University Of Minnesota

NIH Research Projects · FY 2026 · 2026-04

Abstract Lassa virus (LASV) is a rodent-borne enveloped RNA virus within the Arenaviridae family and can cause Lassa fever, a lethal viral hemorrhagic fever (VHF) disease in humans, for which there are no approved vaccines and limited therapeutic options. Lassa fever is endemic in West Africa and, with an estimated 100,000 to 300,000 infections and ~ 5,000 deaths annually, has more cases than any other VHFs (including Ebola and Marburg) except for Dengue. The overall fatality rate of Lassa fever is estimated to be ~ 1 % but can be much higher in hospitalized patients (~18%) and during outbreaks (25%). LASV infection also results in severe disease sequelae including spontaneous abortion in nearly all infected mothers and permanent hearing loss in nearly a third of recovered patients. LASV's natural hosts are local rodents, in particular, the multimammate rats, which have a wide habitat in Africa. Together with an extremely high sequence variation among LASV lineages, rodent-borne LASV has the potential to cause large outbreaks and even pandemics. There are no FDA-approved vaccines or therapeutics against Lassa fever. Treatment mainly relies on supportive care. Given the severe disease burdens of LASV and its pandemic potential, effective and broadly protective vaccines against various LASV lineages are urgently needed. The objective of this R21 proposal is to explore the unique advantages of an arenavirus vector, Pichinde virus (PICV), to develop safe and broadly protective LASV vaccines. PICV is a non-pathogenic arenavirus with a bi-segmented RNA genome. The recombinant PICV vector (rP18tri) is engineered to consist of three RNA segments, which can accommodate two additional open-reading frames (ORFs) to express antigens in the targeted antigen-presenting cells. The live-attenuated rP18tri viral vaccine platform is safe and convenient and induces balanced antibody and T-cell responses. Built upon compelling preliminary data, the proposed research will test the hypothesis that non-pathogenic arenavirus vector (rP18tri)-based multivalent LASV antigens will induce robust and broadly protective immunity against diverse LASV isolates. In this exploratory R21 proposal, we will generate additional rP18tri vector-based multivalent LASV vaccine candidates (Aim 1 ), evaluate their antibody and T-cell responses (Aim 2), and assess the protective efficacy in an established LASV-guinea pig model in BSL4 facility (Aim 3). The study is highly significant in addressing an urgent unmet need for a LASV vaccine by producing at least one candidate with demonstrated safety and broad protection to be advanced to the next phases of preclinical and clinical testing, by generating new knowledge on the protective antigen(s) and correlates of protection to guide the design of next-generation vaccines against LASV and other arenavirus pathogens, and by advancing the development of the new PICV vector platform which holds promise for fighting infectious diseases and cancers.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of 13% that is refractory to immunotherapies. Combination with targeted therapy is a potential approach for overcoming resistance and sensitizing tumors. To this end, recently developed mutant-selective inhibitors targeting oncogenic KRAS, which is mutated in >90% of PDACs, have been shown to remodel the immunosuppressive PDAC tumor microenvironment (TME). This proposal investigates the mechanisms by which KRAS inhibition can promote Natural Killer (NK) cell therapy response in PDAC. NK cells are cytotoxic innate immune cells that play a role in tumor killing. Our transcriptomic analysis of patients with PDAC from The Cancer Genome Atlas revealed that higher expression of NK cell marker, NCAM1 (CD56), is associated with favorable patient survival, indicating that greater NK cell infiltration may indeed promote tumor control. Our preliminary data demonstrate that combining KRAS inhibition with NK cells increases PDAC cell killing in vitro, in part by increasing tumor-cell expression of NK cell activating ligands and altering cytokine/chemokine secretion. In support, using a bioengineered 3-dimensional (3D) collagen matrix platform with quantitative microscopy and migration assays, we find that KRAS inhibition increases NK cell motility and migration towards PDAC cells. To further enhance NK cell homing and tumor killing, we have developed a novel NK cell Tri-specific killer engager (TriKE) targeting B7-H3, an antigen overexpressed on PDAC cells, thereby arming NK cells with tumor-antigen specificity. Our data demonstrate that the B7-H3 TriKE enhances NK cell motility and improves tumor killing, which is further maximized with KRAS inhibition, resulting in complete abrogation of in vivo tumor growth in initial xenogeneic studies. In Aim 1, we seek to further define the signaling mechanisms that regulate NK cells in the context of KRAS inhibition. Specifically, we will determine which KRAS inhibition-induced NK cell ligands and cytokines in tumor cells are responsible for increased NK cell activation, migration and proliferation, and pinpoint the signaling pathways downstream of KRAS in PDAC cells that regulate their expression. We will utilize a combination of in vitro assays and RNA-seq analysis, along with quantitative multi-photon microscopy to study NK cell migration in 3D collagen matrices and ex vivo live tumors. In Aim 2, we propose additional in vivo studies in xenogeneic and syngeneic mouse models to evaluate KRAS inhibition, B7-H3 TriKE and adoptive NK cell combination therapy. Based on preliminary data, we will also perform spatial proteomics on additional human PDAC specimens to examine the spatial interactions of NK cells with other cell types in the TME and identify barriers to NK cell infiltration. Overall, this proposal aims to discover novel mechanisms of NK cell regulation in PDAC and provide pre-clinical evidence for a KRAS inhibitor and B7-H3 NK engager therapy for patients. This proposal provides new multidisciplinary training in tumor immunology, cell therapy, cancer bioengineering, data modeling and multi-omics that is instrumental for my future career as an academic physician-scientist in oncology.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Dysregulated inflammation is a central driver of a significant fraction of all human diseases, including chronic metabolic conditions, tumor metastasis, autoimmune disorders, and aging. Despite numerous advancements in tissue engineering and disease modeling, our ability to accurately capture cell-mediated tissue inflammation in vitro that faithfully mimics in vivo human physiology remains limited. Here, we propose to combine human pluripotent stem cell (hPSCs) and genetic engineering tools to create immunocompetent tissue models that replicate the natural behavior of tissue-resident macrophages with on-demand control over inflammatory states. Specifically, we suggest an immunoengineering strategy to generate human microtissues in a dish containing bona fide resting tissue-resident macrophages. We aim to accomplish this using a “progenitor- based assembly” tissue engineering approach, where myeloid progenitors derived from hPSCs are combined with their developmentally matched tissue and vascular counterparts. Target model systems for this research will include skeletal muscle, liver, and adipose microtissues, as these are all known to exhibit dysregulated inflammation in the context of metabolic diseases—a globally pressing clinical need. Along with strategies to generate and characterize these tissues, we propose to establish bioprocessing procedures to enhance the scale and ability to cryopreserve key progenitors that will enable the dissemination of these tools to labs focused on tissue inflammation research but lack expertise in tissue engineering or stem cell biology. With the development of these microtissues, we then aim to develop and employ genetic engineering tools to overcome known limitations in conventional controllable gene induction systems that are not functionally compatible with hPSCs and their derivatives. Using these tools and a novel lineage tracing and retrieval approach, we further propose to develop multi-lineage CRISPR/Cas9 screens that will identify cell-mediated inflammatory mechanisms that modulate neighboring metabolic tissue cells – the core essence of immunoregulation. Additionally, we will employ these approaches to drive cell-mediated inflammatory and anti-inflammatory states within tissues, overcoming challenges associated with the limited efficacy of in vitro macrophage via recombinant cytokines. Lastly, we will explore using our tool sets to evaluate adoptive hPSC-macrophage transfer strategies as a test bed for immunotherapy development. As part of this effort, we will test hypotheses regarding the “open niche” dependency for successful transfer, the long-term fate and durability of macrophage phenotypes after transfer, and develop additional, more therapeutically relevant genetic tools to modulate these processes. This research will ultimately deepen our understanding of tissue–macrophage biology, create new tools for studying immunoregulatory processes, and develop putative therapeutic strategies for metabolic and inflammatory diseases. Collectively, we aim to greatly expand our understanding of macrophage biology and establish transformative new tools for stem cell-derived tissue modeling and regenerative immunotherapy.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Artificial intelligence (AI) is being developed and deployed across the U.S. healthcare system at a rapid rate with the goal of improving quality and efficiency. AI applications vary dramatically - from predicting risk of sepsis and type 2 diabetes to managing appointment scheduling and billing. Healthcare delivery organizations are therefore faced with the challenge of how to select, implement, and monitor a broad set of AI tools across clinical areas while maximizing value and minimizing risk to patients. Recent data suggest that most healthcare delivery organizations are not succeeding in meeting this challenge, as more than half of US hospitals that have deployed AI are not consistently conducting robust local evaluation of the tools they use. This indicates that organizations are not yet ‘AI capable’ - that is, they do not have the organizational routines, standards, and resources required to successfully navigate the complex and shifting requirements of AI governance. The reasons for the current lag in AI capability are likely variable by the technological capacity, system characteristics, financial resources, patient populations, data practices, and electronic health record infrastructures of different health care organizations (e.g., large health systems, small community health centers). Without evidence-based tools for AI capability tailored to these organizational differences, a digital divide between organizations in their ability to use AI safely and effectively will negatively impact patient care and safety. The proposed project will use mixed methods to identify barriers and mitigation strategies for AI capability across organizational contexts that will ensure AI is safe, effective, and trustworthy throughout the U.S. healthcare system. In Aim 1, we will analyze high-impact AI use cases to identify barriers to and best practices for local AI evaluation routines across heterogeneous organization types (large health system and community health center). In Aim 2, we will identify key attributes of patient-centered AI that promote safety (e.g., oversight), effectiveness (e.g., quality), and trustworthiness (e.g., transparency) through a national survey of the public that multiple common AI applications representing different points along the care continuum (e.g., diagnosing, scheduling) to inform patient-centered AI standards. In Aim 3, we will co-design a modular AI capability toolkit with patients, experts, and healthcare leaders that will adapt to different contexts across the country to ensure organizations can access and safely apply the right AI resources at the right time. To ensure that all organizations are AI capable and narrow the digital divide between them, the proposed project will identify and operationalize key components of AI capability, tailored to varied healthcare delivery organizations.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Clinical tuberculosis outcomes are shaped by host immune responses to Mycobacterium tuberculosis (Mtb), yet the specific innate immune phenotypes that drive Mtb control remain unclear. Human airway macrophages, the first pulmonary cells to encounter inhaled Mtb, differ in their innate ability to prevent infection. Large cohort studies have linked Type I Interferon (IFN) pathways to TB progression, but their role in airway macrophage mediated Mtb control is not well defined. Our preliminary data identify eight airway macrophage clusters from human bronchoalveolar lavage (BAL), with the IFN, interstitial, and chemokine clusters exhibiting the highest number of differentially expressed genes after Mycobacterium infection. Notably, a higher proportion of cells in the IFN cluster correlates with improved Mtb control. We hypothesize that early airway macrophage IFN cluster response is key in determining initial Mtb infection outcomes. In our Aim 1 will define the function of the airway macrophage IFN cluster in early Mtb infection. In Aim 2 will establish a TB close-contact cohort to examine the association between airway macrophage clusters and IGRA positivity following Mtb exposure. To achieve this, we are partnering with the Hennepin County Public Health Tuberculosis Clinic to recruit healthy volunteers and TB close contacts for BAL collection. Using scRNA-seq and ATAC-seq, we will characterize the transcriptomic and epigenetic landscape of airway macrophages. These experiments offer a powerful integrated approach to identify the cellular bases of Mtb infection and leverage these to identify why some people progress to establishment of Mtb infection, and some do not.

