University Of Michigan At Ann Arbor

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Immune functions in the uterus, fetal membranes and placenta are critical to maintaining a healthy pregnancy. These tissues perform a delicate balancing act by maintaining antimicrobial immune defenses while promoting maternal immune tolerance of the fetus. Mounting evidence suggests that environmental toxicants can disrupt key functions of the immune system. However, critical gaps remain in our understanding of how environmental toxicants affect immune functions in gestational tissues. Filling these gaps is necessary to effectively design interventions aimed at preventing adverse pregnancy health outcomes caused by environmental exposures. Volatile organic chemicals (VOCs) like trichloroethylene (TCE) and perchloroethylene (PCE) are widespread immunotoxic environmental contaminants. VOC exposure has been shown to disrupt multiple immune processes, including host defenses against pathogenic bacteria. This has important implications for pregnancy health, as the public health burden of intrauterine infections during pregnancy is high. For example, intrauterine infections with bacteria like Group B Streptococcus (GBS) is associated with outcomes like preterm birth, stillbirth and neonatal sepsis. Studies have identified associations between VOC exposure and immune system dysfunctions, increased risk for certain infections, as well as adverse pregnancy outcomes at least partially mediated by immune cells, like fetal growth restriction. However, TCE and PCE impacts on immune functions during pregnancy are not well understood. Our preliminary data show that a TCE metabolite, S-(1,2- Dichlorovinyl)-L-cysteine (DCVC), blocks immune responses to GBS in fetal membrane explants and suppresses macrophage immune responses to bacterial toxins via downregulation of transcriptional immune pathways and cytokine release. Moreover, we showed that both DCVC and the PCE metabolite S-(1,2,2- trichlorovinyl)-L-cysteine downregulate antimicrobial and immune tolerance pathways in human placental explants ex vivo. These findings suggest that VOC metabolites exert immunosuppressive effects in gestational tissues. We now seek to define the immunotoxic effects of TCE and PCE metabolites across gestational cell types and tissues. In addition, we propose to identify molecular mechanisms underpinning these effects. In this project we will: (1) assess TCE and PCE metabolite impacts on antimicrobial functions in primary uterine decidual macrophages (a key cell type in maintaining immune defenses against intrauterine infections), (2) identify TCE and PCE metabolite impacts on microbial host defense responses to GBS in human fetal membrane explants, (3) identify transcriptomic impacts on specific immune cell types in the placentas of TCE or PCE treated pregnant rats (with or without GBS infection) and (4) determine the extent to which TCE or PCE exposure leads to increased GBS colonization of the uterus, fetal membranes and placenta in a rat model. Using TCE/PCE and GBS as model toxicant-pathogen interactions, this project will provide important insights into how environmental toxicants affect immune functions during pregnancy.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Birth cohort studies have found associations between early-life wheezing-associated respiratory tract infections and the development of asthma in children. These studies suggest that early life respiratory tract infections have a direct effect on lung and/or immune cell development and the risk of asthma. To determine possible mechanisms, the project team established a mouse model of early-life rhinovirus (RV) infection. Infection of six-day-old mice, but not mature mice, induces long-lasting mucous metaplasia, eosinophilic inflammation and airways hyperresponsiveness. For this application, the project team examined changes in the nasal transcriptome of children hospitalized for respiratory viral infections. Twenty-six had bronchiolitis and 32 had asthma. Nasal swab RNA transcripts were measured by bulk RNASeq and differences were calculated in gene expression using DESeq2. Compared to uninfected controls, RV infection significantly increased 2312 transcripts, including those regulating cysteinyl leukotriene (CysLT) metabolism, epithelial mesenchymal transition (EMT) and mast cell proteases. Computational deconvolution of RNA-seq profiles showed increased mast cells and natural killer (NK) cells. However, expression of the NK cell activating receptor KLRK1 (NKG2D) was decreased. On this basis, the team hypothesizes that analysis of the nasal transcriptome in children with respiratory viral infection, combined with mechanistic studies employing mouse models of asthma, can identify novel and impactful pathways underlying asthma development and exacerbation. The following Specific Aims are proposed. 1. Determine the contribution of tuft cell-derived CysLTs in viral-induced asthma development. It is hypothesized that: (i) CysLTs are required and sufficient for the RV-induced asthma phenotype; (ii) airway tuft cells produce CysLTs; and (iii) tuft cell expansion occurs through a process of EMT. 2. Determine the role of dysfunctional natural killer cells in viral-induced asthma development. It is proposed that dysfunctional natural killer cells fail to produce interferon-gamma (IFN-γ) in response to viral infection, permitting type 2 inflammation. In addition, it is hypothesized that: (i) nasal aspirates from children with asthma hold dysfunctional NK cells with reduced IFN-γ production; (ii) in immature mice, lung NK cells fail to produce IFN-γ in response to RV infection; (iii) NK cell activation is required and sufficient to attenuate virus- induced type 2 inflammation in mature mice. 3. Determine the role of mast cells in viral-induced respiratory exacerbations. It is hypothesized that (i) nasal aspirates from children with RV-induced respiratory exacerbations show increased mast cells; and (ii) mast cells are required for RV-induced inflammation and AHR in immature mice. Immature mice and human infants with respiratory viral infections will be studied (flow cytometry, single cell RNASeq and TotalSeq of nasal aspirates). Completion of the proposed work will provide new insight into the pathogenesis of asthma development and identify new targets for prevention.

