Utah State Higher Education System--University Of Utah

NIH Research Projects · FY 2026 · 2026-04

An estimated 6.9 million Americans are currently living with Alzheimer’s dementia, a number expected to reach 12.7 million by 2050. People with dementia, along with others who have decisional limitations, face threats to their legal and autonomy rights to manage health care, residential, and other personal decisions following assessments of decision-making capacity. Capacity refers to a person’s ability to make informed decisions about whether to accept or reject care and is presumed under the law unless a clinician determines otherwise. After a finding of impaired capacity, legal, ethical, and clinical guidance typically directs clinicians to obtain informed consent from a surrogate decision-maker. However, concerns have been raised regarding the effectiveness of surrogate decision-making and its potential for abuse. Additional concerns have been raised about how capacity has been defined and assessed since the 1990s, including the difficulty of making dichotomous judgments about capacity, poor interrater reliability even among experts, and the risk of bias in assessments. At the same time, the legal and policy landscape related to autonomy rights is shifting toward inclusion and supported decision-making rather than exclusion and reliance on surrogate decision-makers. With some exceptions, however, research has focused primarily on the performance of assessment tools and the characterization of capacity deficits in patient populations, rather than on whether approaches to assessing capacity align with evolving legal and policy frameworks for decision-making with people who have decisional impairments. There is limited research on how capacity is assessed in clinical practice overall, and there is little evidence that clinical care has shifted in response to changes in the legal and policy landscape. The specific aims of this project are: (Aim 1) to use qualitative methods to explore experienced clinicians’ current capacity assessment and decision-making practices, experiences, attitudes, and willingness to change across multiple specialties, settings, and geographic regions; and (Aim 2) to develop and pilot test a survey measuring key aspects of capacity assessment and decision-making, enabling a subsequent large-scale quantitative study of clinicians’ practices across diverse specialties and settings. Results from this study have the potential to (1) provide in-depth insight into current capacity assessment and decision-making practices in clinical care that is not currently available; (2) generate empirical evidence regarding how clinicians assess capacity and make decisions for individuals with decisional impairments; and (3) lay the groundwork for future intervention studies aimed at aligning clinical practices with the legal and ethical autonomy rights of people with decisional limitations. Consistent with the goals of R21 grants, this study explores an understudied area, represents an initial step toward a larger research program, and will inform future intervention studies to benefit a population whose fundamental rights currently receive limited protection.