NIH Research Projects · FY 2026 · 2026-04

Abstract Flagella—motile, hair-like appendages extending from the surface of cells—are ubiquitously present across all three domains of life. These organelles carry out diverse functions of cells, including motility, sensory perception, and fluid transport, through their primary ability to move ambient fluids relative to the cells. Thus, understanding the interaction between flagella and their surrounding fluid, particularly their fluid-transport capability, is crucial to addressing a wide range of fundamental biological questions. While advances in electron microscopy and X-ray crystallography have illuminated the ultrastructures of bacterial and eukaryotic flagella, the dynamics of motile flagella in fluid environments remain poorly understood. The challenges in studying flagellar dynamics in fluid media stem from the lack of suitable experimental tools capable of imaging collective flagellar motions in real time at small length scales and mapping the three-dimensional (3D) fluid flow around rapidly beating flagella with high spatial and temporal resolution. Drawing on my unique training and career path, I lead a research group that develops new physical model systems and advanced novel imaging techniques to elucidate fluid-mediated flagellar dynamics in key biological processes. Specifically, we aim to address two critical questions on flagellar dynamics in this R35 MIRA proposal. 1) Resolving the synchronized dynamics of prokaryotic flagella that enable the formation of a bacterial flagellar bundle, a process essential for bacterial motility and chemotaxis. 2) Imaging the 3D fluid flow generated by beating eukaryotic flagella and their various mutants, a long-standing challenge that is central to the understanding of the functional consequences of normal and dysfunctional flagella and the key step towards the development of treatments for ciliopathies. Specifically, in Goal 1 of our proposed research, we will integrate experiments on peritrichous bacteria Escherichia coli and their genetically engineered mutants with a scaled physical model of a bacterial flagellar bundle constructed in my lab. This unique approach will help to reveal the detailed mechanisms, through which different physical factors, such as hydrodynamic interactions, the elastic properties of flagellar hooks, and motor torque fluctuations, control the synchronization and formation of bacterial flagellar bundles. In Goal 2, we will develop a new imaging technique—high-speed tracking holographic microscopy—to measure the temporal variations of the three-dimensional flow around the beating flagella of a green alga, Chlamydomonas reinhardtii, which serves as a premier model for eukaryotic flagella. Our research will deliver the first comprehensive characterization of the 3D flow field generated by isolated motile eukaryotic flagella in their natural, unperturbed state and directly correlate abnormal flagellar structures with their functional deficiencies in fluid transport. Thus, through the innovative model system and the advanced experimental techniques pioneered in our lab, our study will address crucial open questions on the dynamics of motile prokaryotic and eukaryotic flagella in fluid media.