NIH Research Projects · FY 2026 · 2026-04

Abstract Respiratory tract infections are a leading cause of death for lipodystrophy patients. Lipodystrophy syndromes are rare disorders characterized by selective loss of adipose tissue, hyperphagia, severe insulin resistance, type 2 diabetes, hepatic steatosis, and leptin deficiency. The life spans of lipodystrophy patients are reduced by 30 years compared with the general population. While metabolic complications of lipodystrophy are well-documented, the impact on immune function and susceptibility to infections remains poorly understood. Metreleptin, an FDA approved treatment, significantly improves metabolic complications of lipodystrophy but its impact on respiratory tract infections has not been determined. We have shown that leptin deficient mice have impaired host defense against bacterial pneumonia and that exogenous leptin improves pulmonary bacterial clearance and survival. While metreleptin treatment is effective, many patients discontinue treatment due to the development of anti-leptin antibodies. As an alternative, treatment with tirzepatide, a dual acting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) agonist, was shown to be effective in a clinical trial to control metabolic complications of lipodystrophy. However, little is known regarding the impact of tirzepatide on the risk of respiratory tract infections in lipodystrophy or diabetic patients. To address the lack of research on lipodystrophy and bacterial pneumonia, we infected adipocyte-specific lamin A/C knockout (Lmna ADKO) mice, a model of lipodystrophy, and wild type (WT) mice with an intrapulmonary dose of Klebsiella pneumoniae (K.pneumoniae) a common cause of pneumonia in diabetic patients. Lmna ADKO mice exhibited higher lung bacterial burdens as compared with their WT counterparts. In addition, alveolar macrophage phagocytosis of K. pneumoniae and reactive oxygen intermediate production were reduced in cells from Lmna ADKO mice. The long-term goal of this research is to understand how metabolic disease impairs host defense against respiratory tract infections. The overall objective of the proposed research is to determine if leptin, tirzepatide, or a combination of these drugs improve host defense in Lmna ADKO mice following infection with K. pneumoniae. The results of these studies will determine if correcting glucose homeostasis and leptin deficiency with leptin or correcting glucose homeostasis alone with tirzepatide improves host defense. Results from our studies will inform clinicians regarding the best course of treatment for lipodystrophy to normalize glucose homeostasis and mitigate the risk of respiratory tract infections. The central hypothesis is that lipodystrophy impairs host defense against Klebsiella pneumonia by impairing alveolar macrophage phagocytosis and bacterial killing due to metabolic disturbances and leptin deficiency. Correcting these defects by administering leptin will be more effective than tirzepatide and combining leptin and tirzepatide will result in the most effective improvements in host defense against Klebsiella pneumonia.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Melanoma is the most lethal type of skin cancer. About 50% of patients with metastatic melanoma have a meaningful response to treatment with immunotherapy, of which some develop a durable response. Many patients with the best response to immunotherapy develop immunotherapy-induced melanoma-associated vitiligo (MAV), an autoimmune cutaneous side effect. Previous mouse work has revealed that tissue-resident memory T cells (TRM) in vitiligo-skin with specificity for melanoma antigens were required for long-lived protection against melanoma. By examining human specimens, our recent studies revealed that long-term melanoma survivors with MAV maintain tissue-resident memory T cells (TRM) which were long-lived and functional. TRM have recently been recognized by our group and others as critical participants in anti-tumor immune responses. We identified a TRM subset characterized by high interferon gamma expression (TRM-IFNG) that is highly prognostic for improved survival in melanoma patients. Strikingly, TRM-IFNG cells had precursors in the patient’s primary melanoma up to 6 years prior, showing durability of the patient’s natural immune memory response. While there have been many studies focusing on metastatic melanoma, there is a gap of knowledge in understanding how the immune response to primary melanoma affects the recurrence and overall survival of melanoma patients. The goal of this proposal is to investigate the TRM response at the time of primary melanoma diagnosis and test its requirement for immunotherapy response. Our hypothesis is TRM-IFNG cells are established at the time of primary melanoma and are recalled and expanded in order to mediate responses to immunotherapy (IT). We will test this using melanoma mouse models as well as prospectively collected patient specimens to determine how TRM-IFNG formed in skin and tumor at the time of initial melanoma occurrence mediate responses to immunotherapy in the metastatic setting. In a preclinical model, we will utilize a topical immunotherapy to increase the TRM repertoire in primary and metastatic melanomas in order to set the stage for a future clinical trial aimed at treating primary melanoma as a way of inducing durable cancer-fighting TRM cells in patients. Successful completion of this proposal will advance our knowledge of the contribution of early disease TRM establishment to long-lived memory. Our long-term goal is to advance the understanding of durable immunity to cancer and provide new avenues for immunotherapy development and improved patient survival.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Early-life microbial exposure is a key determinant of immune system development, influencing both innate and adaptive immune responses in ways that persist throughout life. During the perinatal period, neonates transition from the sterile environment of the uterus to a microbial-rich external world, where interactions with commensal, symbiotic, and pathogenic microbes provide essential signals for immune education. Epidemiological studies reveal that infants raised in microbially diverse environments—such as farms or households with pets—exhibit reduced susceptibility to allergic diseases and autoimmune disorders, underscoring the role of early microbial encounters in immune tolerance and resilience. In contrast, modern lifestyles characterized by reduced microbial exposure, excessive sanitation, and increased antibiotic use have been implicated in the rising incidence of immune dysregulation, including asthma, inflammatory bowel disease, and atopic conditions. These findings highlight the necessity of understanding how perinatal microbial diversity influences immune cell ontogeny at a mechanistic level. While previous studies have largely focused on the impact of microbial exposure on adaptive immunity, the extent to which early microbial exposure shapes the development and functional specification of innate lymphocytes remains poorly understood. Natural killer (NK) cells, as critical effectors of innate immunity, exhibit remarkable developmental plasticity and are poised to respond rapidly to infection, malignancy, and inflammatory stimuli. However, how perinatal microbial exposure influences NK cell fate commitment remains a fundamental gap. Our preliminary results in specific pathogen-free (SPF) mice—where microbial exposure is restricted—indicate that NK cell cytotoxicity is progressively acquired over time, exhibiting an inverse relationship to TGFβ signaling. Notably, NK cells share developmental pathways with other Group 1 innate lymphoid cells (ILC1s), a population that remains tissue-resident and exhibits distinct functional attributes. The balance between NK cells and ILC1s is tightly regulated in adult tissues, but whether microbial exposure during the perinatal period influences this equilibrium remains unclear. By utilizing 'dirty' mice to model diverse microbial environments, we will: determine impact of perinatal microbial exposure on NK cell fate specification (Aim 1), determine the impact of perinatal microbial exposure on the timing of NK cell cytotoxicity acquisition (Aim 2), and determine the impact of perinatal microbial exposure on NK-to-ILC1 equilibrium (Aim 3). Our research will provide crucial insights into how early-life TGFβ and perinatal microbial diversity—two pivotal yet opposing influences—interact to shape NK cell ontogeny, offering a novel conceptual framework that could redefine preventive and therapeutic strategies in pediatric immunology. This previously undescribed axis of immune modulation promises to advance our understanding of immune resilience and susceptibility in early development, paving the way for targeted interventions that optimize immune health from infancy.

