impairs the capacity of the hippocampus to generate the patterns widely considered most important for the consolidation of memories. However, key questions remain concerning how these sleep-dependent effects interact with the circadian cycle—known to impact learning and memory—and the optimal times and durations for waking and sleep for reactivations and replays that are critical to hippocampal function. In this proposal, we investigate how different periods of extended waking, at different phases of the circadian cycle, plus arousal enhanced by caffeine, impact hippocampal neuronal firing patterns during sharp-wave ripples, in both the awake state and the subsequent sleep. We further investigate the impact of enhancing these events by optogenetically prolonging their duration to test their impact on hippocampus-dependent memory. In sum, this work will help elucidate how sleep pressure and circadian timing interact to impact on hippocampal function and influence the systems-level firing patterns that are considered to support the hippocampal role in memory.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/ Abstract Opioids like morphine are the most effective pain relieving drugs available but their rewarding properties lead to misuse. The rewarding and analgesic properties of opioids are mediated by activation of mu opioid receptors (MOR). Hyperalgesia is an exaggerated pain perception in response to a stimulus that is normally mildly uncomfortable. Hyperalgesia occurs when opioid-dependent people discontinue opioid use, known as opioid withdrawal-induced hyperalgesia (OWIH). Opioids also relieve this hyperalgesia providing motivation for continued opioid use and dose escalation. Midline thalamic (MThal) nuclei are key hubs responsible for activating brain regions involved in opioid modulation of pain and motivation. However, we lack critical details about what aspects of opioid-mediated behavior and physiology are due to MOR activation on thalamic neurons. We have found that glutamate transmission from MThal neurons to cortical and striatal brain regions is inhibited by MOR agonists like morphine. We hypothesize that MThal neurons are a heterogeneous mix of MOR-expressing and MOR-lacking neurons. We further hypothesize that prolonged inhibition of MThal neurons by opioids can induce adaptations leading to hyperalgesia upon opioid withdrawal (OWIH) while acute opioid-inhibition of MThal neurons will attenuate hyperalgesia. The long term goal of this project is to understand what neurons in the MThal express MOR, how these MOR-expressing MThal neurons respond to conditions that cause hyperalgesia, including OWIH, and whether inhibition of these neurons is sufficient to suppress hyperalgesia. We will use behavioral pharmacology, imaging, whole-cell electrophysiology, and optogenetic manipulations in mice to gain a foundational understanding of how opioid action in thalamo- cortico-striatal brain circuits ultimately affect hyperalgesia and antihyperalgesia. Aim 1 will determine the relative abundance of both MOR-expressing and MOR-lacking medial thalamic neurons and determine whether these neuronal populations share convergent or divergent innervation patterns. From this we will learn whether morphine inhibition of neurotransmission in the medial thalamus shows anatomic specificity or is a consistent effect across medial thalamic neurons. Aim 2 will determine whether MOR-expressing medial thalamic neurons are preferentially activated by conditions that cause hyperalgesia. Aim 3 will investigate whether inhibition of MOR-expressing MThal neurons is necessary and sufficient to block hyperalgesia. This will link opioid effects in specific cell populations to behavioral effects on pain processing so that we can better dissociate brain circuits mediating reward and pain relief by opioids. This knowledge will lead to a better understanding of MThal functional anatomy and the role of thalamic neurons in both inducing OWIH and relieving hyperalgesia.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT: The Councils on Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB) and Peripheral Vascular Disease (PVD) of the American Heart Association (AHA) hold an annual Spring Meeting “Vascular Discovery: From Genes to Medicine,” the most recent of which was held in held April 22-25, 2025 at the Marriott Baltimore Waterfront in Baltimore, MD. This meeting was a resounding success with 741 attendees and about 350 abstracts submitted. Feedback from attendees was overwhelmingly positive, with an outstanding 90% rating for “likelihood to recommend” the conference to others. These encouraging statistics provide tangible evidence of the broad interest and commitment of the scientific community in the topic areas of ATVB, PVD and vascular medicine and the overwhelming enthusiasm for the format and atmosphere of this leading meeting. This meeting uniquely brings together basic scientists, translational researchers and clinicians, seasoned investigators and early career scientists, who attend this meeting to share and learn cutting-edge vascular science and network with researchers across disciplines. The meeting is large enough to attract world-class speakers with a diversity of backgrounds and expertise, while still facilitating ease of critical networking interactions that forge new insights and collaborations. This conference includes world- leading Plenary, Keynote, and Distinguished Speakers on the most exciting cutting-edge topics in cardiovascular disease. Concurrent sessions feature outstanding invited faculty speakers from around the world, as well as short talks selected from submitted abstracts addressing topics including atherosclerosis, cardiometabolic disease, lipoproteins, inflammation and immunity, thrombosis and coagulation, coronary and peripheral vascular disease, genomics, and translational therapies. The next Vascular Discovery conference is scheduled to be held in Bellevue, WA, on May 13-16, 2026. This proposal requests support for our young investigator merit-based Travel Awards, to facilitate attendance by early career attendees. A major emphasis of our annual conference is to encourage the active involvement of early-stage investigators to help develop, train, and inspire the next generation of vascular researchers. This meeting provides trainees and new faculty with ample opportunities to present talks and posters, including numerous prestigious award competitions, and to participate in extensive career development programming. Our Young Investigator Travel Awards have been supported by the NIH/NHLBI for 17 years. These awards are an integral part of our strategy to recruit, retain and actively engage young investigators in the fields of arteriosclerosis, thrombosis, vascular biology and vascular medicine research that are of major importance to the NIH-NHLBI and the health of the U.S. population.