NIH Research Projects · FY 2026 · 2026-04

Project Summary In 1966, Francis Crick described proteins as one of biology's two "great polymer languages". Despite progress, achieving fluency in this language—full understanding and the ability to engineer synthetic proteins for precise control of biological systems—remains a foundational challenge. Synthetic proteins, exemplified by engineered gene editors and chimeric antigen receptors, hold immense potential for medicine. While computational biology has advanced protein science through predictions of structure, stability, and mutation effects on disease, engineering multi-domain synthetic proteins remains difficult due to complex fitness landscapes. This limits our ability to build sophisticated proteins that integrate multiple inputs to control cellular states. Current biophysics- based models struggle with large multidomain proteins, and designs are constrained by cellular contexts, such as folding and trafficking. To address these challenges, my lab developed a Multiplexed Assays of Variant Effect (MAVE) pipeline that combines engineering comprehensive synthetic protein variant libraries, analyzing their phenotypes in diverse cellular contexts, with data-driven models of protein structure and function. While this has enabled better synthetic proteins, including opto- and chemogenetic reagents and cell type specific gene delivery vectors, we need to make MAVE cell context aware to understand how cellular contexts impinge on molecular mechanisms that constrain synthetic protein design. Over the next five years, I will pursue this through: 1) studying how protein molecular traits like folding stability relate to their functions within different cells and tissues, providing insight into cell-type specific variation, 2) assessing multiple phenotypes to uncover structure-function relationships and inform engineering strategies, and 3) exploring diverse systems like ion channels and viral capsids while creating biomedical tools. Through collaborations, these approaches will generate discoveries for independent investigation.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Pediatric type 2 diabetes (T2D) is rapidly increasing, with U.S. cases projected to quadruple by 2050. Youth- onset T2D follows a more aggressive disease course than adult-onset, increasing the risk for early microvascular complications. Medication adherence is critical for maintaining glycemic control, yet up to 70% of youth with T2D are nonadherent to their prescribed regimen. Despite the urgent need for adherence interventions, no evidence- based strategies exist for youth with T2D, leaving a critical gap in care. Technology-enhanced adherence interventions, including mobile monitoring devices, tailored text message feedback, and telehealth, have demonstrated efficacy in type 1 diabetes and adult T2D but remain untested in pediatric T2D. This K23 proposal aims to develop and evaluate TEAM-T2D (Technology-Enhanced Adherence to Medication intervention for youth Type 2 Diabetes), an intervention co-designed with key stakeholders (youth with T2D, parents, and healthcare providers) to address adherence barriers of youth with T2D. In Aim 1, the PI and the mentorship team will employ a patient-engaged participatory research approach to develop and refine the TEAM-T2D intervention to ensure feasibility and acceptability. Aim 2 will involve conducting a pilot randomized controlled trial (RCT) to evaluate the feasibility and acceptability of TEAM-T2D intervention in a sample of 40 youth with T2D. Feasibility and acceptability will be assessed through validated surveys and qualitative interviews. Medication adherence will be monitored electronically and serve as a secondary outcome. This K23 award will provide the PI with training in 1) patient-engaged research methods, 2) mixed methodologies for intervention development, 3) advanced training in clinical trial design and conduct, and 4) leadership and management expertise to conduct multidisciplinary research in pediatric diabetes care. Successful completion of this project will yield critical pilot data to inform a future R01-funded Type 2 hybrid implementation/ effectiveness trial, positioning the PI as a leader in adherence intervention research for youth with T2D.

NIH Research Projects · FY 2026 · 2026-04

Project Summary: Stress plays a central role in the development and persistence of substance use disorders (SUDs). Chronic or severe stress can lead to harmful drug use, and exposure to stressors often triggers relapse following prolonged abstinence. Understanding how stress induces neuroadaptations that increase vulnerability to drug use is crucial. Furthermore, stress must be incorporated into addiction models, particularly when evaluating novel therapeutic targets, as it drives profound molecular, cellular, and circuit-level changes that need to be appreciated for rational drug design. The muscarinic M5 receptor is highly expressed in midbrain dopamine neurons and enhances dopamine transmission in the nucleus accumbens. It has recently garnered interest as a therapeutic target for SUDs. Constitutive deletion or pharmacological inhibition of M5 receptors reduces drug self-administration. However, technical limitations have hindered direct examination of how M5 regulation of dopamine transmission influences drug-seeking behavior. Moreover, these studies have not included stress as a factor in their SUD models. Our preliminary data and prior studies show that repeated stress exposure enhances the hedonic evaluation of cocaine reward, measured using the cocaine conditioned place preference (CPP) assay. This same stress exposure disrupts M5 receptor-mediated regulation of dopamine transmission. Additionally, we found that selective deletion of M5 receptors from dopamine neurons potentiates cocaine CPP, mimicking the effects of stress, which contrasts with systemic M5 receptor disruption. Taken together, we hypothesize that stress-induced disruption of M5 signaling within the dopamine system increases subjective drug reward experience that can lead to vulnerability to substance use disorders. We propose that use of positive allosteric modulators directed toward M5 may mitigate the stress-induced potentiation of cocaine reward. We will test this hypothesis through two aims: Aim 1: Determine the effects of selective bi-directional manipulation of M5 receptors in dopamine neurons on cocaine conditioned place preference (CPP). Using transgenic and viral vector strategies, we will selectively manipulate M5 receptor expression in dopamine neurons in male and female mice. We will then assess how these manipulations influence context-cocaine Pavlovian associations and cocaine hedonic evaluation using CPP. Aim 2: Determine whether positive or negative allosteric modulation of M5 receptors can ameliorate the effects of stress on cocaine CPP. We will evaluate whether systemic treatment with M5 positive or negative allosteric modulators mitigates stress-induced potentiation of cocaine CPP when administered post-stress during the conditioning procedure.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Although hearing aids and cochlear implants (CIs) improve the ability of people with sensorineural hearing loss (SNHL) to communicate, performance remains stubbornly low, particularly in noisy backgrounds. This is a critical health issue, not least because of the strong association between hearing abilities and cognitive decline with age. Older adults, even those with typical hearing (TH), also experience deficits understanding speech in noise in ways that remain poorly understood. Our long-term goal is to uncover the mechanisms that limit auditory and speech perception under challenging acoustic conditions in adults with and without hearing loss across the lifespan. This goal is addressed under three specific aims that explore interlinked aspects of the spectro-temporal encoding of auditory and speech sounds. Under Aim 1, the fundamental mechanisms that allow us to detect and identify speech and non-speech sounds in noise are explored. A new hypothesis involving the processing of amplitude fluctuations across frequency is compared with the classic hypothesis involving the processing of energy changes across frequency. Empirical results in adults with SNHL, CIs, and TH across the lifespan will be compared with predictions from state-of-the-art computational models of the auditory periphery and midbrain. Under Aim 2, the relative contributions of peripheral and more central factors to deficits in speech perception in noise with hearing loss and age are studied using a novel intervention approach, rather than more traditional correlational methods. By manipulating the degree of peripheral spectral resolution and temporal fine structure cues available in the speech sounds themselves, the experiments test the hypothesis that the bulk of age effects for speech in noise can be accounted for by changes in peripheral representations. Under Aim 3, auditory and speech perception is studied with respect to the influence of spectral contrast and context effects. Perception is critically dependent on the surrounding context in which the sensory signals are received, but we know little about how these dependencies are altered by either age or hearing loss. The implication is that any changes in our ability to make use of sensory context may be impacted by sensory loss or age in ways that are not detected by standard clinical tests. Our experiments will provide both behavioral and neurophysiological measures of auditory and speech context effects in TH and SNHL across the adult lifespan to test the hypothesis that changes in peripheral processing with hearing loss and age can radically affect how our perception adjusts to the surrounding context, and therefore contributes to the unexplained difficulties in communication faced by older people with and without hearing loss in dynamic acoustic environments. Overall, the results of this project will shed new light on critical perceptual issues surrounding speech understanding in challenging acoustic environments and will contribute to developing new approaches to the diagnosis, treatment, and management of hearing loss.