NIH Research Projects · FY 2026 · 2026-04

Alzheimer’s disease and related dementias (ADRD) are a growing public health burden and understanding modifiable ADRD causes is a national priority. Many classes of environmental chemicals, such as pesticides and per- and polyfluoroalkyl substances (PFASs) contain known neurotoxicants and are thus likely to contribute to ADRD risk, but we lack prospective data with appropriate temporality (exposures measured years before cognitive outcomes) in large and representative populations. Leveraging stored biospecimens from one of the largest, longitudinal, population-based United States cohorts, the Health and Retirement Study (HRS), we will generate a publicly available, prospective, environmental chemical resource, with exposure measures many years before the onset of ADRD or preclinical impairment. HRS participants are ages 50 and older and they have extensive existing biannual cognitive measures and ADRD fluid biomarker measures. Specifically, in Aim 1, we will perform new state-of-the-art non-targeted analysis in serum to measure chemical levels, including PFAS and pesticides, and test for association with cognitive function and decline, ADRD biomarker levels, and ADRD incidence. People are simultaneously exposed to pesticides, PFAS, and other chemicals in the neighborhoods where they live, work, play, and socialize. Social exposures, at the individual- and neighborhood-level contribute to stress and ADRD risk. Chemical and social exposure levels differ across US neighborhoods, with variation by geography and socioeconomic status. Therefore, in Aim 2, we will integrate mixtures of chemical and social exposures into the “exposome”, representing the totality of a person’s environment, when examining complex environmental contributors to ADRD. Additional evidence linking exposures and ADRD can be provided by intermediate molecular markers. These molecular intermediates may serve: 1) as biomarkers of exposure useful when direct exposure measures are not possible, 2) as mediators mechanistically linking exposure and ADRD, and 3) as connecting networks informing on overlapping pathways to deepen chemical and ADRD response understanding. In Aim 3, we will leverage existing measures of molecular intermediates, including DNA methylation, RNA expression, and immune cell profiles, with new measures of endogenous metabolomics and lipidomics, to assess molecular markers as exposure biomarkers or mediators to link exposures with incident cognitive status. Together, this project will identify individual chemicals, mixtures of chemicals, and their pathways that contribute to ADRD risk in a nationally representative sample, which will support ADRD prevention and intervention. Given widespread exposure levels to these environmental chemicals in the US, even modest associations with ADRD could represent a substantial number of preventable cases through individual- and population-level actions.

NIH Research Projects · FY 2026 · 2026-04

Project Summary High levels of drug resistance is a defining feature of the emerging pathogen Candida auris and this is associated with high levels of attributable mortality in ongoing hospital outbreaks, thus necessitating the discovery of new antifungals. Bacteria are a potent source of antifungals, however, traditional routes for antifungal discovery from bacterial natural products often result in either the rediscovery of known antifungals or identification of molecules with high host toxicity. To counteract these hurdles, we propose that focusing on symbiotic bacteria, i.e., those that are able to co-exist with and provide benefit to their eukaryotic hosts, will be more likely to result in discovery of potent antifungal molecules with low mammalian host toxicity. This application details experiments to address a fundamentally and clinically important gap in the identification and development of much-needed antifungals. In our previous work, we identified potent antifungal molecules from symbiotic bacteria, but their mechanisms of action against drug-resistant C. auris are still unknown. We have expanded our collection of symbiotic bacteria from hosts including squid, tunicates, ants, honeybees, fruit flies, mice, and humans. Many of these beneficial bacteria have co-evolved with their eukaryotic hosts to provide antifungal protection of important resources (e.g., externally gestating eggs, underground fungus gardens, and hives). Antifungal screening of these host-associated bacteria revealed many with potent activity against Candida auris, especially when bacteria were co-cultured with environmentally-relevant fungi to induce metabolite production. Given our extensive symbiotic bacterial library, our suite of previously isolated antifungal molecules, and our fungal genetic tools to identify mechanism of action of new antifungals, we are primed to discover and characterize new, selective antifungal molecules with low host toxicity. In this proposal, we describe our rapid screening platform for novel antifungals that prioritizes activity against resistant fungi, incorporates early understanding of mechanism of action, and deprioritizes samples with mammalian toxicity. Aim 1 focuses on development of a rapid screening platform to induce and characterize novel antifungals from crude and semi-purified extracts of symbiotic bacteria, including our prioritization pipeline for samples with new mechanism and low toxicity. Aim 2 focuses on using yeast genetics approaches to define mechanism of action, starting with existing antifungal molecules from symbiotic bacteria. Together, these studies will advance new concepts for how host-associated bacteria can be exploited and induced to identify potent, selective antifungals with novel mechanism of action that overcome resistance with corresponding low mammalian toxicity, laying a critical foundation for treating this urgent and emerging public health threat.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Intracellular delivery of protein- or nucleic acid-based biologics is critical for many of the current therapeutic strategies as well as for basic research in cell biology. Various strategies have been reported for gene delivery, including viral and non-viral approaches, with notable successes of lipid nanoparticles and cationic polymers in mRNA-based vaccines. However, delivering protein biologics into the cytoplasm is more challenging due to limited efficiency in crossing cell membranes. Current strategies for delivering protein biologics to interfere with intracellular signaling pathways include engineered bacteria or liposomes decorated with membrane fusion peptides. Other approaches based on endocytosis often face limited endosomal escape into the cytoplasm. Direct delivery of transmembrane proteins or lipid molecules to cell membranes is under-explored but offers opportunities for introducing receptors or signaling lipids, expanding intracellular delivery beyond nucleic acid or protein biologics. Presently, a versatile delivery technology for nucleic acid, soluble or transmembrane proteins, and lipids does not yet exist. We propose a generalizable strategy for the delivery of various cargos to cellular membranes by leveraging DNA-mediated membrane fusion via small synthetic vesicles. Combined with cell-free expression of membrane proteins — a strategy our lab excels in — this platform may enable the direct reconstitution of membrane proteins into living cells. To achieve these goals, we propose the following aims in this technology development proposal: in Aim 1, we will develop and optimize DNA-mediated membrane fusion of small vesicles with different cargos to cell membranes in various cell types, thereby establishing the strategy to deliver proteins, nucleic acids, and lipids into cells. Aim 2 will establish direct membrane protein reconstitution into cellular membranes by combining cell-free expression and DNA-mediated membrane fusion. Various types of transmembrane proteins will be reconstituted into small vesicles before allowing them to fuse with cellular membranes. Finally, in Aim 3, we will demonstrate this new membrane protein reconstitution approach in a vertebrate tissue model system using Xenopus laevis embryo explants. We will introduce a soluble nanobody to interfere with actin cytoskeleton dynamics as well as the transmembrane tight junction protein claudin-6 into Xenopus explants in situ using our proposed methodology. The technology developed through this project will have broad utility for direct intracellular delivery of proteins and lipids, providing a novel research tool for delivering exogenous biomolecules in situ without the need for genetic manipulations in recipient cells.