NIH Research Projects · FY 2025 · 2026-04

SUMMARY Investigating Syndecan-1 in Hepcidin Regulation and Iron Metabolism. Iron is an essential trace mineral, involved in many vital cellular and organismal functions. Organismal iron content is controlled by dietary absorption, iron partitioning in erythrocytes, iron recycling by macrophages and iron storage in hepatocytes. The hormone, hepcidin is a master regulator of systemic iron content as it negatively regulates ferroportin, the primary cellular iron exporter mediating iron flow from enterocytes, macrophages and hepatocytes into the circulation. We have shown that heparan sulfate is key component of hepcidin regulation. Inhibition of heparan sulfate biosynthesis in hepatoma cells and in mice reduces baseline, BMP6-stimulated, and IL6-stimulated hepcidin expression and worsens the pathophysiology characteristic of anemia of inflammation. We have now identified syndecan-1 as the primary HSPG regulating liver hepcidin expression based on genetic and pharmacological inactivation of syndecan-1 expression in human and mouse hepatoma cells. Our findings imply that endogenous hepatic syndecan-1 serves as a template to support signaling complexes regulating hepcidin expression and iron metabolism. We propose to extend our studies to human hepatocytes; to determine the mechanism underlying the requirement for Sdc1-mediated regulation of hepcidin expression; and to exploit this information to develop strategies to treat disorders characterized by iron overloading. To achieve these goals, we will (i) Examine the role of syndecan-1 in driving basal and iron- inducible hepcidin expression in human hepatocytes; (ii) Determine the mechanism of syndecan-1 regulation of hepcidin expression and (iii) Evaluate the efficacy of genetic and pharmacological syndecan-1 targeting to correct iron dyshomeostasis in iron-loading disease models. The overarching goal of this proposal is to evaluate the relationship of syndecan-1 structure to iron metabolism, with the long-range goal of defining new potential targets to reduce the risk of iron-loading disorders, such as anemia of inflammation.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Air pollution is a leading health threat, and 131 million people in the US live in a county with unhealthy levels of air pollution. Pregnancy is a period of increased susceptibility to the effects of air pollution, which is a complex mixture of hazardous chemicals. Common pollutants, including fine particulate matter (PM2.5), ozone (O3), nitrogen dioxide (NO2) and excess heat, have each been associated with placental insufficiency. This condition affects half a million pregnancies annually in the US and is a major source of perinatal morbidity and mortality. PM2.5, O3, NO2, and heat may interact to potentially exacerbate risk of placental insufficiency, but most methods lack the flexibility and interpretability to characterize this risk. The goal of this study is to determine whether mixtures of PM2.5, O3, NO2, and heat synergistically increase risk of placental insufficiency during pregnancy. This will be done using an emerging machine learning method for causal inference, which adjusts for confounders and calculates confidence intervals. Residential exposure to ensemble-modeled 1 km2 estimates of these pollutants are available for all 9,447 participants in our existing prospective pregnant cohort. In AIM 1A, we use the causal random forest algorithm to estimate the effects of mixtures exposure on placental insufficiency for each gestational week, accounting for time-to-event structure. Variability in these effects will be characterized in AIM 1B with an uplift model, which will describe effect modification across body mass index, a risk factor for placental insufficiency. Although residential air pollution exposure is commonly used in health models, this exposure assignment contributes to uncertainty in the health effects of air pollution. In AIM 2A we will use a microsimulation activity space model developed at Oak