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT During the past decade, the tobacco product landscape has evolved rapidly with a remarkable decrease in cigarette smoking prevalence, a dramatic increase in the popularity of electronic cigarettes (e-cigarettes), and the emergence of other novel tobacco products such as heated tobacco products. E-cigarettes have been the most used tobacco products among US middle and high school students for several years. In response to this trend, the Surgeon General declared an epidemic of e-cigarette use among youth in 2018. The escalating use of e-cigarettes, particularly among adolescents and young adults, raises significant concerns about their nicotine exposure and potential health harm. Therefore, it is essential to understand the complex interplay of individual modifiable risk factors and the initiation of e-cigarette use to craft effective preventive strategies for reducing e-cigarette use among these young demographics. Survey data has traditionally been the cornerstone of tobacco regulatory research, offering valuable insights into behavior patterns, monitoring changes in tobacco usage, and evaluating the impact of regulatory measures. Yet, as more comprehensive tobacco-related datasets become available, innovative methods are needed to analyze this wealth of information and to extract deeper behavioral insights, forecast trends, and investigate the causes of these trends. Despite the proven value of causal machine learning in various fields, their use in tobacco control has been limited. Therefore, I plan to integrate this advanced approach with survey data to enhance the understanding and prediction of tobacco use behaviors and aid in designing optimal tobacco interventions. I will focus on understanding the uptake of e-cigarette use and studying causal pathways leading to this behavior among tobacco-naïve adolescents and tobacco-naïve young adults. To achieve this, I will need further training in machine learning, statistics, and youth e-cigarette use. As such, I will take a series of formal courses to fill in my knowledge gaps. In addition, I will work closely with my mentors and collaborators whose areas of expertise will help me to realize my training and research goals. This K01 proposal will provide me with the protected time to acquire the skills and training necessary to become a leading researcher specializing in the application of causal machine learning to address tobacco-related issues and develop policy assessment tools.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY / ABSTRACT Antiphospholipid syndrome (APS) is an immunothrombotic disease that is characterized by recurrent thrombosis and pregnancy losses. Current management hinges on chronic anticoagulation. However, anticoagulation is ineffective in approximately 20% of patients with APS and does not adequately treat the potentially fatal microangiopathic features of APS. Thus, there is a critical need to develop a better understanding of disease mechanisms to advance therapies in APS. Neutrophils are implicated in the pathophysiology of APS and metabolism plays an important role in guiding physiologic and pathologic neutrophil functions. The overall goal in this proposal is to evaluate how dysfunctional mitochondrial autophagy (mitophagy) alters neutrophil metabolism to promote pathogenic neutrophil extracellular trap release in APS. This project will play a crucial role in helping the candidate achieve his long-term career goals, which include: (1) to achieve expertise in the metabolism of inflammatory diseases, (2) to become an established and well- funded principal investigator, and (3) to develop into a trusted mentor and advisor for future trainees. These goals will be accomplished by incorporating a strong mentorship environment and a formal instructional plan. Mentorship Environment: The candidate is an Assistant Professor in the Divisions of Rheumatology and Pediatric Rheumatology at the University of Michigan, with 75% protected time for research. He has received mentorship from Dr. Jason Knight in APS pathogenesis and from Dr. Costas Lyssiotis in cellular metabolism. With this proposal, he is seeking support to expand his research into investigating dysfunctional neutrophil mitophagy as a mediator of APS pathogenesis. To support this project and his career development, the candidate has assembled a strong team of mentors, who are experts in their respective fields. Formal instruction: The scientific goals for this proposal include: (1) to build skills to assess mitochondrial function and mitophagy in humans and mice, (2) to develop a deeper understanding of cellular metabolism, and (3) acquire proficiency in disease-relevant mouse models. These will complement the following career development goals: (1) to develop the leadership, team building, and mentoring skills needed to manage a translational research team, (2) to improve oral and written communication skills in support of disseminating research and obtaining independent grants, and (3) to engage with a community of scientists to become a trusted citizen of the rheumatology field. These goals will be accomplished through a combination of formal didactic instruction, mentorship, and laboratory-based experimentation. Research: The specific aims for this proposal are to: (1) characterize the derangements in mitophagy and the subsequent impact on mitochondrial function and metabolism in APS patient neutrophils, and (2) define mechanisms by which neutrophil mitophagy modulates metabolism, NETosis, and thrombosis in APS.