NIH Research Projects · FY 2026 · 2026-03

Abstract Once obesity develops and becomes entrenched, achieving sustained weight loss is extremely difficult. Thus, preventing the accumulation of excess adiposity in high-risk individuals is the ideal course of action. Adolescents/young adults (AYAs) are high-risk individuals, as this is a life stage characterized by susceptibility for accelerated weight gain. However, most obesity prevention interventions targeting AYAs have reported null findings or modest effects. It is possible that failure to address the underlying physiology of the energy regulatory system is at least partly responsible for the underwhelming results. Previous obesity prevention interventions in AYAs have almost entirely focused on modifying individual behaviors and/or external environmental conditions and have not addressed the biological pathways driving energy regulation. Effectively targeting the underlying physiological processes promoting body fat storage, such as with pharmacotherapy, may be an essential component of successful obesity prevention for some individuals. When used in combination with lifestyle-based weight gain prevention counseling, low-dose preventative pharmacotherapy has the potential to halt or slow unhealthy weight gain by targeting key mechanisms in the energy regulatory system. Phentermine/topiramate is among the most cost-effective obesity medications approved for adolescents and adults. Its mechanisms of action may be ideal for impeding weight gain and ultimately preventing the onset of obesity because they are multifactorial and involve reducing appetite, enhancing satiety, and potentially increasing energy expenditure. Flexible dosing with phentermine/topiramate provides the option to introduce preventative pharmacotherapy at low levels of exposure yet allows for dose escalation if weight gain were to ensue. In the proposed clinical trial, we plan to diverge significantly from historical obesity prevention approaches by pairing lifestyle-based weight gain prevention coaching with low-dose preventative pharmacotherapy to target the underlying biological processes implicated in weight gain. We will target AYAs (18 to <25 years old) at risk of developing obesity: defined as those with a BMI between 25-29.9 kg/m2 (overweight classification) and a family history of obesity (one biological parent with severe obesity and/or two biological parents with obesity). We will randomize 140 of these individuals (1:1) to phentermine/topiramate or placebo with both groups additionally receiving lifestyle- based weight gain prevention coaching. Over a period of two years, we will: 1) compare changes between groups in BMI trajectories as well as incidence of obesity and regression to normal weight; 2) identify mechanisms of action related to appetite, satiety, cravings and energy expenditure as well as determine if there are differences between groups in diet quality and disordered eating behaviors; and 3) investigate changes in visceral adipose tissue and its relation to cardiometabolic risk. In this study we will take a fundamentally different approach to the science of obesity prevention by targeting the underlying biological processes driving unhealthy weight gain in AYAs, a group that has been underrepresented in medication trials.

NIH Research Projects · FY 2026 · 2026-03

Project Summary The over-arching goal of this project is to develop new strategies for the integrative analysis of high-throughput biomedical data, that are generally applicable to a wide variety of applications and scenarios. This is needed, as rapidly developing molecular “omics" and imaging technologies have allowed for more comprehensive measurement of multi-faceted biogical systems at lower costs. As a result, data for a given study will often have high-throughput data that are linked across multiple sources (e.g., different technologies) and multiple dimensions or ways (e.g., multiple tissues, cell types, regions, or time points). We have a strong track record of developing impactful statistical methodology and widely used software for data integration in this general setting, motivated by tangible applications to neurodegenerative disorders, pulmonary disorders, early-life nutrition, and other domains. For this project we will undertake new methodological aims that are driven by emerging data challenges in these areas, including integration across multiple sample groups or “cohorts". Our central methodological objective is to develop a very flexible framework for bidimensional regression and factorization that simultaneously identifies covariate-driven effects and auxiliary structured variation in multi-source, multi-way and multi-cohort data. Our general model will be able to address the following tasks, as needed: (a) the decomposition of covariate effects and low-rank structure which may be shared across any sources or sample sets via a general objective function, (b) Bayesian inference for the identified decomposition with efficient posterior sampling algorithms, (c) missing data imputation, (d) classification of the sample co- horts, and (e) tracking progression for longitudinal data. We will apply our methods to address tasks in diverse biomedical areas, including (a) identifying multi-omic signatures in human breast milk that correlate with infant brain development, (b) identifying a comprehensive model for progression of Friedreich's ataxia across multiple modalities, and (c) identifying multi-omic molecular pathways indicative of HIV-association chronic obstructive pulmonary disease across different tissues. The broader impacts of this work extend to the wider biomedical research community, as open-source software packages will facilitate the adoption of these methods by other researchers to enable the integration of multi-source, multi-way, and multi-cohort data, filling a critical need in the rapidly expanding landscape of biomedical studies.