Ridge National Laboratory to create simulated movement patterns for our pregnant cohort. The effect of activity space exposures on risk of placental insufficiency will be compared against the effect of residential exposures in AIM 2B. This study will provide insight into the effects of air pollution mixtures on placental insufficiency, as well as effect modifiers and uncertainty. The results could alter our conclusions about the safety of air pollution during pregnancy. Training will take place at the University of Utah and Oak Ridge National Laboratory under the mentorship of experts in maternal-fetal medicine, atmospheric science, machine learning, computation, and trustworthy data science. Through this training plan, the applicant will develop the foundational skills to prepare for an academic career dedicated to studying maternal air pollution exposure with advanced methods.

NIH Research Projects · FY 2026 · 2026-04

PROJECT ABSTRACT Over the course of aging, the immune system undergoes changes that impair responsiveness to challenges such as of viral infection and cancer, maladies that require a sufficient responsive from cytotoxic CD8 T cells. CD8 T cells reflect the broadly observed weakening of immunity and such, the age-associated sub- optimal activation and dysfunction of CD8 T cells permits the often-lethal persistence of viral infection and cancer. T cell activation, differentiation, and effector function are regulated by T cell receptor (TCR) signaling, which are modulated be by various signaling networks. One notable group of modifiers are transmembrane protein such as CD28 as their extracellular domain can be targeted through monoclonal antibody therapeutics. While the broad networks associated with the TCR and adaptor-modulated signals have been elucidated for some time, there is currently a paucity in identification of novel druggable targets that can alter CD8 T cell outcome. To improve T cell-targeted therapeutics, especially in susceptible populations like the elderly, it is paramount to expand our knowledge regarding TCR-associated signaling networks. We propose to define the novel ligand-independent role for transmembrane costimulatory receptor CD7 in modulating TCR signaling and determine how CD7- mediated signals helps direct CD8 T cell activation, differentiation, and function. Notably CD7 expression declines with age in parallel with diminished immune responsiveness. We hypothesize that the loss of CD7-modulated TCR signaling is a major contributor to the reduced responsiveness to immune challenge observed in aging adults. To address this hypothesis, in Aim I, we will determine how reduced CD7 expression in aged CD8 T cells influences TCR signaling and contributes to hyporesponsiveness. We will first assess the differences in TCR signal initiation and propagation through targeted analysis of critical signaling axes in naturally arising murine CD7+, CD7–, and engineered CD7KO T cells. To complement these findings, we will additionally perform unbiased mass spectrometry- based phosphoproteomic characterization of the kinase signaling that occurs in TCR engagement in the presence and absence of CD7. In Aim II, we will determine the functional consequences of loss of CD7 in anti-viral T cell responses. We will assess differences in activation, differentiation, and function among CD7+, CD7–, or CD7KO CD8 T cells in response to acute LCMV infection by flow cytometry as well as single cell RNA sequencing. Sufficiency for ectopic expression of CD7 to rescue diminished anti-viral responses in naturally occurring CD7– will also be tested. Our long-term goal is to understand how CD7 functions to direct T cell fate function over the course of aging, then utilize these discoveries to help develop novel immunomodulatory therapies. Upon completion, we believe these findings will positively impact the field by expanding our mechanistic understanding of a novel therapeutic target that programs T cell fate and function to reprogram diminished immune responses later in life.