NIH Research Projects · FY 2026 · 2026-05

Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of death in patients with epilepsy. SUDEP mechanisms are not understood, although there is evidence to implicate apnea, autonomic dysfunction, and cardiac arrhythmias. Genes encoding voltage-gated sodium channel subunits are high SUDEP risk genes. Loss- of-function variants in SCN1A are linked to the Developmental and Epileptic Encephalopathy (DEE) Dravet syndrome (DS). Importantly, SCN1A is expressed in both heart and brain. Thus, we proposed that cardiac arrhythmias contribute to the mechanism of SUDEP in channelopathy-linked genetic epilepsies. We have shown evidence for altered cardiac myocyte sodium current density, calcium handling, and action potentials (APs), as well as cardiac arrhythmias in mouse models of DEE. We also showed that induced pluripotent stem cell (iPSC)- derived cardiac myocytes derived from DS patients have substrates for arrhythmias. DS patients also often display disordered breathing, suggesting dysfunctional neural control of respiration may underly SUDEP risk. Importantly, no mouse or iPSC model can completely replicate the human DS phenotype. Because mouse cardiac APs are very different from humans, we used human iPSC-cardiac myocyte models to investigate cell autonomous effects of SCN1A haploinsufficiency, however, cells in 2-dimensional culture cannot replicate complex cardiac tissues, cardiovascular changes, or cardiac autonomic innervation. From the control of breathing standpoint, mouse metabolic adaptability makes them more resistant to hypoxia and prolonged apneas than humans. Thus, we developed a transgenic rabbit Scn1a DS model because rabbits more closely replicate human cardiac and respiratory physiology than mice and, unlike iPSCs, provide a complete organism to translate to the clinical setting. The goal of this proposal is to use DS rabbits to test the hypothesis that Scn1a haploinsufficiency results in altered cardiac and brainstem excitability in addition to generalized seizures, leading to cardiac arrhythmia, altered heart rate variability (HRV), and impaired respiratory pattern generation in the brainstem. We will test our hypothesis by addressing three Aims: 1. To determine whether DS rabbits have cardiac arrhythmias and altered HRV in addition to seizures and to determine whether acutely isolated ventricular and atrial cardiac myocytes have altered excitability. 2. To determine whether DS rabbits have altered regulation of respiration, including changes in the pattern of respiratory motor output, altered patterns of dorsolateral pontine respiratory-related neuronal activity in an intact pontomedullary respiratory circuit, and altered excitability of and GABAergic synaptic transmission onto brainstem dorsolateral pontine neurons. 3. To determine whether intracerebroventricular administration of a TANGO antisense oligonucleotide targeting Scn1a haploinsufficiency can alter brainstem respiratory-related neuronal activity, HRV, or cardiac arrhythmias secondary to autonomic dysfunction in DS rabbits.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT The global incidence of autoimmune diseases grows annually. On average, autoimmune diseases require 4.6 years and 4.8 physicians to receive an accurate diagnosis. This is in part due to the multiple strategies needed for diagnosis which extend the timeline to receive treatment. Early detection and treatment of autoimmune diseases prevents the progression of more severe diseases. The cytokine interleukin-23 (IL-23) is a key driver of autoimmune pathogenesis in diseases like multiple sclerosis, and the continuous monitoring of IL-23 in people suspected of having an autoimmune disease will aid in their diagnosis and ultimately treatment. Additionally, continually monitoring IL-23 could help people with an existing autoimmune disease diagnosis monitor their disease progression and inform any changes in treatment. Synthetic cell receptors like Modular Extracellular Sensor Architecture (MESA) are well suited for monitoring biomarkers due to their sensitivity, independence from natural cell signaling pathways, and self-renewal. MESA consists of engineered cell surface receptors that, upon binding a soluble biological target, trigger an internal cell response to produce a fluorescent reporter protein. Therefore, production of fluorescence corresponds to the detection of a target biomolecule above a specific threshold. MESA has been used to monitor soluble biomarkers like interleukin-10 and vascular endothelial growth factor and potentially could be applied to monitor IL-23. I propose to engineer a cell-based sensor of IL-23 using MESA to aid in autoimmune disease detection and monitoring. I plan to 1) incorporate IL-23 specific binders into existing MESA receptors and screen for functional designs, 2) modify the receptor geometry to amplify the output signal-to-noise ratio, and 3) develop a biomaterial encapsulation platform on which to validate MESA sensors in vivo. Preliminary screenings identified at least two viable receptor designs. These novel modifications to MESA will enable continuous, real- time biomolecule observation at a sensitivity unmatched by current methods. When combining cell sensors for IL-23 with existing sensors for interleukin-10 and vascular endothelial growth factor, we will enable multifactorial immune monitoring that will improve patient care and broaden our understanding of autoimmune signaling pathways.