NIH Research Projects · FY 2026 · 2026-04

Abstract Acute leukemia represents a group of diseases associated with distinct genetic alterations that lead to differentiation block and increased proliferation of hematopoietic progenitor cells. Patients with Acute Myeloid Leukemia (AML) have very poor prognosis with currently available treatments, reflected by only ~27% 5-year survival rate. Upregulation of HOX genes is associated with numerous cancers, including acute leukemias. In AML the elevated level of HOX genes, in particular HOXA9, is associated with refractory or relapsed disease and very poor clinical outcome, supporting the urgent need for new therapies. Therefore, small molecules capable of reducing the expression level of HOX genes are highly desired as they should represent novel promising treatment strategies for acute leukemia patients. ASH1L (Absent, small or homeotic 1-like) protein is a histone methyltransferase, which belongs to the Trithorax group of proteins regulating HOX genes expression. Knockdown studies demonstrated the critical role of ASH1L in the development of acute leukemia with MLL1 (KMT2A) translocations, which are associated with HOXA9 and MEIS1 overexpression. Furthermore, our own studies validated that the catalytic SET domain of ASH1L plays a crucial role in leukemogenesis, supporting ASH1L as a valid therapeutic target in acute leukemias with upregulated HOX genes. We developed first-in-class small molecule inhibitors of ASH1L, which bind to the catalytic SET domain and inhibit its histone methyltransferase activity. Medicinal chemistry optimization resulted in compounds with nanomolar binding affinities and high selectivity to ASH1L. Our ASH1L inhibitors strongly block proliferation, induce differentiation and downregulate HOXA genes in the ASH1L-dependent leukemia cells through reduction of H3K36me2 level, supporting the on-target mechanism of action. We also demonstrated that our ASH1L inhibitors reduce leukemia burden and block leukemia progression in vivo in mouse models of the MLL1- rearraged leukemia. In this project we propose to develop the next generation of ASH1L inhibitors with optimized potency and drug-like properties. We will apply highly interdisciplinary approach, involving medicinal chemistry, structure-based design, biochemistry, pharmacokinetic (PK) and biological studies, to develop highly optimized ASH1L inhibitors with strong in vivo efficacy in aggressive models of high HOXA leukemia. In Aim 1, we will employ medicinal chemistry to improve potency and drug-like properties, including metabolic stability, PK and solubility, of the lead compounds that we already identified. In Aim 2, we will characterize new ASH1L inhibitors in a panel of high HOXA leukemia cells and primary patient samples to assess their potency and mechanism of action. Aim 3 will be devoted to assess in vivo efficacy of our new ASH1L inhibitors in advanced leukemia models. We expect this work will result in the next generation of ASH1L inhibitors with strong activity and optimized drug- like properties that will provide novel therapeutic approach for acute leukemia.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY / ABSTRACT Cellular organelles interact at membrane contact sites, enabling inter-organelle communication and coordination of basic cellular processes through lipid transfer, calcium signaling, and membrane dynamics. Membrane contact sites have also been shown to regulate cellular responses to infection, including scaffolding innate immune signaling complexes, generation of antimicrobial effectors, degrading pathogens, and resolving inflammation. However, the role of membrane contact sites in antifungal innate immunity are underexplored. Fungal pathogens can cause invasive and life-threatening disease, and the incidence of invasive fungal disease and antifungal resistance has increased in recent decades. In particular, Candida albicans is a commensal colonizer of human mucosal epithelia and opportunistic pathogen that can cause bloodstream infections with a high mortality rate. C. albicans infections were recently estimated to cause nearly a million deaths per year. As phagocytic cells are crucial to protect against systemic C. albicans infection, understanding regulators of the antifungal functions of phagocytes will be crucial for development of host-targeted therapeutic strategies to treat fungal disease. This proposal aims to address the regulation of membrane contact sites in macrophages and their roles in antifungal innate immunity. Preliminary data providing rationale for this proposal include that the ER stress sensor IRE1α coordinates membrane contact sites between the ER and endocytic vesicles to promote phagosomal calcium flux shortly after phagocytosis of C. albicans. This phagosomal calcium flux supports phagosome maturation, fungal killing, and the degradative capacity of macrophages. Additionally, IRE1α coordinates mitochondrial stress responses during C. albicans infection. Mitochondrial stress responses are known regulators of host responses to viral and bacterial infection but are poorly understood in antifungal innate immunity. These findings suggest crucial roles for membrane contact sites in antifungal innate immunity, although there is a fundamental gap in our understanding of the regulators of organelle dynamics and how they coordinate antifungal responses. Therefore, Aim 1 will characterize regulators of phagosomal calcium flux and its roles in fungal infection and the degradative capacity of phagolysosomes. Aim 2 will investigate the role of ER-mitochondria contact sites and mitochondrial stress responses in fungal infection. The mentored phase of this award is supported by a comprehensive training plan that will provide necessary training in quantitative and super-resolution imaging and bioinformatics. The candidate’s background in innate immunology, molecular biology, and host-pathogen interactions will be unified by mentors with expertise in cell biology, fungal genetics and pathogenesis, and bioinformatics. The overall outcome of the proposed research will be to uncover new roles for organellar interactions in antifungal innate immunity, revealing key molecular regulators of macrophage antifungal responses and potential targets for therapeutic intervention. This research will also yield fundamental understanding of the cellular processes of phagocytic cells and their ability to contain rapidly growing pathogens.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Autoimmune diseases collectively rank among the top causes of death for adult females. Systemic lupus erythematosus (SLE, or lupus) is a prototypic and serious autoimmune disease of largely unknown etiology that disproportionately affects females and people from certain racial and ethnic groups. There is a critical need to identify environmental exposures in the general population that contribute to the development and progression of autoreactivity and autoimmune diseases such as lupus, in order to inform prevention and control efforts. Per- and polyfluoroalkyl substances (PFAS), also referred to as “forever” chemicals, are toxicants with extensive distribution and persistent effects in the environment, for which chronic, low-dose exposures are common. Data are accumulating on immunotoxicities associated with PFAS. This project will interrogate the contributions of environmental and epigenetic factors to autoimmunity and lupus, utilizing data and biospecimens from two complementary, population-based and extensively phenotyped cohorts: (1) the Michigan Lupus Epidemiology & Surveillance (MILES) Program of persons with lupus and general population controls from southeastern Michigan, through which our group has pioneered the public health surveillance and monitoring of lupus; and (2) the Study of Women's Health Across the Nation (SWAN), a multi-site cohort of women followed for over two decades from midlife. A leading paradigm for lupus etiology and potential mechanism by which exposures exert immunotoxic effects involves epigenetic alterations to lymphocyte DNA that increase the propensity for lupus development and flares. This project will examine relationships between PFAS exposures, immune dysregulation, phenotypic autoimmune expression including lupus, and T cell epigenetics (DNA methylation). Our overarching hypothesis is that PFAS exposures are associated in dose- dependent fashion with markers of immune dysregulation in both adults from the general population (SWAN and MILES) and persons with lupus (MILES). We also hypothesize that PFAS are associated with alterations in lymphocyte DNA methylation patterns of key genes/pathways involved in immune regulation among persons with lupus. We will address these hypotheses via these specific aims: 1) characterize the relationship between PFAS exposure biomarkers and immune dysregulation in adult females from the general population (without autoimmune disease), assessed separately in SWAN and MILES cohorts; 2) delineate associations between PFAS exposures and autoimmune disease development over 20 years of follow-up in SWAN and with lupus activity in MILES; and 3) identify whether DNA methylation differences in CD4+ T lymphocytes in autoimmune- and lupus- relevant genes are associated with PFAS exposures in MILES. Overall, this research will provide novel data related to the role of these toxicants in immune dysregulation and autoimmune disease and inform future intervention and prevention strategies.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Chemotherapy-resistant disease is frequently observed among the most common T-cell lymphomas (TCL), and few durable responses are achieved with novel agents. Consequently, outcomes are dismal, improved therapeutic strategies are needed, and clinical trial participation remains the “standard of care” for many of these patients. Our own work suggests that the mechanisms promoting treatment failure in the TCL are multifactorial and interdependent, including a “high-risk” genetic landscape, activation of oncogenic transcriptional programs, and the creation of lymphomagenic niches within the tumor microenvironment. These insights have led to the identification of novel therapeutic strategies and targets that are now being investigated in multiple clinical trials. However, the published (and unpublished) experiences with these, and alternative, targeted therapies demonstrate suboptimal rates and durations of response. Collectively, the historical and contemporary experience with targeted therapies suggests that a multitargeted approach will be required to improve survival in high-risk and chemorefractory TCL. The overarching premise for this application is grounded in our prior work demonstrating significant crosstalk between cell-autonomous mechanisms of oncogenesis and the tumor microenvironment (TME), and further, their mutual cooperation in promoting treatment failure. For example, we (and others) have shown that antigen- and costimulation-dependent signaling promotes the growth and survival of malignant T cells and confers their resistance to conventional chemotherapy. Antigen- and costimulation-dependent signaling cascades are propagated by exogenous ligands provided by constituents of the TME, particularly lymphoma-associated macrophages (LAM). We have demonstrated that LAM are transcriptionally polarized by malignant T cells, promote their growth and survival, and are a bona fide dependency in these lymphomas. Therefore, LAM are attractive, yet largely unexplored, therapeutic targets in the TCL. Our preliminary data suggests that malignant T cells and LAM survival are BCL- xL dependent. Therefore, we and our collaborators have developed novel BCL-xL antagonists that will be utilized in complementary and orthogonal PDX and GEM models to address our overarching hypothesis that BCL-xL is a dependency in both malignant T cells and within their TME, and to examine BCL-xL antagonists in rationally designed combinatorial strategies.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ ABSTRACT This research seeks to understand how mammalian cells respond to fluctuating extracellular phosphate levels. Inorganic phosphate (Pi) is a critical component of life – an essential regulator of numerous cellular functions, including energy metabolism, cellular signaling, membrane integrity, and nucleic acid synthesis. To ensure these critical activities are functioning effectively, cells must sense, acquire, and maintain intracellular Pi at suitable levels. Indeed, disruption of Pi homeostasis has major consequences for cellular function and organismal health. For mammals, the focus of this proposal, too little systemic Pi can cause undermineralized bone, as in rickets, as well as muscle weakness, while complications from even modest Pi increases include inflammation, anemia, extraskeletal calcifications, and soft tissue damage. While the hormones that regulate the endocrine control of circulating Pi levels are beginning to be understood, we lack a detailed, mechanistic understanding of the cellular handling of Pi. Our preliminary work in understanding how osteogenic cells function in the endocrine control of serum Pi homeostasis identified Pi response components that appear conserved across cell types. In our work we identified Pi-responsive signaling proteins such as RGS14 (regulator of G protein signaling isoform 14) and SGK1 (serum/glucocorticoid regulated kinase 1), as well as changes in cellular Pi uptake and efflux in response to both long-term and short-term fluctuations in extracellular Pi, suggesting the presence of both a long-term Pi adaptation mechanism and a short-term Pi sensing and response. In this proposed research, we are motivated by these findings to understand the control of cellular phosphate homeostasis more generally across mammalian cells. We seek to understand how distinct mammalian cell types may differentially sense, respond to, and process Pi to ensure cellular and organismal homeostasis. Over the five-year funding period, the goals of this project are to initially: (i) determine how mammalian cells control Pi uptake and efflux in response to changes in extracellular Pi, (ii) dissect the signaling pathways that regulate the cellular response to these fluctuations in extracellular Pi, and then using these findings (iii) determine how perturbations in Pi regulatory mechanisms in different tissues disrupt organismal function. As control of cellular Pi homeostasis is key to overall organismal health, the successful completion of this work will establish the molecular mechanisms responsible for controlling cellular phosphate homeostasis, with important implications for the treatment of phosphate-related diseases.