NIH Research Projects · FY 2026 · 2026-03

Project Summary This project is designed to train Alex Dayton, MD, PhD and to help him transition into an independent career as a physician-scientist studying kidney disease. Tacrolimus (tac) is the most widely used immunosuppressive medication after solid organ transplantation. Tac usage is complicated by the development of chronic kidney disease (CKD), which develops in over 50% of non-renal solid organ transplant patients. This CKD can cause devastating consequences in these patients, leading to shortened lifespans, increased hospitalization, and even the need for dialysis or kidney transplantation. Previous studies have shown that tacrolimus can activate the renal nerves, but no study has evaluated the effect of the removal of the renal nerves (renal denervation, RDN) on the development of tac nephrotoxicity. This is particularly of interest at this time because RDN has recently been approved for clinical practice. The central hypothesis of this proposal is that prophylactic RDN is protective against the development of tac nephrotoxicity. Our laboratory has generated compelling preliminary data that suggests that RDN is protective against the development of tac nephrotoxicity in rats. We show that rats who receive RDN prior to tacrolimus treatment have increased GFR relative to sham controls and also have decreased kidney fibrosis relative to shams. Furthermore, even when only one kidney undergoes RDN within a rat, that RDN kidney demonstrates improved GFR, indicating that the protective mechanism underlying RDN is at least partially kidney-specific and not a consequence of circulating hormones or cardiovascular parameters. This grant will evaluate the mechanisms responsible for RDN’s protective effects against tac nephrotoxicity in two specific aims. In specific aim 1, we will evaluate a whole-animal model of tac nephrotoxicity and will perform a thorough investigation of renal physiology, renal cortical transcriptome, including single-cell transcriptome, and cardiovascular parameters in rats subjected to either RDN or sham and treated with tac or vehicle. In specific aim 2 we will take advantage of the powerful ability to perform RDN on only one kidney in the rat, while leaving the nerves to the other kidney intact. By using this method, we will take a detailed look at the intrinsic renal pathways underlying RDN’s protective effect on tac nephrotoxicity, including assessments of GFR, renal transcriptome and renal metabolome. The impact of this grant is rapidly translatable to patients. RDN is an FDA-approved technology and the detailed physiological insights gained in this grant will pave the way for a new treatment paradigm in solid- organ transplant recipients: by RDN at the time of transplant we may prevent the development of the devastating disease of tac nephrotoxicity.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY The leading cause of hospital-acquired, infectious diarrhea in the United States is a gastrointestinal pathogen known as Clostridioides difficile. C. difficile can be found in the guts of many healthy individuals but typically only becomes problematic after disruption of the gut microbiota and is thus often associated with the administration of broad-spectrum antibiotics. The pathology that accompanies infection varies from one person to the next, ranging from relatively mild symptoms like diarrhea to severe, and potentially life-threatening conditions, known as pseudomembranous colitis and toxic megacolon. All these symptoms are the product of three toxins secreted by the bacterium during infection known as Toxin A, Toxin B, and the C. difficile Transferase (CDT). While Toxins A and B have historically been considered the drivers of the disease that accompanies infection, recent studies have suggested a potential synergy among all three toxins in the most severe cases. These observations have underscored the need to develop a better understanding of how CDT contributes to disease. The goal of this proposal is to expand our understanding of the intoxication mechanism governing CDT activity by addressing two key questions: 1) how is toxin assembly regulated and triggered? and 2) what is the mechanism underlying CDT delivery into host cells? We will use a combination of cryogenic electron microscopy (Cryo-EM), biochemical/biophysical assays, and cellular biology to describe these two points in molecular detail thereby generating a framework that can be used to deduce the precise role of CDT during infection. We also anticipate our analysis will uncover new structures and activities that will be exploited in future studies aimed at developing CDT inhibitors. As a third goal, we aim to leverage the toolkit we have assembled to probe the activity of two extrachromosomal CDT variants. Our plan is to use our full array of biochemical/biophysical assays, cellular biology, and Cryo-EM to generate a detailed description of the activity of these variants to better understand their potential to cause disease. Our work will thereby inform future studies that seek to understand how variation among toxins leads to different clinical outcomes. Together, this proposal will develop a thorough understanding of the function of CDT, an often overlooked, yet problematic, virulence factor associated with a notorious pathogen.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY Autoimmune type 1 diabetes (T1D) is caused by the T cell-mediated destruction of insulin producing beta (β) cells in the pancreas. The incidence of T1D is rising globally. This is thought to be linked to early life exposure to microbes, environmental pollutants, and even diet. Viral infections in mouse models of diabetes have shown both acceleration and protection of diabetes, but these differences occur at different ages and degree of insulitis. The deciding factor in whether CD4+ T cells will prime the immune system to initiate T1D is the inflammatory context of the initial peripheral antigen encounter, particularly the timing of type I interferon (IFN-I) exposure triggered by microbes. Unfortunately, the vast majority of research has utilized specific pathogen free (SPF) mouse models examining activation in the absence of IFN-I. These conditions are very different from the environment in which humans live. At UMN, we have created a ‘dirty’ mouse model or normal microbial environment (NME) to study how the immune system responds or develops in the presence of microbes and viral pathogens, a more physiological environment driven by IFN-I production. Thus, we now have a diabetes model that we can study with NME conditions. Depending on the age and duration of time in NME, our NOD mice can be completely protected from diabetes. Our goal is to understand how infections impact immunity to either trigger or protect against diabetes. A better understanding of this process could provide therapies that prevent or treat human diabetes. We will test three specific aims; 1) Determine the role of IFN-I on naïve CD4 T cell fate following TCR activation in SPF conditions, 2) Determine the mechanism(s) by which NME prevents autoimmune diabetes, and 3) Develop autoimmune diabetes therapies. Our goal is to determine the role of IFN-I during initial T cell fate decision between Teff and Tregs. We hypothesize this fate decision leads to iTregs and will focus on induction, survival or enhanced suppressive function. Finally, we will explore IFN-I therapy and engineered TCR Tregs for autoimmune therapy.

NIH Research Projects · FY 2026 · 2026-02

Abstract. HIV-1 replicates in host cells to produce new virions by two alternative routes. As free virus, HIV-1 buds from infected cells and circulates in the host until encountering a new permissive target cell. In addition, HIV-1 can efficiently spread by direct transmission from infected to uninfected CD4+ T cells at confined local sites formed between the two cells and designated virological synapses (VSs).2,11,13 Within VSs, budding virions are concentrated in close proximity to the membrane of an uninfected cell and their envelope glycoproteins (Envs) can interact with the CD4 and CCR5/CXCR4 receptors to mediate efficient HIV-1 entry.1 In vitro studies indicate that HIV-1 cell-cell transmission (C-CT) is significantly more efficient than free virus infection. Increasing evidence suggests that in vivo C-CT contributes to viral spread and immune evasion. C-CT between cells can contribute to multiple aspects of HIV-1 pathogenesis, replication in tissues, and transmission. Specifically, close interactions between CD4+ T cells could potentially contribute to massive replication in lymph nodes during clinical latency of HIV-1 in people living with HIV-1,6 play a role in HIV-1 reactivation from latency upon anti-retroviral therapy discountinuation,7 and accelerate growth of viral foci during initial virus transmission in non-human primate models of HIV-1 prevention.8 Moreover, in vitro and in vivo studies provided evidence for different levels of resistance of C-CT to small molecule drugs and broadly neutralizing antibodies. Despite potential contribution of C-CT to HIV-1 pathogenesis as well as immune and therapeutics evasion, the mechanisms of HIV-1 C-CT is still not fully understood because of significant obstacles to investigate C-CT that limit our ability to thoroughly study HIV-1 C-CT, especially in primary CD4+ T cells. Here we propose to fill this gap in knowledge by comprehensively dissecting the molecular determinants of HIV- 1 C-CT at a population level of hundreds of different viral strains using highly sensitive tools combined with high- resolution imaging methods that we have recently developed. We will also study the contribution of C-CT to HIV- 1 replication in vivo. Our central hypothesis is that efficient HIV-1 C-CT depends on specific Env determinants and cellular host factors and is vulnerable to targeting host proteins and to cell cytotoxicity. In Aim 1 we will define Env determinants that contribute to HIV-1 C-CT using viral, structural and evolutionary biology approaches. We will also evaluate C-CT during HIV-1 replication in humanized mice, in tissues from patients, and C-CT efficiency of Env that evolved in vivo in patients. In Aim 2 we will study the vulnerabilities of HIV-1 C-CT. Our preliminary results show that type I interferons (IFNs) α and β efficiently inhibit C-CT and we will identify the related gene(s) and underlying mechanism in the context of T cell lines and primary CD4+ T cells. In parallel, we will study the vulnerability of HIV-1 C-CT to cellular cytotoxicity mediated by chimeric antigen receptors and a synthetic T-cell-IgG receptor (TIR) that recognize HIV-1 Envs. Our study will define the C-CT landscape mediated different Envs and provide insights into vulnerabilities of HIV-1 spread by C-CT.