NIH Research Projects · FY 2026 · 2026-05

Project Abstract Evidence from pandemics and seasonal epidemics indicates that influenza is associated with bacterial coinfections which increases morbidity and mortality. One of the most common bacteria found in coinfection is Staphylococcus aureus, and Methicillin resistant staphylococcus aureus (MRSA) is a newer strain that is resistant to methicillin antibiotics which has made infections more difficult to treat. Viruses and bacteria are recognized by extra-cellular or intracellular pattern recognition receptors (PRRs). Toll like receptor 9 (TLR9) is a class of PRRs that senses bacterial and viral DNA containing unmethylated cytosine-guanidine motifs. TLRs have been associated with exacerbation of disease and increase inflammation during infections. Most research to date has investigated the function of TLR9 in immune cells, but the function of TLR9 in non-immune cells is much less understood. Studies from our laboratory have shown that TRL9 knockout mice fare better during coinfection suggesting that TLR9 is associated with more inflammation and poor survival outcomes. Additionally, we have preliminary data indicating that TLR9 expression in structural cells is detrimental during coinfection. In this proposal we seek to identify the role of TLR9 in lung structural cells, mainly epithelial cells and fibroblasts, during coinfection with influenza virus and MRSA. We have preliminary data showing that TLR9 is upregulated in epithelial cells and fibroblasts following influenza virus infection, and mice that lack TLR9 only in epithelial cells have a decreased bacterial burden following coinfection indicating improvement in disease burden. In this proposal my central hypothesis is that upregulation of TLR9 in epithelial cells and/or fibroblasts post-IAV alters cytokine production to impair alveolar macrophage phagocytosis and killing of MRSA and results in increased bacterial burden and lung injury during coinfection. This hypothesis will be tested through two specific aims: 1) Assess the upregulation of TLR9 in lung alveolar epithelial type II cells post-IAV and its effects on innate host responses during coinfection with IAV and MRSA and 2) Investigate the upregulation of TLR9 in lung fibroblasts post-IAV and its effects on macrophage antibacterial function during coinfection with IAV and MRSA. Experiments for these aims will be completed with the use of genetically engineered mouse models, cells derived from such mice, and in vitro assays to study the effect of TLR9 on macrophage phagocytosis and killing of MRSA. The results from these innovative studies may inform treatments that help improve coinfection outcomes. Completion of this proposal will also allow me to receive rigorous training in experimental design, implementation, and interpretation that will help me become a successful, independent scientist.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT Osteonecrosis of the jaw (ONJ) is a damaging condition characterized by exposed and necrotic bone in the maxillofacial region, and arises most commonly in patients taking anti-resorptive medications, including bisphosphonates (BPs) and anti-RANK ligand antibodies (denosomab). This pathology, which can lead to, among other symptoms, chronic pain, jaw bone infections, and disfigurement, is most common amongst cancer patients taking high doses of these drugs, who harbor a ~5% risk of developing ONJ. Treatment strategies for ONJ vary, but none are without their downsides, making prevention of this condition, and prediction of its risk all the more important. Our goal with this proposal is to identify the mechanisms that give rise to ONJ while taking BPs, and develop a polygenic risk score based on genetic factors that we identify as associated with susceptibility to this condition. To do this, we will build upon our previous work that identified novel regulators of bisphosphonate function to investigate how use of these drugs can lead to ONJ. Using genome-wide CRISPR screens, we found over 200 genes that affect the cellular response to BPs, and identified ATRAID as encoding a lysosomal protein required for the trafficking of BPs. Loss of Atraid inhibits the effects of BPs on mouse models of osteoporosis, and in our preliminary data, variants in this gene were enriched in patients who developed ONJ. Our overall proposal applies an integrated approach to (i) elucidate mechanisms that give rise to ONJ, including which cell types, and which molecules, including ATRAID, are driving this dysregulated response, and (ii) identify genetic markers of ONJ susceptibility by conducting pharmacogenomic analyses of germline DNA collected in SWOG S0702, an NCI-funded clinical study that has available DNA and ONJ information from more than 2000 patients with metastatic bone disease treated with zoledronate, a commonly prescribed bisphosphonate, ~5% of whom developed ONJ. We will then validate these genetic loci with high-throughput cellular CRISPR screens using our previously established BP screening tools. Upon completion of this proposal, we expect to have a mechanistic understanding of ONJ and a detailed knowledge of the genetic factors that confer susceptibility to ONJ. These will have a positive impact by providing critical insights that will enable patient-centered treatment strategies for these drugs that both help alleviate concerns about ONJ among patients who need these drugs, and reduce the risk of its occurrence.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Nearly 11% of the adult US population have a food allergy, resulting in 200,000 emergency room visits a year from anaphylaxis. Anaphylaxis is a rapid allergic reaction caused by allergen crosslinking of the FcεRI receptor on mast cells, leading to mast cell degranulation. Recent studies have demonstrated the importance of mast cell-neuron interactions in phenomena ranging from itch to allergen avoidance behavior and anaphylaxis-related temperature drop. This F31 proposal seeks to identify a role for mast cell-sensory neuron (MC-SN) interactions in the systemic spread and rapid speed of anaphylaxis. Two moieties of interest are cell adhesion molecule-1 (CADM1), as a binding partner between mast cells and neurons, and focal adhesion kinase (FAK) as a regulator of mast cell degranulation. Mast cell adhesion to sensory neurons requires CADM1 and enhances mast cell degranulation, while inhibition of FAK, the initiator of focal adhesion complexes, decreases degranulation. Preliminary data from our group suggest that the use of a FAK inhibitor is sufficient to block anaphylaxis in mice and validates the expression of CADM1 on both sensory neurons and mast cells. This data indicates a role for both molecules in MC-SN communication that assists the propagation of IgE-mediated anaphylaxis This proposal will test the hypothesis that the formation of a MC-SN “synapse” via CADM1 binding propagates anaphylaxis through FAK-mediated activation. This hypothesis will be tested through two specific aims: 1) Determine CADM1’s role in MC-neuron binding during the sensitization phase prior to anaphylaxis and 2) Define the role of FAK and sensory neurons in the effector phase of IgE mediated anaphylaxis. To accomplish these aims, in vitro co-cultures and in vivo engineered mouse models will be used to study cell-cell interactions and anaphylaxis reactions with manipulation of FAK and CADM1. The results of these studies will further elucidate the mechanisms behind anaphylaxis propagation and the role of mast cells as a sensing extension of the nervous system in allergic diseases. Better understanding of the pathophysiology behind anaphylaxis will allow for the development of more effective treatments and repurposing of already existing drugs. The experimental design for this research project was independently created. All research will be conducted in the lab of Dr. Charles Schuler at the University of Michigan. Support will be provided by other senior lab members, core facilities, and collaborators in the neuroscience and bioinformatics department. Bioinformatic courses and career development seminars will be provided by the Program in Biomedical Sciences and Office of Graduate and Postdoctoral Studies. A dissertation committee has been formed and will meet twice each year to assess and guide research and career development progress.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Idiopathic pulmonary fibrosis (IPF) is a form interstitial lung disease of unknown etiology. It is the most common chronic fibrosing lung disease with a median survival of 3-5 years after diagnosis. Fibrosis is thought to be a form of pathologic wound healing that is characterized by excessive accumulation of the extracellular matrix leading to the formation of scar tissue. Fibrotic progression in IPF results in lung dysfunction and ultimately death due to respiratory failure or other severe complications. Given its rising prevalence, lethality, and lack of curative treatments, there is an urgent need to elucidate the molecular mechanisms underlying IPF pathophysiology. Plasminogen activator-inhibitor 1 (PAI-1), has been widely implicated in the pathology of pulmonary fibrosis. PAI- 1 is a critical regulator of fibrinolysis and wound healing through its inhibitory action against tissue and urokinase type plasminogen activators (tPA/uPA). It is also known the interact with the provisional matrix protein, vitronectin, which stabilizes its active confirmation. However, we and others found that PAI-1 does not promote fibrosis through either of these known interactions. Using a proteomics approach, we have identified the intracellular sorting receptor, Sortilin-related receptor 1 (SorLA), as the most highly enriched binding partner for PAI-1 in the fibrosing lung, and our preliminary data reveal that PAI-1 requires SorLA to exert its full profibrotic effects. Additionally, we found that both PAI-1 and SorLA expression are upregulated in human IPF lung tissue, and that they colocalize in cells. Moreover, cellular uptake of PAI-1 is increased in cells expressing SorLA compared to cells not expressing SorLA. Based on these data, we hypothesize that PAI-1 promotes pulmonary fibrosis through unknown cytosolic interactions mediated by SorLA. We will test this hypothesis with two independent, but complementary aims. Aim 1 will map the intracellular trafficking patterns of PAI-1 and SorLA and determine their effects in promoting fibrotic cell phenotypes. Aim 2 will use proximity labeling and proteomic analysis to identify previously unknown PAI-1 cytosolic interactions and investigate their impact on profibrotic signaling and cell phenotypes. The proposed studies will characterize novel mechanisms that will be informative for the development of IPF treatments. The studies planned to address these two aims will provide me with significant training opportunities, including in the isolation, culture and characterization of primary cells from transgenic mice, experience with proximity labeling, and proteomics. I will also gain experience in bioinformatic analysis techniques. These skills will be directly developed in pursuit of the specific experiments proposed in my research plan and will serve as a solid foundation for my long-term goal of becoming an independent investigator. The environment at the University of Michigan and in the Department of Molecular and Integrative Physiology is ideally suited to support my studies and lay the foundation for my future success.