NIH Research Projects · FY 2026 · 2026-03

Regenerating soft tissue is critical for adequate healing after injury across many tissue types, but often does not occur due to inadequate microenvironmental cues. There remains an unmet clinical need to heal chronic wounds, and similar problems exist are ubiquitous across many wound types including: dysregulation of inflammatory processes and insufficient signal from regenerative factors. We propose a research program dedicated to deepening our understanding of chronic wounds and developing translational treatments that centers around four basic questions about reprogramming cellular responses in wound microenvironments: i) how do T-cell phenotypes contribute to inflammatory dysregulation?, ii) can T-cells be reprogrammed to mitigate inflammation and resolve injury?, iii) how does dynamic secretion of alarmin proteins impact healing?, and iv) can we reprogram cellular responses to alarmins to respond with regenerative factors. We know that multiple types of T cells are involved in healing wounds, but it is not clear how they interact and directly influence healing or if reprogramming inflammatory T cells to regulatory ones could improve healing. Furthermore, we know that alarmins play a critical role in clearing pathogens and debris, but it is suspected that overexpression of alarmins contributes to inflammatory dysregulation and non-healing. We hypothesize that a synthetic biology approach could enable more precisely dissecting this biology and yield responsive cell therapies that target chronic wounds for regeneration. Proposed herein we harness two models of chronic wound healing i) diabetic skin wounds and ii) the foreign body response to implants, and we use these models to probe fundamentals of cellular responses to injury and develop improved regenerative therapies.