NIH Research Projects · FY 2026 · 2026-04

Abstract RNA-based therapeutics hold great promise for treating diseases, yet their full potential relies on a deep understanding of how gene expression is regulated at the RNA level. RNA is a diverse and dynamic molecule that undergoes various post-transcriptional processing. Among these, chemical modifications widely installed on RNA significantly expand its diversity, and have great potential to regulate gene expression through modulating RNA’s structure, stability, localization, and interactions, among others. Several types of RNA modifications have been extensively studied and found to influence multiple stages of the RNA life cycle and impact numerous physiological pathways. Dysregulations of RNA modification landscape or malfunctions of their associated effector proteins have been linked to various human diseases. However, despite this progress, most RNA modifications remain underexplored, and their impact on RNA function is still largely unknown. Our research program aims to advance the fundamental understanding of RNA modifications by addressing three key challenges. The first critical challenge is identifying proteins that specifically interact with the modified nucleotides. Revealing these “reader” proteins is the key to understanding the functions of the modifications and biological processes regulated by them, potentially providing new insights into disease mechanisms. While “reader” proteins have been identified for a few types of modifications, effector proteins for most other modifications remain largely unknown. We will develop a new approach to systematically identify modification- mediated RNA-protein interactions as they occur in cells. Additionally, precise mapping of modification sites raises fundamental questions regarding the rules governing their selective deposition. While sequence motifs can often be acquired from modification mapping data, RNA structures that contribute to modification selectivity is challenging to determine and remains largely unexplored. We will investigate RNA structural features that support the site-specific deposition of the RNA pseudouridine modification during its biosynthesis. Lastly, probing the dynamic nature of RNA modifications has been a significant challenge, as current methods are inefficient for dissecting their spatial and temporal dynamics in living cells. We are developing genetically encoded biosensors to enable real-time probing of RNA modification dynamics in living cells. We will apply this tool to study RNA modifications in physiological contexts, such as neuronal development. By integrating innovative biochemical, multi-omics, and imaging approaches, our work has the potential to transform the field by providing novel tools that can be applied to a wide range of RNA chemical modifications in various biological systems, while also accelerating our understanding about the functions, deposition mechanisms and dynamic regulations of RNA modifications. Moreover, our research may lead to new insights into disease mechanisms, facilitate the development of diagnostic tools, and reveal new drug targets related to RNA-based gene expression regulation mechanisms.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract The hippocampus was long described by seminal memory models to not be necessary for procedural (motor) learning. In contrast, neuroimaging studies from the last two decades consistently show hippocampal recruitment during motor sequence learning. These conflicting results show that the extent to which the hippocampus contributes to motor learning is unknown. We argue that this knowledge gap is attributed to a lack of causal neuroimaging evidence elucidating the role of the hippocampus in motor memory. Failing to address this critical gap will be a missed opportunity to update the field’s conceptualization of memory system organization and will prevent the development of interventions targeting hippocampal-mediated motor learning and memory processes. The overarching goal of this project is therefore to causally test for the role of the hippocampus in motor memory in young healthy adults using a novel non-invasive experimental intervention (i.e., temporal interference stimulation - TIS). TIS is a potentially groundbreaking intervention that was developed in rodents and recently translated to human research. It enables focused - yet safe and noninvasive - neural stimulation at depth and therefore holds immense promise for the modulation of activity in deep brain regions. In this project, we will evaluate the effect of TIS on human hippocampal responses related to motor learning using functional magnetic resonance imaging (MRI). We will causally test a framework of hippocampal involvement in motor learning that will potentially reconcile previous contradictory findings. This framework proposes that the hippocampus supports abstract representations of motor sequences encompassing their spatio-temporal coordinates that are reactivated offline and can be generalizable across learning episodes. To causally test this framework, we will administer HC or sham TIS during motor learning and examine the effect of stimulation on both the behavioral (Aim 1) and neural (Aim 2) correlates of online and offline learning. Our central hypothesis is HC-TIS will specifically enhance offline motor learning via the modulation of HC responses. This innovative research project will lead to a breakthrough, as it will provide direct causal evidence for a role of the hippocampus in motor learning. It will also significantly impact the biomedical, behavioral and clinical fields because it will validate the use of TIS as a novel and groundbreaking technique to modulate motor learning-related (re)activation patterns in deep brain regions of the human brain. Ultimately, such an approach can be translated to the clinical domain in order to mitigate motor learning-related deficits in specific populations.