NIH Research Projects · FY 2026 · 2026-05

SUMMARY Analog enzyme-linked immunosorbent assay (ELISA) is a commonly used technique, in which the detection signal varies continuously with analyte concentration. To improve the detection limit, digital ELISA was developed, which allocates individual analytes to an ensemble of microunits (such as microbeads) and then counts the fraction of the “bright microunits” that emit light. While very sensitive, digital ELISA has a very limited dynamic range due to the fundamental assumption it relies on, i.e., the averaged analytes per microunit is far below 1. To extend the dynamic range, samples need to be serially diluted to a concentration within the digital ELISA dynamic range. However, the appropriate dilution factor needs to be determined through multiple trials. For multiplexed detection involving multiple analytes with vastly different concentrations, it is impossible to find a one-size-fits-all dilution factor. Other strategies include stitching the digital and analog calibration curves or extrapolating the digital calibration curve beyond the single-molecule assumption. However, it is difficult to determine the cut-off concentration between digital and analog mode and there is a discontinuity in digital and analog calibration curves due to two completely different methods used to obtain the corresponding detection signals. All these lead to large measurement errors. Here we propose a microlaser ensemble quenching bioassay platform that achieves an ultra-high sensitivity and ultra-large dynamic range with a unified method and without artificial digital-to-analog stitching. A microlaser ensemble consists of thousands of microfabricated high quality vertical cavity surface emitting lasers (VCSELs), which has a lasing threshold distribution when the microlaser ensemble is exposed to analytes. By scanning the VCSEL pumping level and counting the fraction of the bright VCSELs, we essentially probe the lasing threshold distribution, which in turn maps the analyte distribution in the microlaser ensemble. Similar to digital ELISA, the analyte distribution in an ensemble relates to analyte concentration in solution, which can be established through a statistical model. However, in contrast to digital ELISA that cannot differentiate a microunit with 1 analyte from that with more than 1 analyte, our method takes advantage of the non-linear (or threshold) behavior of laser emission and the tunable pumping level to turn the VCSELs on and off to differentiate the VCSELs with different analytes (i.e., mapping the distribution), thus significantly increasing the dynamic range. There are two specific aims. Aim 1. Fabricate and characterize VCSEL ensembles. We will fabricate arrays of microfluidic VCSELs using semiconductor microfabrication technologies. Each array will consist of 10,000 microfluidic VCSELs. The VCSELs’ quality and the lasing threshold distribution will be characterized in the absence and presence of quenchers. Aim 2. Develop an assay protocol and test the assay platform. We will use interleukin-6 in buffer and in serum as a model system. IL- 6 concentration will be varied from 0.01 pg/mL to 106 pg/mL to cover a range of eight orders of magnitude. The detection variability, detection limit, dynamic range, and recovery rate will be characterized.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract The microbiome revolution created a combinatorial explosion in microbiology. There are thousands of species of bacteria that impact our health, and each microbe responds differently to an exponential number of environ- ments and stressors. Human scientists alone cannot study the response of every bacterium in all possible environments. Instead, the Jensen Lab develops AI-driven robotic scientists that plan, execute, and interpret thousands of scientific experiments each day. Our robot scientists have performed over one million automated experiments to map the phenotypic landscape of human-associated bacteria and identify novel quorum sensing pathways that mediate intercellular communication. Our lab’s previous research made two key discoveries about the streptococci, a genus replete with species that impact human health. First, we learned that each species has a unique and complex pattern of auxotrophies. These different nutrient preferences are surprising since many streptococci live exclusively in the same niche and share an evolutionary history of co-adaptation. Our second discovery is that streptococci possess multiple quorum sensing pathways that interact within and across species. Our genome mining has uncovered several novel classes of quorum sensing systems that streptococci use to communicate, interact, and colonize humans. Our future research will integrate metabolism and quorum sensing into a comprehensive, quantitative view of a pathogen’s global context. We will transition from studying metabolism and quorum sensing in isolation to a systems-level view that explains how environmental and genetic factors rewire individual pathways. This ambi- tious goal will require us to train our robot scientist to perform genetic perturbations on demand and incorporate our newly developed expertise in automated fluorescence microscopy. Bringing together imaging, combinatorial phenotyping, and high-throughput genetics will automate the dis- covery of interactions between genes, cells, and environmental stressors. Our approach to automated science can be transferred to other cellular networks and organisms, accelerating scientific discovery and advancing our understanding of the complex bacteria that shape our health.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease, affecting approximately 30% of the world population. MASLD can result in an increase in inflammation in the liver and can progress overtime to liver fibrosis, characterized by excess extracellular matrix deposition. A major collagen producing cell type in this setting is the myofibroblasts from the trans-differentiation of activated hepatic stellate cells (HSCs). While the activation of HSCs primarily occurs through transforming growth factor beta (TGF-β) signaling pathways, several other pathways also play essential roles. One such pathway implicated in fibrosis progression is the Janus Kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) pathway. STAT3 is canonically activated by cytokines and growth factors, such as interleukin (IL)-6, leptin, or TGF-β. However, cytokine-induced activation of STAT3 is rapid and transient through negative feedback mechanisms. We have observed high levels of basal STAT3 activation in the human HSC cell line, LX2. Our preliminary data demonstrates that glucose is essential to maintain high basal levels of STAT3 activation. Additionally, our findings indicate that glucose plays a crucial role in facilitating the activation of STAT3 by canonical signaling pathways, such as TGF-β and IL-6. Mechanistically we find that glucose drives the secretion of a metabolite that activates STAT3 in an autocrine and paracrine manner. Based on these preliminary data, I hypothesize that hepatic stellate cell glucose metabolism is critical for fibrotic activation by maintaining STAT3 activity via autocrine signaling. This hypothesis will be tested through two aims. Aim 1 will define the metabolic pathways necessary for glucose mediated STAT3 activation. Aim 2 will define the requirement of glucose mediated fibroblast STAT3 activation in a mouse model of liver fibrosis. Through these aims I will elucidate a novel metabolic pathway that sustains STAT3 activation in liver fibrosis and potentially reveal new targets and therapeutic strategies for treating MASH related liver fibrosis.

NIH Research Projects · FY 2026 · 2026-05

Abstract The human immunodeficiency virus (HIV) remains as an incurable pandemic pathogen that lacks an effective vaccine. While antiretroviral therapies (ART) can effectively suppress HIV replication, it does not eradicate the virus. As a result, people living with HIV (PLWH) remain vulnerable to AIDS in part due to viral immune evasion strategies. The HIV accessory protein Nef plays a crucial role in this process. Nef enhances viral replication and immune evasion by altering the trafficking and promoting the degradation of immune receptors. One of Nef’s most well characterized functions is the disruption of the major histocompatibility class I (MHC-I) trafficking to target it for lysosomal degradation. This Nef function prevents cytotoxic T lymphocyte (CTL) recognition and clearance of infected cells thereby enabling evasion of the immune response. While some pathways targeted by Nef are well studied, the full breadth of Nef’s host interactions— especially in the context of other HIV accessory proteins— remains poorly understood. One approach to address this gap in knowledge is unbiased proteomic analysis of Nef-host protein interactions. Three prior studies have utilized proteomic approaches to investigate Nef functions. However, their conclusions have been limited by using systems that express Nef in isolation, the use of potentially disruptive affinity tags, and failure to block degradative pathways, utilized by Nef. Our preliminary data as well as the work proposed here address these limitations. In our preliminary studies and proposed aims we will use both T cell lines and primary T cells expressing all HIV accessory proteins (Vif, Vpu, and Vpr, Rev and Tat) and a novel functionally validated tagged Nef protein. Using this system, we identified the Nef interactome in a T cell line in the presence and absence of lysosomal inhibition by TMT-based quantitative proteomics. Furthermore, with our approach we have identified novel Nef binding proteins associated with inflammatory, innate immune response and viral sensing pathways. Subsequent analyses have confirmed these novel interactions in both a T cell line and primary T cells. Based on our strong preliminary data, we will test the overarching hypothesis that novel Nef interacting proteins that have not previously been reported will reveal new pathways targeted by Nef that promote viral pathogenesis. We will evaluate our hypothesis with the following aims. In Aim 1, we will confirm our preliminary data and extend the characterization of the Nef interactome to primary T cells, and we will identify the Nef binding domains responsible for novel Nef-host protein interactions. Furthermore, in Aim 2, we will determine the functional significance of novel Nef interactions with inflammatory and antiviral pathways. The work proposed in this study will provide a complete, unbiased characterization of the Nef interactome as well as reveal pathways that are essential for HIV pathogenesis. Furthermore, these findings hold promise for identifying novel therapeutic targets for HIV infected patients.