NIH Research Projects · FY 2026 · 2026-03

Project summary: Turning fleeting life experiences into long-lasting memories is a fundamental function of the brain and critical for survival. Across animal species, this process, which is linked to plastic changes at synapses between neurons, has been shown to require transition into a sleeping brain state. However, very little is known about 1) how and where this plasticity is brought about by state-specific brain activity, and 2) how sleep states facilitate de novo memory consolidation. The Aton laboratory has recently made inroads to addressing these gaps by studying contextual fear memory (CFM) in mice, a simple form of memory consolidation in which learning occurs in a single training trial (contextual fear conditioning; CFC), and consolidation occurs subsequently in a sleep-dependent manner. We have recently found that CFC selectively drives long-term transcriptional changes in the hippocampal dentate gyrus (DG), and that post-CFC sleep is essential for reactivation of “engram” neurons in DG – i.e. the population of neurons that encode CFC context during fear learning. Brief post-CFC sleep deprivation (SD), which disrupts CFM consolidation, prevents DG engram neuron reactivation in the first few hours following CFC. While sleep-associated coordination of activity between thalamocortical circuits and the hippocampus is thought to be critical for memory storage, the precise synaptic and circuit-level mechanisms affected by corticohippocampal communication during sleep remain unclear. Here, we propose to investigate the precise sleep-dependent processes that are associated with and necessary for successful CFM consolidation, with a focus on sleep regulation of corticohippocampal information transfer from entorhinal cortex (EC) to DG. These studies will use recently developed genetic tools for targeted recombination in activated populations (TRAP), which will allow selective visualization and manipulation of context encoding engram neurons in the EC and DG, as well as the connections between them. We will first quantify sleep-dependent reactivation of engram neurons in these two structures, in the hours immediately following CFC. We will then use state-targeted optogenetic manipulations to disrupt EC engram neurons’ input (or all EC input) to DG during bouts of post-CFC non-rapid eye movement (NREM) sleep, REM sleep, or wake. We will test how these state- specific disruptions of EC input affect reactivation of DG engram neurons, overall hippocampal network activity, and CFM consolidation. Finally, in collaboration with the Soiza-Reilly lab at the University of Buenos Aires, we will use nanoscale array tomography (AT) to quantify changes in synaptic density, size, and protein content resulting from CFC and post-CFC sleep vs. SD. These studies will separately characterize synapses formed between EC and DG engram neurons vs. corticohippocampal synapses where one or both partners are non- engram neurons. These studies will test the hypothesis that post-CFC sleep is required for the selective strengthening of excitatory synapses between EC and DG engram neurons. These studies will provide a highly detailed mechanistic understanding of sleep-dependent memory storage in corticohippocampal circuits.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Dental enamel is formed by ameloblasts that are derived from dental epithelium. How dental epithelial stem cells (DESCs) commit to ameloblast lineage remains elusive. A potential critical factor that drives the commitment of DESCs to the ameloblast lineage is retinoic acid (RA). The complex system that drives ameloblast lineage commitment and the abundance of molecules that determine the RA signaling system require us to examine the transcriptomics of developing teeth at single-cell and spatial levels, followed by biological validations. Our preliminary data showed the diversifications of DESCs and the continuous differentiation of ameloblasts in a mouse incisor scRNAseq dataset. We sorted the differentiating ameloblasts into novel clusters in both mouse and human incisor scRNAseq datasets and replicated these findings using RNAscope. Our findings also suggest that RA signaling is inhibited in pre-secretory stage ameloblasts but activated when ameloblasts transition into the secretory stage. We identified potential RA response elements (RARE) in genes that are critical for secretory stage enamel formation. Therefore, we hypothesize that the sequential ameloblast differentiation is specified by critical genes through the retinoic acid (RA) signaling. By integrating scRNA-seq data analyses with molecular validations in developing teeth, we can 1) elucidate the differentiation trajectory of ameloblasts and 2) reveal critical roles of RA signaling in ameloblast differentiation. Aim 1. Determine the ameloblast differentiation trajectory. We will integrate the scRNAseq data obtained from 14 studies in different tooth types from mice, rats, and humans. We will conduct cluster analysis within tooth types and species to identify each phase of the continuous differentiation paths predicted by trajectory inference. We will compare the ameloblast differentiation trajectory across tooth types and species, with an emphasis on molecules relevant to RA degradation and signaling activation. To validate the trajectory defined by bioinformatic analyses, we will perform RNAscope HiPlex assay on mouse developing teeth using identified genes. Aim 2. Determine the critical roles of RA signaling at the onset of secretory stage enamel formation. First, we will conduct spatial transcriptomics and consequent bioinformatic analyses to map spatial distributions of molecules involved in RA synthesis, signaling activation, and metabolism, together with potential target genes of the RA signaling, in mouse enamel organ epithelium and adjacent dental mesenchyme. Second, we will perform the CUT&Tag sequencing to identify RAREs in RA signaling targets across the genome in mouse secretory ameloblasts. We will validate these findings by analyzing spatial transcriptomic and existing scRNAseq data. The completion of this project will allow us to identify critical factors in ameloblast differentiation. These insights will shed light on the mechanisms of tooth morphogenesis and congenital tooth disorders. This project will provide essential information to the development of bioengineering strategies for tooth regeneration.