NIH Research Projects · FY 2026 · 2026-04

Melanoma accounts for the majority of skin cancer deaths due to its propensity to metastasize to distant organs. Since 2011, several new therapies have been FDA-approved for this disease, but brain metastases are often the cause of treatment failure. Patients with brain metastases have a dismal prognosis and despite current therapies, median overall survival is only ~one year from the time of diagnosis. Given this grim prognosis, more effective treatments are urgently needed for these patients. A major challenge in developing therapies for brain metastases has been the lack of preclinical models that develop metastases similar to the human disease. Using data obtained from human melanomas, which demonstrated increased levels of phosphorylated AKT (P-AKT) and decreased levels of PTEN in brain metastases, we generated a mouse model of melanoma with hyperactivation of AKT1 signaling that develops lung and brain metastases similar to the human disease. We used this model to delineate the mechanisms by which AKT promotes metastasis and evaluated whether this could be exploited therapeutically. Historically, the use of AKT inhibitors in melanoma clinical trials has either had limited efficacy or exhibited significant toxicity. To identify alternative targets, we used a proteomics approach and discovered that melanoma cells expressing activated AKT1 displayed elevated levels of focal adhesion (FA) factors and phosphorylated focal adhesion kinase (P-FAK). FAK is a non-receptor tyrosine kinase that promotes cell motility, invasion, and metastasis, and we observed that pharmacological inhibition of either AKT or FAK in vitro reduced invasion. Therefore, FAK may be a viable alternative therapeutic target that can be combined with standard of care targeted therapy (e.g., BRAF and MEK inhibition) and/or immunotherapy. In support of this, our preliminary data show that the combination of avutometinib, a novel dual RAF/MEK inhibitor, and VS-4718, an ATP-competitive FAK inhibitor, significantly reduces mutant BRAF- driven melanoma cell growth and also inhibits the growth of melanoma patient-derived xenografts (PDX) that are resistant to standard of care dabrafenib and trametinib, which target mutant BRAF and MEK, respectively. Since avutometinib binds to wild-type MEK and locks it in an inactive complex with A, B, and CRAF, we hypothesize that these compounds will be efficacious in other melanoma molecular subtypes with active MAPK signaling including those driven by mutant NRAS or loss of NF1 for which no targeted therapies exist. In addition, active FAK has been reported to promote an immunosuppressive tumor microenvironment (TME), which suggests that inhibition of FAK may improve responses to immunotherapy. The goal of this project is to test the hypothesis that combined RAF, MEK, and FAK inhibition can effectively reduce the growth of melanomas harboring NRASQ61R or loss of NF1 while at the same time stimulating an anti-tumor immune response. Importantly, this project addresses a critical unmet need for a more effective combination regimen in treatment refractory patients with brain metastases or at risk of developing brain metastases.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Effector functions of NK cells are regulated through a balance of activating and inhibitory receptor interactions. NK inhibitory receptors of the Ly49 (mouse) and KIR (human) families have been well characterized with both Ly49C and KIR being dominant players in NK cell inhibition and licensing. Like many of the NK receptors, Ly49C and KIR binds to MHC Class I molecules to inhibit NK cell effector functions such as lysis of tumor target cells. The identified binding site for Ly49C and H-2Kb MHC class I occurs at the base of the MHC class I molecule with no direct contacts to the peptide MHC interface that binds T cell receptors. The binding site for KIR2DL3 for HLA- C1 has also been identified and there are crystal structures for both NK inhibitory receptors. As innate germline encoded receptor, Ly49C and KIR2DL3 binding to MHC class I molecules would be consistent with its function for assessing missing MHC on the target cell surface. However, early research discovered a puzzling level of peptide specificity to the molecules that regulated NK cell cytotoxicity. For Ly49C, a series of follow-up analyses has for the most part been unable to provide a clear explanation for the effects of peptide bound to MHC at a distinctly different site. Even crystallographic studies failed to identify peptide-dependent differences that could alter Ly49C interaction with MHC class I and NK cell biology. Based on our experience in assessing differential T cell receptor interactions with peptide:MHC, we propose to investigate whether differential bond lifetimes, and not affinity, explain the function of Ly49C and KIR inhibitory receptors to control NK cell function. Our preliminary findings have identified dramatic differences in the characteristics of the bond between Ly49C/KIR and their respective peptide:MHC molecules. Our proposal will build on this preliminary data to provide mechanistic clarity on how Ly49C or KIR2DL3 distinguishes different peptide:MHC molecules. These innovative insights into how NK inhibitory receptors can sense different peptides presented embedded in MHC class I would dramatically shift our understanding of their function from a simple on/off switch to a more sophisticated receptor system dependent on cellular forces to regulate NK cell function.