NIH Research Projects · FY 2026 · 2026-05

This 5-year K23 Mentored Career Development Award resubmission proposes a research and training program to facilitate the applicant’s development as a physician-scientist with expertise in technology-augmented adaptive behavioral interventions for reducing binge drinking and aggression in young adults (YA; ages 18-30) seeking care at Emergency Departments (EDs), while addressing resource linkage and structural and social determinants of health (SSDH). CONTEXT: YAs are at the highest risk for engaging in binge drinking and aggression, with some groups disproportionately affected due to SSDHs. However, scalable, efficacious interventions for YAs are generally lacking despite the fact that YAs often seek care in EDs. SafERteens, a Health Coach (HC) delivered, ED brief intervention (BI) that uses motivational interviewing (MI) and cognitive skill- building techniques (CBT) shows promise for reducing alcohol consequences and violence among teens. However, SafERteens has not been tested among YAs, who may benefit from tailored intervention content addressing issues for older ages (e.g., family, partnerships, career) and extension of the intervention post- discharge. Such extensions may include portal messaging and text messaging, which are novel modalities that can provide therapeutic content and early resource connections after an ED visit. Further, considering the range of responses to behavioral interventions, adaptive interventions (ADIs) are an innovative approach to address heterogeneity by individualizing timing, intensity, and/or type of treatment. RESEARCH STRATEGY: To inform the adaptation of a technology-augmented ADI (MiGuide) for ED YAs engaging in recent binge drinking and aggression, the applicant will adapt the SafERteens HC delivered BI for older YAs, as well as text messaging (completely automated) and portal messaging (using a HC) platforms, and conduct a Sequential, Multiple Assignment, Randomized Trial (SMART). To inform MiGuide adaptation, Aim 1 will focus on the iterative refinement of a technology-augmented ADI using a community engaged approach. Aim 2 will pilot a non- restricted SMART (N=80) of MiGuide, examining acceptability, feasibility, and fidelity, as well as preliminary efficacy to inform a fully powered SMART (R01). TRAINING PLAN: To facilitate the applicant's goal of becoming an independent physician-scientist focused on developing interventions to reduce binge drinking and aggression, parallel training goals are: Aim 1: gain expertise in theory-based interventions for high-risk alcohol behaviors, including content tailored to unique characteristics among a broad sample of ED patients, and MI/CBT techniques to reduce binge drinking and aggression; Aim 2: develop expertise in intervention science with a focus on adapting/testing ED-based technology-augmented ADIs using a community engaged approach; and, Aim 3: obtain training in ADI/SMART analytic approaches to develop future ADIs. These training aims will be accomplished through applied research experiences, working closely with mentors, attending didactic activities/conferences, and completing manuscript/grant proposal (i.e., R01) submissions.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Dopamine (DA) release from terminal axons in the striatum is crucial for regulating movement and associative learning. Dysregulation of DA release contributes to substance use disorders like nicotine use disorder (NUD), leading to significant health impacts in the United States. DA release in the striatum is controlled by the regulation of action potential (AP) firing in dopaminergic (DAergic) cell bodies as well as inputs onto DAergic axons in the terminal region of the striatum. Decades of research have brought insight into the somatic mechanisms regulating AP initiation, but the mechanisms controlling axonal excitability are not well understood due to difficulties in recording axonal voltage. There is therefore a gap in the understanding of how DA release is modulated by axonal inputs. To fill this gap, we will use direct recording of axonal voltage to record excitability of DAergic axons during physiological striatal transmission that modulates DA release. Striatal cholinergic interneurons (CINs) are large neurons that densely innervate the striatum with terminals that release acetylcholine (ACh). They are involved in reward-related behaviors and the development of substance use disorders and are also central to the axonal regulation of DA release through a novel axo-axonic excitatory synaptic transmission. CINs release ACh directly onto DAergic axons, activating nicotinic receptors (nAChRs) to produce depolarizing potentials that can initiate APs and evoke DA release. Despite clear evidence from brain slice preparation that CINs cause DA release, new evidence suggests they may also inhibit DA release. Thus, the complexities of CIN-mediated control of DAergic axons remain poorly understood. The research in this proposal will clarify how CINs regulate DA release to better understand NUD etiology. Our central hypothesis is that the spontaneous activity of CINs controls DA axon excitability over prolonged durations. We will employ our new technique for direct voltage recordings from DAergic axons in the striatum to address three specific aims: (1) Establish how tonic CIN firing affects AP kinetics and propagation in DAergic axons, focusing on resting membrane potential (RMP) regulation, AP-mediated calcium entry, and nAChR modulation of AP propagation. (2) Determine the mechanisms regulating cholinergic axo-axonic synaptic transmission by tonic CIN activity, identifying synaptic properties and nAChR desensitization dynamics through voltage recordings and optical measurements. (3) Reveal how nicotine modulates DAergic axonal excitability, examining nicotine's effects on axonal nAChRs and axo-axonic ACh signaling. The research here is innovative, in our opinion, because we will directly measure the voltage of DAergic axons during physiological patterns of CIN activity. The research is significant, because it provides new insight into the mechanisms regulating terminal DA release by clarifying how CINs modulate axonal excitability. The findings will reveal how endogenous ACh and nicotine modulate presynaptic terminals, offering insights into potential therapeutic targets for NUD.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Neutrophil (PMN) recruitment into mucosal tissues is an essential part of the innate immune response critical for host defense and promotion of repair. However, too much or too little PMN influx into intestinal tissues can lead to chronic inflammation and impaired wound healing. Leukotriene B4 (LTB4) is a potent chemoattractant that binds to PMN expressed BLT1 (a high affinity LTB4 receptor) to guide PMN recruitment. While it is known that LTB4 signaling is key driver for PMN migration, precise mechanisms by which LTB4-driven PMN influx promotes wound healing is unknown. Furthermore, we are the first to demonstrate that LTB4 is essential for initial PMN recruitment from the blood stream into injured mucosal tissues. My central hypothesis is that LTB4 produced by injured intestinal epithelial cells (IEC) initiates early PMN recruitment into injured mucosa, which is crucial for effective mucosal wound repair through regulation of mechanosensitive pathways in IECs. Our preliminary data reveals an increase in LTB4 within colonic wounds that precedes PMN infiltration into the mucosa and transient upregulation of leukotriene A4 hydrolase (LTA4H), the terminal enzyme in the pathway leading to LTB4 biosynthesis in the IECs following injury resulting in secretion of LTB4. In Aim 1, we will use in vivo models of mucosal injury and novel epithelial specific Lta4h conditional knockout mice, to determine the relative contribution of IEC and PMN derived LTB4 to neutrophil intestinal recruitment following injury. Our data demonstrates that injury-mediated hypoxia in mucosal wounds induces Lta4h expression via hypoxia-inducible factor (HIF) signaling. In Aim 2, we will elucidate mechanisms by which injury-mediated hypoxia regulates epithelial LTA4H expression during mucosal injury and repair. While excessive PMN influx can damage tissues, our data reveals that PMN depletion significantly impairs mucosal wound healing in mice that correlates with downregulation of signaling pathways influenced by ECM stiffness including mechanosensation, IEC migration and cell-matrix adhesion in IECs. Therefore, in Aim 3, we will investigate mechanisms by which PMN regulate matrix stiffness to promote epithelial migration during mucosal wound repair. Successful completion of this work will uncover the basic mechanisms that regulate temporal recruitment of neutrophils and shift the paradigm in support of regulated neutrophil influx promoting mucosal wound healing. The proposed K99/R00 research and training plan will enable me to expand my expertise in mucosal immunology and mechanobiology by acquiring training in immune cell characterization, whole mount imaging of mucosal wounds and characterization of wound matrix stiffness. This award will further support my professional development through comprehensive training in building a supportive and collaborative research and training environment. I will also train in laboratory management and leadership, science communication, and targeted preparation for faculty position applications. University of Michigan's outstanding scientific and professional environment is perfectly positioned to facilitate the proposed training and enable my successful transition to an independent research career.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT The International Society for Environmental Epidemiology (ISEE) is the preeminent scientific society focused on relationships between environmental agents and human health. Its Annual Conference serves as a critical forum for the exchange of ideas and advancement of solutions to pressing environmental health challenges of regional, national, and global significance. The conference is regularly attended by prominent epidemiologists from academia, industry, and government. As one of the most important forums for the presentation of human health research related to environmental exposures, it provides a unique opportunity for scientists, policymakers, and public health professionals to present their work, cultivate new collaborations, and develop solutions to emerging environmental health issues. It also plays a key role in training, education, and professional networking for students and early-career investigators. The 38th ISEE Annual Conference will be hosted in Munich, Germany from August 30th to September 2nd, 2026. It will feature interdisciplinary presentations of new research and methods that are of profound significance to the field of environmental epidemiology. In doing so, the conference also aims to facilitate open and respectful exchange of ideas and information between epidemiological investigators and public health practitioners from around the world. Scholarships will be provided to distinguished experts, young investigators, students, and promising new scientists who might not otherwise be able to participate in this meeting. In addition, funds will be allocated to cover journal publication fees so that accepted abstracts are publicly accessible to all to promote transparency and dissemination of science that is rigorous, reproduceable, and generalizable. Collectively, this meeting will strengthen the environmental health work force, promote scientific collaboration, and enhance knowledge exchange.