NIH Research Projects · FY 2026 · 2026-02

TYRO3, AXL and MERTK receptor tyrosine kinases (TAM RTKs) function in maintaining homeostasis of a number of tissues and organs by eliciting two complementary but non-identical principal effector functions in cells – phagocytosis of dead cells and anti-inflammatory signaling. Understanding of TAM RTK biology comes from three decades of mouse knockout studies that revealed phenotypes spanning increased susceptibility to endotoxic shock, lymphoproliferation and broad-spectrum autoimmunity, defective spermatogenesis and sterility, retinal degeneration and vision loss, and worsening synaptogenesis index and memory in an Alzheimer’s disease (AD) model. Despite the unequivocal strength of these studies, advances have somewhat stalled as the precise effector function of TAM RTK that underlies the phenotype in each of these scenarios – phagocytosis, anti-inflammatory signaling or both – remains undetermined. We propose to generate and validate a series of TAM RTK mutant mice that are not knocked out or devoid of all functions of TAM RTKs, but instead have a single, specific effector function knocked out. RTKs are phosphorylated on a series of tyrosines (Y), each of which recruits specific adaptors and engages a particular cascade. By substitution of a single Y residue by phenylalanine (F), a specific signaling axis can be ablated while maintaining intact other downstream signaling. Pioneering studies from Hanafusa and Birge labs, and more recently from Creixell, White and Meyer labs have demonstrated that TAM RTK pleiotropic signaling and function can also be disentangled, albeit using in vitro cell culture systems. Inspired by these studies we have established the proof-of-concept that TAM RTK signaling is amenable for in vivo disentanglement by generating Mertk Y867F/Y867F YàFIN motif-mutant mice to disable MERTK-dependent phagocytosis and Mertk Y680F/ Y680F immunoreceptor tyrosine-containing inhibitory motif (ITIM) mutant which has resulted in increased inflammation. We have employed CRISPR-Cas9 to introduce YàF substitutions in mice in defined motifs in MERTK and AXL, including YàF/VIN, ITIM and immunoreceptor tyrosine-based switch motif (ITSM). We will extend this approach to engineer the corresponding mutations in converved motifs in TYRO3. We will test the concept that TAM RTK-dependent phagocytosis can be segregated from TAM RTK-dependent negative regulation of inflammation by assaying primary cells for phagocytosis of dead cells and NF-kB activation both in vitro and in vivo. We anticipate that these T/A/M YàF mouse models will comprise an essential toolkit for the next decades, to be used by us and to be shared with colleagues, to untangle TAM RTK effector functions in a vast array of physiologic system and disease models including immune resolution and chronic inflammatory diseases, photoreceptor turnover and vision loss, macrophage function and cardiovascular diseases, microglial biology and AD, magnitude of the immune response and anti-tumor immunity. This in turn would improve our mechanistic understanding and precise therapeutic targeting of TAM RTKs to overcome the current bottleneck in translating TAM-based therapeutics.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Bone disease is a major type of complication of diabetes. Fracture risk in patients with type 1 diabetes (T1D) and T2D can be six-fold and four-fold higher than those without diabetes. The impact of diabetes on bone health is becoming more evident because of the obesity epidemic and the aging of the population. Understanding how diabetes increase bone fragility is important to identify therapeutic targets and treat patients at risk. To treat diabetes, multifactorial approaches including lifestyle modifications and medications are required. However, some dietary regimens and antidiabetic drugs may negatively affect bone health. On the other hand, anti- osteoporosis drugs may affect glucose metabolism. In this project, we propose to test if genetic and pharmacological elevation of O-linked N-Acetylglucosamine (O-GlcNAc) signaling prevents diabetic osteoporosis in preclinical models. The enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) mediate the addition and removal of the O-GlcNAc modification to/from serine and threonine residues on intracellular proteins. We and others have established the pivotal role of protein O-GlcNAcylation in physiological homeostasis, as well as disease conditions including diabetes, neurodegeneration, and aging. In the bone, we found that O-GlcNAc is enriched in the multipotent bone marrow stromal cells (BMSCs) that can become either bone-forming osteoblasts or adipocytes. While O-GlcNAc is dispensable for homeostatic turnover of the bone, we found that ablating OGT in adult Lepr+ BMSCs accelerates bone loss specifically in diabetic animals. We will test the central hypothesis that protein O-GlcNAcylation modulates the differentiation fate, metabolic fitness, and niche function of Lepr+ BMSCs, thus impeding diabetic osteopathy and inflammation. Aim 1 will define the functional effects of O-GlcNAcylation on BMSCs and bone health. We expect to find that declined protein O- GlcNAcylation in BMSCs drives maladaptive bone remodeling in diabetic mice. Aim 2 will determine the mechanisms by which O-GlcNAcylation links diabetes to BMSC dysfunction. Specifically, OGT is required for hormonal regulation of BMSC metabolism, proliferation, and differentiation. Aim 3 will characterize O-GlcNAc- dependent stromal-myeloid interactions. We anticipate that stromal O-GlcNAc signaling inhibits bone resorption by limiting BMSC-derived osteoclastogenic niche factors. The completion of the proposed study will establish O- GlcNAcylation as a potential molecular target of future interventions to treat osteoporosis in patients with diabetes.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Epstein-Barr virus (EBV) establishes lifelong infection in humans and contributes to a spectrum of diseases, including infectious mononucleosis, nasopharyngeal carcinoma, oral hairy leukoplakia, post-transplantation lymphoproliferative disorder (PTLD), AIDS-related lymphomas, and certain B-cell malignancies, etc. Despite their substantial health impact, current treatment options remain limited, with no targeted therapies available. Therefore, there is a critical need to develop effective interventions for the treatment of EBV-associated diseases. Within cells, EBV genome is stably maintained as an episome by its encoded viral protein EBNA1 and host cellular factors. While the role of EBNA1 in EBV episome maintenance is well-characterized, the host factors essential for this process remain largely unexplored. We hypothesize that identifying host factors essential for EBV episome maintenance will provide novel therapeutic targets for EBV eradication and the treatment of EBV-associated diseases. In this proposal, we aim to identify host factors essential for EBV episome maintenance through two complementary approaches: 1. Identification of host factors essential for EBV episome maintenance using a genome-wide CRISPR screen. We have developed a novel EBV episome monitoring system, AKATA-EBV-EGFP-Cas9, in which the EBV episome can be monitored via EGFP signal upon IgG induction. Using this system, we will perform a genome-wide CRISPR screen to systematically identify host factors essential for EBV episome maintenance. 2. Determination of host factors that contribute to EBNA1 complex formation. EBNA1 forms complexes with host factors to facilitate EBV maintenance. We hypothesize that host factors critical for EBNA1 complex formation represent potential targets for disrupting EBNA1 function and EBV maintenance. To identify the protein composition of the EBNA1 complex, we have tagged EBNA1 with TurboID, a biotin ligase that uses ATP to biotinylate proximal proteins. In subsequent studies, mass spectrometry will be used to systematically map the proteins involved in EBNA1 complex formation. In summary, this study aims to identify host factors essential for EBV episome maintenance, addressing fundamental knowledge gaps in EBV-host interactions. Our findings will provide critical insights into the mechanisms of EBV persistence and serve as the foundation for a subsequent R01 investigation. The R01 follow-up study will elucidate how EBV hijacks cellular machinery to maintain its episome and evaluate the therapeutic potential of targeting these host factors in EBV-associated diseases.