NIH Research Projects · FY 2024 · 2026-03

PROJECT SUMMARY/ABSTRACT Knee osteoarthritis (KOA) is a pervasive and debilitating disease, affecting over 15 million people in the US alone. Symptoms include pain, stiffness, and ultimately loss of joint function. Medical therapies are the mainstay of treatment as surgical joint replacement is typically reserved for advanced disease. Only half of patients treated by medical management with disease not severe enough to warrant surgery experience adequate pain relief, resulting in an estimated population of 3.6 million Americans who are left suffering. Genicular artery embolization (GAE) is a novel, minimally invasive treatment that uses radiologic techniques to catheterize pathologically hyperemic genicular arteries using live X-ray guidance with subsequent occlusion of these vessels using injected microspheres. GAE is performed to inhibit or blunt synovial inflammation thought to be a primary phenotype of KOA. While initial GAE studies have shown to significantly reduce pain associated with KOA, these studies do not account for the greater than 40% placebo effect known to occur with KOA treatments. A sham-controlled study is therefore central to validating the efficacy of this procedure. Prior to performing this pivotal trial, we propose to conduct a pilot sham-controlled GAE study of 40 patients to document feasibility of enrollment and understand the magnitude of effect between these two interventions for future statistical power analysis. We also hope to establish MRI as an objective imaging biomarker for positive remodeling of the knee that occurs after GAE due to decreased synovitis. If the results of this study are positive, we plan to conduct a definitive sham-controlled study to justify the use of GAE in medically refractory KOA and help provide a treatment option to the millions of people with this disease.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract Interval timing, the ability to estimate event durations on the scale of seconds to minutes, is crucial for adaptive behaviors. Prior work investigating the neural basis of interval timing has focused on brain circuits in the basal ganglia and frontal and parietal cortices. However, recent research, including our own, indicates that the entorhinal cortex (EC) also plays a key role in the learning of timing behavior. In our recent work, we have discovered "time cells" in the medial entorhinal cortex (MEC) that fire at fixed intervals, forming sequences crucial for timing behavior. In contrast, lateral entorhinal cortex (LEC) neurons exhibit ramping activity over seconds to minutes as animals forage and/or perform spatial navigation tasks. This suggests distinct neural dynamics in the LEC and MEC for encoding elapsed time, hinting at different roles in timing behavior. A major limitation of this interpretation is that all LEC recordings to date have been from animals not engaged in active timing tasks, making it impossible to determine whether these neural correlates of ramping activity are actually involved in timing behavior or are simply a result of other task demands. To determine the functional roles of LEC and MEC in timing behavior, it is necessary to use tasks with explicit timing demands. Using a novel behavioral paradigm in which mice are trained to report non-matching stimuli durations, combined with neural recording and manipulation techniques, this proposal tests a model in which LEC and MEC function together to encode elapsed time and drive interval timing behavior. Specifically, we hypothesize that LEC encodes event boundaries through brief phasic activity, which then helps align sequential dynamics in MEC to these salient moments. In Aim 1, we will determine if LEC activity is necessary to align MEC time cell sequences and whether LEC activity is essential for learning timing behavior. In Aim 2, we will examine neural dynamics simultaneously in LEC and MEC during timing behavior to see if they function independently or in an integrated manner. Since interval timing is a fundamental component of nearly all major brain functions, understanding the cellular and circuit mechanisms of interval timing will provide a basis for understanding how the brain performs complex functions that depend on encoding time on the scale of seconds to minutes. This work also has the potential to guide the development of therapies targeting specific neural mechanisms in a wide range of diseases and psychiatric disorders that display altered temporal processing, including Alzheimer’s Disease, Parkinson’s Disease, and Schizophrenia.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT This K23 award application is for Dr. Rebecca Kim, a board certified hepatologist with advanced training in clinical research methods and implementation science, who is establishing herself as an early career investigator in health services research. Dr. Kim’s long-term goal is to use social drivers of health (SDoH) screening and interventions to improve outcomes among populations with chronic liver disease (CLD) who face social challenges. This K23 award will provide Dr. Kim with the support necessary to accomplish her Training Aims: 1) acquire training in data science, specifically informatics methods 2) gain expertise in community-engaged methods, 3) apply prior training in implementation science and expand it to health policy, and 4) obtain advanced skills to design and lead pragmatic clinical trials. To achieve these goals, Dr. Kim has assembled an interdisciplinary mentoring team comprised of two co-primary mentors: Dr. Molly Conroy, a clinician researcher with expertise in pragmatic clinical trial design and Dr. Jennifer Price, a physician-scientist and expert in community-based interventions; and two co-mentors: Dr. Andrew Gawron, a health services researcher with expertise in applying informatics methods to clinical research, and Dr. John Inadomi, a prominent researcher and leader whose studies have led to changes in guidelines and health policy. CLD is a leading cause of morbidity and mortality, and disproportionately impacts individuals with low income and education, rural populations, and others with increased social risks. Due to the impact of SDoH, these populations suffer worse health outcomes related to their CLD. Intervening on modifiable SDoH has been shown to improve health in other chronic diseases. Therefore, to improve CLD outcomes, understanding and intervening on SDoH for CLD patients must be prioritized. Dr. Kim’s objective is to use electronic medical record data to define SDoH patterns associated with poor CLD-related outcomes. Then, Dr. Kim plans to use these data, in addition to feedback from CLD patients, to modify and compare interventions to reduce social needs like food insecurity. This study’s Specific Aims are: 1) Train and test a natural language processing model to extract SDoH data on CLD patients to identify SDoH prevalence and patterns associated with specialty liver care access; 2) Modify two established SDoH interventions for use among CLD patients with food insecurity; and 3) Conduct a pilot feasibility study comparing a CLD-specific Food Pharmacy intervention that provides fresh food and health coaching to address food insecurity with and without a clinic-based intervention that connects patients to community resources to address food insecurity and other social needs. Completion of these aims will lead to novel interventions to improve care for CLD patients. Dr. Kim’s new skillsets, combined with the data obtained, will provide the foundation for a future multi-site R01 study to test SDoH interventions among CLD patients on a larger scale.