NIH Research Projects · FY 2026 · 2026-04

Food allergy has increased at an alarming rate from 2005-2014 in the US, with a disproportionally higher incidence in children2-5. Clinical symptoms of food allergy (FA) range from mild reactions to severe, potentially lethal anaphylaxis6 and there are limited FDA-approved treatment options for food allergy, with food avoidance remaining the only safe option15. A better understanding of the immune mechanisms and signaling pathways underlying food allergy is clearly warranted to permit development of effective and safe therapies8. Over the last 15 years, our team has made several seminal contributions that unveiled a critical role for IL-9/IL-9R-axis in the increase in GI MC density in the predisposition and severity of food allergy19-23. Furthermore, our group unveiled an obligatory role for IL-9/IL-9R signaling in the regulation of intestinal MC expansion19,20,24. A current gap in knowledge is the cellular origin of IL-9 and the signals that stimulate induction of IL-9 and drive GI MC expansion and predisposition to food allergy. In preliminary studies, we have identified three IL-9eGFP+ cell populations within the GI tract of food allergic mice, FcRI+ common myeloid progenitor (CMP), innate lymphoid cell type 2 and CD4+ Th2 cells. Strikingly, we observed 1) that FcRI+ CMPs are the dominant source of IL-9 in the GI tract and levels correlated with food allergy severity and 2) the presence of CD34+ IL-9+ and CD4+ IL-9+ cells in duodenal biopsy samples from peanut allergic individuals. Collectively, these studies support the concept 1) that FcRI+ CMPs are the predominant source of IL-9 in food allergy and 2) the presence of GI tissue specific signals in the induction IL-9 in FcRI+ CMPs. We hypothesize that FcRI+ CMPs secrete IL-9 and regulate GI MC density and predisposition and severity of food allergy. To test our hypothesis, we propose three aims: To test our hypothesis, we propose three aims: 1) define the requirement of FcRI+ CMP-derived IL-9 in the expansion of GI MC density and Food Allergy; 2) determine the GI specific signals in the induction of IL-9 in FcRI+ CMPs and the role of IL-9+ FcRI+ CMPs in MC progenitor proliferation and maturation and 3) define human IL-9+ FcRI+ CMPs in Peanut allergy. With respect to the expected outcomes, Aim I will define a requirement for FcRI+ CMP-derived IL-9 in induction of GI MC expansion and predisposition of food allergy; 2) demonstrate a requirement of intestinal epithelial IL-33 signaling in the induction of IL-9 in FcRI+ CMPs and that this cell directly drive MC progenitor proliferation and maturation 3) establish FcεRI+ CMP-derived IL-9 as a central mediator in the pathogenesis of peanut allergy. Successfully completing the proposed studies will provide a new and substantive departure from our current understanding of the underlying molecular mechanisms underpinning GI MC density in food allergy and the requirement of this cell in increased MC tissue density in food allergy, thereby directing the development of new and pre-existing therapeutics for treating food allergy and anaphylaxis.