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 · 2026-03

This study aims to develop new methods for detecting pre-cancerous dysplasia on colonoscopy and histology in patients with inflammatory bowel disease (IBD). IBD is associated with a higher incidence of colorectal cancer compared to the general population. However, IBD dysplasia is more difficult to detect on colonoscopy because lesions are flat, irregular in shape, and coincide with inflammation. In efforts to combat visualization problems, most gastroenterologists continue to perform random mucosal biopsy for increased sensitivity of dysplasia detection on colonoscopy. Accessory measures to help enhance dysplasia detection including high- definition endoscopy, dye chromoendoscopy, and narrow band imaging require extensive expertise, increase procedure duration, and have not been definitively shown to improve dysplasia detection rates. In addition to difficulty detecting dysplasia on colonoscopy, pathologists face similar ambiguity when evaluating dozens of biopsies provided from every colonoscopy. Beyond reviewer fatigue, pathologists are challenged to separate inflammation from dysplasia and the grade of severity, typically requiring referral to experts at high volume centers for second opinion review. Machine learning and computer vision methods are well suited to address clinician limitations in detecting visual features of IBD-related colonic dysplasia. Our multi-disciplinary team’s prior work developing methods to improve endoscopic disease activity assessments and quantify histologic imaging using machine learning will be adapted and applied to dysplasia detection in this proposed project. We will pursue three aims to achieve our goal of determining whether computer vision models can match or exceed the diagnostic ability of experts for detecting dysplasia on colonoscopy and histology. Aim 1 will build computer vision models trained to infer histologic ground truth using endoscopic imaging for detecting the presence of dysplasia on standard colonoscopy video from multiple centers. Methods will incorporate both still image classifier pipelines and new generative diffusion-based model architectures for full video analysis. Aim 2 will evaluate the performance of both experts and new FDA-approved AI assistant tools in colonoscopy for detecting dysplasia on colonoscopy, comparing results to best performing video-based dysplasia models. Finally, Aim 3 will apply computer vision quantitative histology to predict the presence of dysplasia on routine colonic biopsy, leveraging state-of-the-art histologic image segmentation methods for both enhanced pathologist annotation and modeling. Optimized dysplasia model performance will be tested and piloted in a real-world digital pathology workflow to evaluate the feasibility and performance of automated dysplasia detection in clinical practice. We expect these advancements will transform IBD dysplasia assessment by eliminating the need for cumbersome mucosal interrogation methods, improving accuracy of dysplasia detection, personalizing dysplasia surveillance and management, and providing a deployable technologic solution to elevate the quality of IBD care rendered by less-experienced clinicians.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Traumatic brain injury (TBI) affects 1.7 million Americans each year and is the leading cause of disability worldwide. TBI is defined as having two distinct pathophysiological phases: the primary injury, or initial impact, leads to a secondary injury cascade that lasts minutes to years later defined by an energy deficit and ionic imbalance in cells that contribute to neuronal death. Mitochondria play a large role in maintaining cellular homeostasis and meeting energetic requirements of neurons, making their dysfunction integral to the pathophysiology of secondary injury. Central to the health of the mitochondria, and therefore to the cell, is the tight regulation of coordinated cycles of fission and fusion, known as dynamics. Imbalance between these states leads to an altered electrochemical gradient and membrane potential, which reduces energetic efficiency, and resembles the hallmarks of the TBI secondary cascade. My hypothesis is that the disruption of key molecular regulators of mitochondrial dynamics plays a causal role in the progression of secondary injury following trauma. To test this, I will 1: establish the extent and timing of mitochondrial morphologic disruption after in vitro primary neuron axon stretch injury (ASI) using super-resolution live-cell microscopy with Ca2+, ROS, and ΔΨm fluorescent probes paired with the machine learning mitochondrial morphology classifier developed in the Sanderson lab. I will then gain insight into the activation and influence of fission and fusion regulatory proteins after ASI using novel gain- and loss- of function primary neurons from the lab’s transgenic conditional knockouts of Drp1 and Oma1, which mediate fission and inhibit fusion, respectively. Furthermore, I will 2: interrogate the role of mitochondrial dynamic regulatory proteins in the progression of secondary injury using the controlled cortical impact (CCI) mouse model paired with the Drp1 and Oma1 conditional knockout transgenic mice. Behavioral deficits and lesion size will be measured to confirm injury, and cutting-edge biochemical and imaging techniques, including whole slice immunofluorescence and mitochondrial segmentation of key brain regions, will be used to measure changes in pathology. Collectively, this research will provide crucial insight into the molecular underpinnings of mitochondrial dysfunction after brain trauma, potentially providing a route of therapeutic development to reduce cell death during the progression of the secondary injury.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Acute ischemic stroke (AIS) is a leading cause of death and permanent impairment in adults. There are highly efficacious treatments for AIS, including intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT). Stroke treatment is exquisitely time-sensitive, and guidelines recommend time targets for receipt of thrombolysis [door-to-needle (DTN) time] and interhospital transfer for EVT [door-in-door-out (DIDO) time]. However, most US hospitals do not have in-person stroke specialists to facilitate these life-saving stroke treatments. Telestroke is an acute form of telehealth that virtually connects stroke experts to acute stroke patients presenting to such hospitals. Telestroke has expanded stroke care access, increased rates of IVT and EVT, and approximately half of all emergency departments in the US now have telestroke services. Yet, multiple prior studies and our own preliminary work have demonstrated significantly prolonged DTN and DIDO times for AIS patients who get telestroke evaluation compared to conventional in-person evaluation. The mechanisms for these treatment and transfer delays via telestroke remain poorly understood. The aims of this project are: 1) to identify modifiable systems factors associated with DTN and DIDO time delays via telestroke using the national Get With the Guidelines-Stroke registry; 2) to ascertain telestroke-specific determinants of DTN and DIDO time through a sequential mixed methods study within the Paul Coverdell Michigan Acute Stroke Registry; and 3) to use systems engineering methods to rank order factors associated with DTN and DIDO delays via telestroke and develop a first-generation Acute Telestroke Toolkit using participatory design. This project is a critical step in discovering effective telestroke interventions that reduce DTN and DIDO times and reduce permanent neurological impairment after stroke. The candidate, Brian Stamm, MD MSc, will pursue a mentored research plan designed to enhance his skills in the methods necessary to understand the mechanisms of DTN and DIDO delays via telestroke and to develop interventions to improve these systems. A detailed career development plan will promote Dr. Stamm’s development of expertise in three key areas: 1) advanced statistical analyses using multilevel modeling to perform large-scale study of stroke registry data; 2) mixed methods study design and qualitative data analysis to understand complex systems of care; 3) systems engineering and participatory design to develop stroke systems interventions. This K23 award will enable the candidate, Dr. Stamm, to become an independent physician-scientist focused on understanding and improving acute telestroke systems of care. The project will result in a first-generation Acute Telestroke Toolkit to be tested in a future R01. This work could influence clinical care guidelines, lead to faster treatment times, and improve patient outcomes via telestroke.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Glioblastoma (GBM) is the most common aggressive primary brain tumor and is uniformly fatal with a median survival of around 1.5 years. Like surgery and chemotherapy, radiation (RT) is a critical treatment for nearly every patient with GBM and has repeatedly improved patient survival in multiple randomized trials. Still, 80% of GBMs recur within the high dose RT field. Thus, there is a critical need to develop strategies to overcome GBM RT- resistance to further improve patient outcomes. GBM cells exhibit profound cancer-specific metabolic abnormalities, including elevated purine synthesis, to fuel proliferation, invasion and survival. We have found that the metabolic phenotype of elevated purine synthesis also mediates resistance to RT in GBM by promoting the repair of RT-induced DNA damage. This purine-mediated RT resistance can be overcome in preclinical models by mycophenolate mofetil (MMF), an FDA-approved and CNS-penetrant inhibitor of purine synthesis. In this research proposal we will determine how the RT response and purine synthesis regulate one another in GBM. We will also determine if the GBMs with the greatest activity of purine synthesis derive the greatest benefit from MMF treatment. Finally, we will perform a clinical trial to determine the maximum tolerated dose of MMF given in combination with RT for patients with GBM and confirm that this dose reaches active concentrations in GBM tissue. Together, these studies will (1) Determine mechanistic links between the RT response and purine metabolism in GBM that will facilitate the rational combination of metabolic inhibitors with DNA damage inducing therapeutics, (2) Determine whether measuring purine synthesis rates could predict GBM response to MMF treatment, and (3) Determine whether combined RT and MMF should be evaluated in randomized trials for patients with GBM.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Systems neuroscience is acquiring exponentially more neural activity data in vivo and is employing richer stimuli to study ethologically relevant behaviors. Models of neural dynamics in low-dimensional spaces (‘neural manifolds’) are increasingly state-of-the-art for describing the underlying neurobiological mechanisms to encode rich stimuli and evoke behavior. However, causally testing these theories remains challenging, as it requires dynamic manipulation of activity across neurons and time, conditioned on the individual brain, task, or environment. Here, we propose to build new machine learning methods to construct low-dimensional neural manifolds shaped by external stimuli in real time, and design perturbations of neural dynamics on these manifolds to directly test hypotheses of neural circuit function. We will broadly learn how external stimuli drive ongoing neural dynamics and which neuronal stimulations optimally align with these latent vectors. Our real-time approach will also enable us to consider multiple competing models in parallel and choose stimulations to differentiate between them, causally testing competing hypotheses of neural manifold landscapes. We will validate our models in vivo in the larval zebrafish using high-dimensional visual stimuli concurrently with holographic optogenetic photostimulation. In Aim 1, we will develop real-time dimensionality reduction algorithms to construct neural manifolds shaped by external stimulus information. In Aim 2, we will design probabilistic models for predicting the effects of neural stimulations on latent neural dynamics. In Aim 3, we will develop a method for jointly optimizing external stimuli and direct neural stimulation patterns to shape ongoing neural dynamics in real time. Successful completion of this project will result in generalizable machine learning methods that can automatically learn stimulus-shaped neural dynamics and optimize neural stimulations to drive dynamics on the manifold. These tools will be widely available and broadly useful to many neuroscientists.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Our work and others, suggest that interactions between genetic and modifiable dietary factors are key determinants of cognitive aging trajectory. We propose to conduct the first comprehensive analysis of the genetic determinants of cognitive resilience under conditions of caloric restriction (CR) using a systems genetics resource—the Diversity Outbred (DO) panel of mice. The DO mice were specifically designed to discover complex genetic and environmental interactions that control variation of cognitive outcomes observed in human populations. The goal of this project is to identify genetic factors and mechanisms underlying variation in cognitive outcomes following adult-onset CR, one of the most robust and reproducible dietary interventions for extending lifespan. We previously found that this highly robust and reproducible dietary intervention for extending lifespan (40% CR) in aging DO mice causes an increased incidence of memory impairment. This is considered a ‘worst case’ outcome for individuals, caregivers, and health care systems looking for interventions that ultimately reduce the time patients require dementia care. There are currently no CR studies in humans powered for genome-wide discovery of modifiers of cognitive outcomes. This proposal will use innovative mouse models to identify genetic mechanisms that modify the age at onset and severity of cognitive performance in a cohort of male and female aging DO mice (Aim 1). Candidate genes and networks will be tested for associations against the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) CR longitudinal trial in humans, as well as in ‘normal’ aging and Alzheimer’s disease (AD) cohorts to identify resilience factors conserved in humans (Aim 2). We will test the role of these candidate genes predicted to promote healthy brain aging (resilience), as well as those associated with a negative shift from normal cognitive aging toward AD pathophysiology (Aim 3). Specific innovations include the use of multi- scale neural network methods to identify resilience genes that are capable of distinguishing perturbations and latent factors that initiate cognitive resilience from those that merely correlate; our cross-species translational platform for testing candidates identified in mice in multiple human cohorts; the mouse resources and expertise of The Kaczorowski Laboratory, which will be leveraged for gene validation and creation of precision AD models; and our team of experts in human and mouse genetics, multi-omics, computational modeling, electrophysiology and genome editing for functional validation. IMPACT: We will discover and validate targets for promoting healthy brain aging in response to CR, and test their relevance in the context of resilience to AD. The identification of genetic factors and mechanisms underlying variation in normal cognitive aging in response to adult-onset CR in, and that may lead to pathologic brain aging (e.g. AD/ADRD), will likely point to novel therapeutic strategies in humans.