NIH Research Projects · FY 2026 · 2026-03

PULSE (Program Understanding and Learning through Strategic Evaluation) Project Summary The evaluation of T32 training programs, which represent a cornerstone of biomedical research education in the United States, requires valid, reliable, and precise measurement instruments to assess program outcomes and trainee progress effectively. However, many programs lack validated instruments and systematic approaches for collecting and analyzing these various types of evidence. For this project, we will develop and validate a comprehensive evaluation system for T32 training programs that will be disseminated broadly and made freely accessible. Instruments will include surveys for trainees, mentors, program administrators, and program alumni. Validation will be completed through collaborations with around 50 diverse T32 programs to collect responses from at least 450 trainees, 300 mentors, 100 program administrators, and 150 alumni. While validating instruments, we will develop evidence-based implementation resources that support effective implementation of the evaluation system. These resources will include a Survey Administration Manual that provides protocols for timing, administration procedures and data management, a Program Evaluation Framework Guide that describes structured approaches for evaluation planning, a Data Interpretation Guide that outlines strategies for analyzing results and implementing improvements based on National Implementation Research Network frameworks, and a Technical Manual that documents the psychometric properties of all survey instruments, including detailed information about validation methodology, reliability evidence, and guidelines for appropriate interpretation. Finally, the validated instruments and supporting materials will be made freely available through a dedicated PULSE website. Instruments will be shared in different formats that can be readily used by T32 programs. Shared resources will include customizable presentation templates for use by programs to communicate their evaluation results, and a link to a GitHub repository to download and install custom survey platform software.