NIH Research Projects · FY 2026 · 2026-02

Summary Regulation of immune responses is critical to provide beneficial immunity against pathogens and cancer, while avoiding autoimmune diseases and immunopathology. A population of memory-phenotype CD8+ T cells, expressing the transcription factor Helios” has been proposed to play a key role in preventing excessive and autoimmune responses following vaccination or infection. However, the precise identity of these Helios+ “regulatory” CD8+ T cells, the factors controlling their differentiation and maintenance, and the exact ways in which they contribute to immune homeostasis are highly controversial. In this exploratory proposal, we develop model systems intended to dissect the development, homeostasis and specificity of these CD8+ T cells, position ourselves for future studies on the physiological role and therapeutic potential of Helios+ CD8+ T cells.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Aging is a fundamental driver of many chronic conditions, including obesity, type II diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as fatty liver disease). Numerous aging-related pathologies are promoted by overnutrition and are associated with dysregulation of key metabolic pathways, particularly those related to lipid metabolism and energy homeostasis. We have previously found that the cell cycle protein cyclin D1 is induced in hepatocytes in response to feeding and overnutrition, and that it unexpectedly regulates key metabolic pathways in the liver, independently of its role in proliferation. In particular, we find that cyclin D1 represses several steps of lipid catabolism, which play an important role in health and lifespan. We now find that cyclin D1 increases with age in hepatocytes of mice and humans, suggesting a link between cyclin D1 and age-related metabolic dysfunction. However, the mechanisms by which age and overnutrition promote cell cycle-independent expression of cyclin D1 have not been defined. In addition, we have significant gaps in our understanding of how this protein modulates downstream metabolic events. Using the nematode C. elegans, we have established that the links between cyclin D1 and repression of lipid catabolism are fundamental biological responses conserved between species. Using the auxin-induced degron (AID) system, we have developed a new genetic tool in C. elegans that allows visualization of the worm ortholog of cyclin D1, encoded by the cyd-1 gene, as well as a means of reducing expression in a temporal and spatial manner. Preliminary studies indicate that genetic manipulation of cyclin D1/CYD-1 alters lipid metabolism in the worm and targets pathways involved in lipid catabolism. We will now use this powerful genetic model system as a discovery platform to define the mechanisms by which cyclin D1/CYD-1 influences lipid metabolism, aging and age-related metabolic dysfunction. Our proposed studies will establish a mechanistic foundation for further translational work, focusing on identifying strategies to inhibit cyclin D1 expression or manipulate its downstream targets as therapeutic approaches to combat age-related metabolic dysfunction.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Islet transplantation is a promising treatment for insulin-dependent forms of diabetes, including type 1 diabetes and surgical diabetes induced by total pancreatectomy. In the U.S., total pancreatectomy with islet autotransplantation (TPIAT)—which is performed to relieve pain in patients with chronic pancreatitis-- has been the most prevalent form of islet transplant to date. At the same time, islet allotransplantation for type 1 diabetes is growing, and will continue to grow with the success of stem-cell derived islets and future approaches to reduce immunosuppression risks via technological advancements, genetic editing, or newer immunomodulation. Islet autotransplant is a useful research model to study adjunctive therapies for glycemic control and islet graft survival because it is free of the confounding factors of alloimmune rejection and recurrent type 1 diabetes. In TPIAT, about 70% of patients require exogenous insulin despite having some endogenous islet function, and attrition of islet function over time occurs in both auto and allografts. This attrition appears to be at least in part driven by metabolic stress on the transplanted beta cells. This pilot clinical trial, submitted in response to PAS-25-102, is designed to gather preliminary data on the efficacy and safety of SGLT2 inhibitor therapy (SGLT2i) in islet autotransplant recipients who have partial islet function. Our rationale for studying SGLT2i in this population is: (1) SGLT2i reduces blood glucose levels through increased glucosuria and do not directly stimulate islets (avoiding extra metabolic stress), nor does the benefit depend on presence of insulin resistance, which is often absent in islet transplant; (2) in both T1D and total pancreatectomy, there is evidence of reduced prandial glucose excursions with SGLT2i, which in turn may reduce metabolic beta-cell stress on transplanted islets in TPIAT; (3) SGLT2i are acceptable to patients as a once-daily oral medication. However, safety of these agents is unknown in TPIAT, and in theory they may increase risk for diabetic ketoacidosis in this population of patients who have partial insulin deficiency. We will enroll 30 patients with partial islet function >1 year after TPIAT, randomized to a standard care control arm (n=10) or one of 2 doses of empagliflozin (n=10 on 10 mg; n=10 on 25 mg) for 3 months, followed by a 3 month extension during which all patients will receive empagliflozin (25 mg daily). Specific Aim 1 will determine if empagliflozin improves glycemic control and reduces beta-cell specific endoplasmic reticulum stress after islet autotransplant. Specific Aim 2 will assess safety and feasibility of empagliflozin in islet autotransplant recipients. If results from this pilot study are promising, we will conduct a larger randomized blinded study. PI Bellin has led two multicenter TPIAT studies and has relationships with other centers to build a larger randomized trial. Importantly, we expect that results from this study will also inform the field of islet allotransplant for type 1 diabetes.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY/ABSTRACT Risk for Alzheimer’s Disease and AD-related dementia (ADRD) in late life is sensitive to social and environmental exposures in childhood—a critical period of brain development. Children who grow up in families and neighborhoods with few socioeconomic resources and those who are exposed to lead (Pb; a potent neurotoxicant) in their environment may have higher risk of ADRD as they age. However, evidence supporting these associations is limited by retrospective recall of childhood conditions and/or small, non-population based samples. Furthermore, the pathways underpinning these relationships are unclear. We propose to create a novel data source for conducting research on early life origins of ADRD by linking participants of the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS; N=15,792) to their household records in the 1930, 1940, and 1950 U.S. Censuses, which occurred when they were children. The overall objectives of this project are to (a) provide prospective estimates for the independent and synergistic effects of childhood SES and Pb exposure on later life ADRD incidence, (b) examine how these early life exposures contribute to ADRD etiology using data from brain imaging scans (beta-amyloid from PET, vascular disease from MRI) and plasma biomarkers of neurodegeneration, and (c) investigate how these relationships are mediated across the life course using >35 years of prospectively collected ARIC data. We will also (d) examine the consistency of these relationships by race and sex. This project has four specific aims: (Aim 1) Investigate the relationship of childhood individual- and neighborhood-level socioeconomic resources with risk of incident ADRD and biomarkers of neuropathology. Census-derived measures of family SES were reported by participants’ parents. Using full-count Census data, we will also construct aggregate measures of SES in participants’ childhood neighborhoods. (Aim 2) Investigate the relationship between childhood Pb exposure and incident ADRD and biomarkers of neuropathology. We will accomplish this by using historic data on Pb exposure through water (Pb plumbing and water acidity), Pb gasoline (automotive and aviation) and Pb mines and smelters. (Aim 3) Examine whether childhood SES modifies the association between Pb exposure and incident ADRD. (Aim 4) Create infrastructure for future explorations using census-linked ARIC-NCS data. This Aim will support the secure, efficient, and reproducible use of these novel early-life data for future investigations by the broader research community. This project is innovative because it will rely on contemporaneous rather than retrospective measurement of childhood circumstances, evaluate incident ADRD in a diverse population, and provide etiologic insights using the deeply phenotyped ARIC-NCS data. The proposed research is significant because it will consequentially improve our understanding of the connections between early-life socioeconomic disadvantage, Pb exposure, and ADRD risk in late-life, which may inform policy and future interventions.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Maintaining healthy adipose tissue function is essential for metabolic homeostasis and the prevention of metabolic diseases. As potent endocrine cells, adipocytes secret various bioactive molecules and extracellular vesicles that influence the function of tissues and organs throughout the body. Besides adipocytes, multipotent stem and progenitor cells in adipose tissue are crucial for tissue maintenance and repair throughout life. With aging, adipose tissue undergoes species-conserved changes, including decreased subcutaneous adiposity, increased visceral adiposity, and a decline in the thermogenic capacity of brown and beige adipose tissue. In contrast to the detrimental effects of adipocyte hypertrophy, hyperplasia, a process known as adipogenesis, supports tissue development, repair, and metabolic health. However, adipogenesis is impaired during aging, which has been linked to adipose progenitor cell senescence, potentially contributing to the development of metabolic diseases. Recent studies indicate that extracellular vehicles (EVs), particularly adipocyte-derived EVs (Ad-EVs) play a role in intercellular communication within adipose tissue, regulating its function. Ad-EVs exhibit heterogeneity, with large and small Ad-EVs differing in protein and lipid composition, suggesting functional diversity. However, the specific subtypes of Ad-EVs secreted by adipocytes and their distinct roles in local and systemic metabolic regulation remain unexplored. Our preliminary studies indicate that Lipocalin 2 (LCN2), a novel phosphatidic acid (PA) binding protein, plays a potential role in senescence and adipogenesis of adipose stem and progenitor cells (ASPCs) through EV-mediated intercellular communication. Lcn2 deficiency impairs adipogenesis and results in hypertrophic obesity. Stromal- vascular (SV) cells from the brown and white adipose tissue of Lcn2 knockout mice exhibit increased senescence and decreased adipogenesis. Importantly, we have identified LCN2 in a distinct subpopulation of Ad-EVs that is separate from adiponectin-containing Ad-EVs. In this proposal, we aim to characterize the cargo composition and function of LCN2-containing EVs (LCN2+EVs) released from adipocytes, examining their role in ASPC senescence and adipogenesis during aging. We hypothesize that adipocyte-derived LCN2+EVs possess anti-senescence properties that maintain ASPC health and adipogenic capacity through adipocyte-to-ASPC communication within adipose tissue, and this effect is context-dependent. We propose two aims to characterize the cargo composition of LCN2+EVs released from adipocytes upon metabolic and inflammatory stress, and 2) determine the role of adipocyte-derived LCN2+EVs in ASPC senescence and adipogenesis during aging. The project outcomes are expect to provide new perspectives on the pathogenesis of aging-related metabolic disorders and pave the way for developing new therapeutic strategies targeting adipose tissue function.