NIH Research Projects · FY 2026 · 2026-03

Abstract Genes promoting their own transmission to the next generation are often in evolutionary arms races with other competing DNA sequences. The mouse X chromosome harbors a recently acquired gene family Slx and Slxl1, which is in an evolutionary arms race with a Y chromosome gene family Sly, to influence sperm fertilization success. A mechanistic understanding of how these two X- and Y-linked gene families compete will help address how evolutionary arms races evolve and how they influence sperm fertilization success. This proposal hypothesizes SLX and SLXL1 directly compete with SLY1 and SLY2 to influence sperm fertilization success. This hypothesis is based on preliminary data of the proteins interacting directly with specific domains of known and putative spindlin proteins. We will use a combination of novel in vitro genomic approaches (e.g. massively parallel sequencing screens and yeast three-hybrid competitions) to model how the X- and Y-linked gene families compete. The in vitro studies will inform in vivo transgenic studies to assess how the gene family variants influence sperm fertilization success. We will determine how the dosage of SLX and SLXL1 proteins influences the molecular competition with SLY1 and SLY2 in vitro. We will determine the most competitive alleles of SLXL1 and SLY2 via an in vitro saturation mutagenesis competition and comparative evolutionary analyses. Our understandings of the in vitro competitions will be translated into testing whether competitive SLXL1 and SLY2 alleles influence sperm fertilization success in mice. Collectively, our studies will deepen and expand our understanding of how proteins evolve to compete in evolutionary arms races and how the competitions can influence sperm reproductive success. This knowledge will provide new insights into the molecular basis of male infertility, sex ratio distortion, and the mechanics of how proteins compete.

NIH Research Projects · FY 2026 · 2026-03

Project Abstract Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD) affect 51 million people worldwide, a prevalence expected to triple by 2050. Two-thirds of those with AD/ADRD live in low- and middle- income countries (LMICs) where the greatest growth in AD/ADRD prevalence is expected, but where services to diagnose and manage this condition are scarce and data regarding dementia burden are limited. Although the Lancet Commission on Dementia, Prevention, Intervention, and Care has identified 14 modifiable risk factors that contribute to 45% of AD/ADRD cases worldwide, there are limited data regarding the prevalence and role of these modifiable risk factors in LMICs. Thus, interventions targeting these factors may have limited impact on AD/ADRD risk in LMIC settings. This proposal’s overall objective is to assess the prevalence rate of AD/ADRD and associated risk factors among adults age ≥55 years in urban and rural Zambia, a LMIC in sub- Saharan Africa. Based on our pilot work, we hypothesize that the prevalence rate of AD/ADRD among adults age ≥55 years will be approximately 9.5% and prevalence of associated risk factors will differ between urban and rural participants. These hypotheses will be tested through a population-based study of adults age ≥55 years in the urban Lusaka and rural Mazabuka Districts of Zambia. AD/ADRD prevalence will be assessed using formal neuropsychological testing, participant, and informant report according to DSM-V criteria. Additional validated questionnaires, a physical examination, and laboratory investigations will assess AD/ADRD risk factors. This project will also build and expand the neuropsychiatric expertise and workforce necessary to conduct prospective AD/ADRD research by providing training and AD/ADRD research experience for a Zambian neuropsychologist, neuropsychologists-in-training, and a cohort of community health workers. The proposed research is highly innovative because it examines AD/ADRD prevalence in a population with limited existing data and expected growth in rates of AD/ADRD and associated risk factors. Knowledge gained from this work will determine (1) the prevalence of AD/ADRD and (2) the prevalence of modifiable risk factors which have the greatest impact on AD/ADRD prevalence in this rapidly aging population. This project will have a significant impact by expanding the capacity for AD/ADRD studies in Zambia and will lay the groundwork for the conduct of future longitudinal studies and trials assessing low-cost interventions to reduce AD/ADRD prevalence and improve patient care.