NIH Research Projects · FY 2026 · 2026-04

Measuring antigen-specific immune cells is likely to provide substantial insights into immune function in response to infection, cancer, vaccination, and autoimmunity. Nevertheless, a lack of adequate technologies exist to probe antigen-specific immune cell function in vivo. Antigen-specific cells are rare in the blood and assaying their antigen-specificity typically requires ex vivo expansion which is expensive, time consuming, and can alter cell phenotypes. Furthermore, monitoring these antigen-specific cell populations is likely to boost precision medicine strategies in autoimmunity and help identify subtypes of disease and therapeutics likely to be effective in an individual patient, much like genomic sequencing has revolutionized cancer care. In the proposed work, we will build on preliminary efforts developing new tools for characterizing antigen-specific cell populations that leverage implantable biomaterials and drug delivery strategies to enrich antigen-specific cells at accessible pre-defined locations in vivo. These strategies enable harvest and analysis of large numbers of antigen-specific cells from inflamed tissue without the need to biopsy a vital organ. Our preliminary data indicate that loading antigen within biomaterials is able to enrich antigen-specific CD4 T cells, and we plan to expand on these findings to examine how varied methods of antigen loading alter these responses and how these approaches might impact other antigen-specific cells. Moreover, we plan to mechanistically characterize how these antigen-loaded materials enrich these cells. Finally, we will test the hypothesis that antigen loaded materials provide a more accurate model of target tissue immune function (e.g. central nervous system in multiple sclerosis) than do unloaded materials and we will use these approaches to monitor treatments targeting adaptive immune cells in a mouse model of MS.

NIH Research Projects · FY 2026 · 2026-04

Project Abstract Pneumonia is a leading cause of infectious deaths worldwide; over 2 million people die of pneumonia each year. The leading bacterial cause of pneumonia is Streptococcus pneumoniae (Spn), an opportunistic pathogen that colonizes the human respiratory tract. While there are >100 known serotypes of Spn worldwide, current immunization strategies protect only against a limited few. Recent advances in our understanding of mucosal immunology have identified lung-resident CD4+ memory T (TRM) cells as critical determinants of broad protection against multiple serotypes of Spn. However, despite their clinical value from the public health perspective, little is known about mechanisms that drive the establishment of these CD4+ TRM cells in the lungs. Furthermore, it is unclear whether Spn may alter CD4+ TRM cell formation in the lungs using its own virulence factors. Understanding these mechanisms is instrumental for development of next generation cross-protective immunization strategies against this pathogen. Relevant to this, our preliminary data suggest that the Spn toxin pneumolysin (Ply) and bacterial sensing by NLRP3 are both key to recruitment and establishment of CD4+ TRM cell in the lungs. However, it remains unclear whether pore-forming activity or complement-activating biology of Ply is required for CD4+ TRM cell formation nor is it known how NLRP3 sensing of Spn may coax CD4+ TRM cell formation. In this proposal we will test the hypothesis that Spn drives CD4+ TRM cell formation via Ply’s pore forming activity and induction of macrophage-epithelial crosstalk via NLRP3. This hypothesis will be tested through two specific aims: Aim 1 will determine whether pore formation activity of Ply drives CD4+ TRM cell formation by boosting T cell recruitment, and Aim 2 will determine whether NLRP3 sensing of Spn is required for macrophage-epithelial crosstalk to drive CD4+ TRM cell formation. These studies will be accomplished by using isogenic Spn mutant strains, genetically engineered mice, intratracheal murine infection models, adoptive transfers, spectral flow cytometry, and single cell- and bulk-RNA sequencing. Findings from these innovative studies will guide development of more effective, broadly protective Spn immunization strategies that will prevent life-threatening Spn-pneumonia and subsequent diseases. This proposal will support the applicant with her scientific, technical, personal, professional, and career development which includes courses and workshops, guidance from a strong mentoring team and dissertation advisory committee, opportunities to develop science communication skills, and opportunities to mentor junior students in the lab and classroom. The University of Michigan offers top academic training, connections with esteemed faculty in pulmonology, microbiology, and immunology, and state-of-the-art resources to achieve the proposed aims. Completion of this proposal will also support the applicant’s rigorous training in experimental design, microbiology and immunology techniques, and data interpretation that will usher her towards becoming a successful, independent scientist.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Rates of obesity have steadily increased in the US, with about 50% of Americans projected to be obese by 2030. Recent advances include GLP-1 peptides, such as semaglutide, approved in 2021 for adult obesity, and setmelanotide, approved in 2020 for early-onset syndromic obesity due to POMC and leptin receptor deficiency. However, setmelanotide is not sufficiently effective for MC4R haploinsufficiency or common dietary obesity, causes hyperpigmentation, and requires daily injections. GLP-1 therapies also show variable efficacy, with 23% of patients losing less than 5% of body weight after two years and up to 30% experiencing nausea. To improve the potency and specificity of MC4R peptide agonists like setmelanotide, we performed extensive structure-activity relationship work involving the synthesis and characterization of 426 new melanocortin peptides (MCs). This work led to discovery of MCs with 4X increased potency relative to setmelanotide, and with reduced hyperpigmentation. Also exciting, we recently discovered that MCs increase the dose-sensitivity to GLP-1s without increasing malaise or activity in the brain’s emesis center. This finding could help reduce well-known toxicity of GLP-1s, allowing more patients to benefit from GLP-1s. To realize cost-effective and facile PLGA microsphere encapsulation and delivery of the MCs and GLP-1s, we recently discovered an extremely simple, efficient, and generalizable water-based remote encapsulation method for peptides, involving short-term mixing of aqueous peptides and empty poly(lactic-co-glycolic acid) (PLGA) microspheres. In this R56 grant our team will further develop and optimize the remote-loading method for GLP-1s, while further advancing the mechanism of the rapid and spontaneous remote peptide loading based on peptide-polymer binding with or without additional excipients at physiological temperature. The new encapsulation method will allow for the combination of multiple formulations of sterile empty PLGA microspheres that encapsulate the peptide drugs to achieve constant drug release. We will determine the dosing of both single MC and MC/GLP-1 combinations in acute and chronic animal models of both genetic (MC4R+/-) and dietary obesity. For MCs we will use remote-loaded setmelanotide formulations already developed in the lab. We will evaluate pharmacokinetics of the remote-loaded GLP-1s to facilitate microsphere combination for constant peptide release and to test their release performance in vivo. Hence, this new drug delivery approach using MCs and their GLP-1 combinations could be useful for future treatments of a wide variety of forms of obesity.