NIH Research Projects · FY 2025 · 2026-01

Project Summary/Abstract This project proposes to investigate the underlying neural mechanisms within the nucleus accumbens (NAc) driving cue-elicited reward seeking during aversion-resistant alcohol drinking (ARD), defined as drinking despite negative consequences or “compulsive alcohol drinking”, using optogenetics and simultaneous in-vivo electrophysiology and optogenetics in male and female Long-Evans rats. Environmental reward predicting cues provide a source of motivation for reward-seeking which may be heightened following extended alcohol use, resulting in maladaptive, ARD, a defining feature of alcohol use disorder (AUD). Despite the well- established role of the NAc in mediating cue-elicited reward seeking, motivation, and ARD, the neural signature within the NAc during cue and alcohol access in ARD is not known, which greatly limits prevention and treatment of AUD. The NAc is innervated by glutamatergic projections from the paraventricular nucleus of the thalamus (PVT). This projection is thought to be relevant for processing motivational conflict and preventing unproductive reward seeking, while sparing normal affective behavior. However, the PVT-to-NAc pathway’s role in modulating NAc encoding during ARD or how the activity of PVT-to-NAc neurons alter ARD is not known. Thus, the central hypotheses of this project are 1) the NAc encodes cue and outcome information related to ARD. Specifically, neural activity in the NAc responds to reward (alcohol access) predictive cues and to alcohol rewards in a discriminative stimulus task and that over continued alcohol use, this activity increases in correlation with the development of ARD and 2) the neuronal activity in the NAc is causally related to an excitatory projection from the PVT that acts to prevent ARD initially, but erodes over time resulting in ARD. This project will assess the neural mechanisms of cue-elicited reward seeking and ARD during a discriminative stimulus task using both optogenetic circuit manipulations and simultaneous optogenetics and awake-and- behaving electrophysiology recordings. The training plan for this project is curated in an ideal research environment in the Department of Neuroscience at the University of Minnesota which will provide training in cutting edge neuroscience techniques, professional development, and research ethics that will amass an ideal training experience to facilitate my career as an independent alcohol research scientist. The specific research hypotheses are 1) Optogenetic inhibition of PVT-to-NAc neurons at cue presentation and alcohol reward will cause ARD in otherwise aversion-sensitive rats. 2) Optogenetic excitation of PVT-to-NAc at cue presentation and alcohol reward will reduce ARD, causing aversion-sensitivity, in otherwise ARD rats. 3) Ensembles of neurons within the NAc encode cue and alcohol rewards during ARD. This encoding is facilitated by the PVT- to-NAc projection whereby PVT-to-NAc inhibition will increase NAc encoding of cues and alcohol rewards and PVT-to-NAc excitation will reduce this encoding within the NAc. Completion of the proposed work will elucidate understanding of the neural mechanisms of ARD and will aid in the prevention and treatment of AUD.