NIH Research Projects · FY 2026 · 2026-03

Our research focuses on nicotinic acetylcholine receptors (nAChRs), a diverse family of ligand-gated ion channels known for their role in modulating the release of central nervous system neurotransmitters and their involvement in brain disorders including addiction. Recent studies have highlighted their pivotal roles beyond the central nervous system, influencing significant disease processes such as peripheral neuropathic pain, inflammation, tumorigenesis, and stress-induced pathologies. Over the next five years, our goals include: • Developing a unique library of probes targeted to nAChR subtypes that lack selective ligands. We will accomplish this through structure-activity-relationship studies and mining the plethora of nAChR- targeted peptides refined over millions of years of evolution by carnivorous cone snails. • Exploiting existing ligands as tools to elucidate the structural, functional, and regulatory mechanisms of nAChRs. • Determining the functional role of nAChR subtypes in the pathophysiology of neuropathic pain states. Understanding this mechanism may offer ways to prevent pain development rather than merely masking symptoms and provide an alternative to opioid-based therapies. Our program addresses a critical need by providing potent, precision ligands that selectively target individual nAChRs. By creating highly selective probes and making them widely available to the research community, we will enable researchers to answer fundamental questions. These ligands will not only advance scientific understanding but also drive the development of new therapeutics, potentially serving as lead compounds for innovative treatments. Since specific subtypes of nicotinic receptors are utilized in a broad array of organs and tissues, the wider impact of our work may be felt across multiple fields, accelerating progress in both basic and applied research.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Charcot Marie Tooth disease (CMT) is a progressive neurologic disease that causes a characteristic cavovarus foot deformity associated with pain, decreased ambulation, and escalating disability. CMT primarily presents in children and adolescents, but lack of objective treatment algorithms limits the ability of adolescents with CMT to maintain independence and preserve mobility during their development and transition to adulthood. Variability in treatment planning is caused in part by the wide variability in presentation and poor characterization of foot structure and function across the spectrum of genetic subtypes that prevents objective decision-making about physical therapy, orthotic design, and surgical intervention to maximally protect mobility. While the deformity of CMT is believed to be caused by alignment change, recent research suggests that differences in bony morphology additionally contribute. Further, muscle strength is known to be decreased but muscle morphology has not been studied in CMT and the variability of foot symptoms in CMT is not currently linked to specific genetic subtypes or foot shape. The main objective of this study is to characterize bone morphology across genetic subtype and treatment conditions and to investigate the relationships between bone morphology, muscle morphology, and functional outcomes in adolescents with CMT. In Aim 1, I will utilize statistical shape modeling (SSM) from retrospectively collected weight-bearing computed tomography (WBCT) datasets to evaluate differences in bony morphology and foot alignment between genetic subtypes of CMT. I will further analyze differences in foot structure with use of ankle-foot orthoses or following surgical correction of cavovarus deformity. In Aim 2, I will expand this modeling technique to image data from WBCT and magnetic resonance imaging (MRI) to create combined SSMs of bone and muscle morphology. I will then use these models to analyze differences in morphology relative to genetic subtype and age and to correlate morphology with muscle strength and functional ability. Together, these aims will contribute to a better understanding of CMT-associated foot and ankle deformity to ultimately improve treatment planning for this complex population. My interdisciplinary team of mentors will provide training in medical imaging, computational modeling, and pediatric human-subjects research, complemented by clinical mentorship and shadowing in orthopaedics, neurology, and rheumatology. The training plan was developed in collaboration with my Sponsors to address my primary goals of conducting independent, collaborative human-subjects research; advancing communication and grant-writing skills; learning mentoring and leadership; and honing clinical skills. This training is ideal for a future physician-scientist with the goal of improving patient care in pediatric neuromusculoskeletal medicine.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT The metabolic functions of organelles like mitochondria are central to eukaryotic cells, including humans and apicomplexan parasites that infect human cells. These protozoan microbes diverged from animals and fungi early in cellular evolution and acquired unusual molecular and metabolic adaptations that specialize them to grow inside animal cells. These adaptations include altered mitochondrial functions and acquisition of a non- photosynthetic plastid organelle called the apicoplast. Our long-term goal is to understand the metabolic mechanisms that specialize these early-diverging eukaryotes for intracellular growth and survival. Unraveling these molecular mechanisms will elucidate new molecular paradigms for organelle metabolism, shed light on the metabolic adaptations that distinguish intracellular parasites and humans, and identify pathogen-specific vulnerabilities. In MIRA-funded work, we discovered that Plasmodium parasites, unlike most eukaryotes, have lost mitochondrial fatty acid synthesis (FASII) but retain a divergent acyl carrier protein (mACP) that cannot tether acyl groups. Nevertheless, this unusual mACP is essential for stabilizing the Fe-S cluster assembly complex via a divergent molecular interface that decouples mitochondrial Fe-S and fatty acid metabolism. We also discovered that these organisms retain a second essential ACP protein within the apicoplast (aACP), where it has a critical function independent of the FASII pathway in this organelle and involves an unprecedented association with a key pyruvate kinase enzyme that appears to require the 4-phosphopantetheine group on aACP. Our five-year objective is to unravel the molecular mechanisms of divergent ACP functions at the nexus of mitochondrial and apicoplast metabolism in Plasmodium. In the mitochondrion, we will elucidate a second critical role for mACP in maturation of the Rieske Fe-S protein that has mechanistic features distinct from human mitochondria. We have also identified a parasite-specific LYR-family adapter protein that binds mACP and whose function in mitochondrial metabolism we propose to unravel. In the apicoplast, we will dissect aACP association with pyruvate kinase and test a model that this interaction plays a key regulatory role to sense host nutritional status and couple it to variable pyruvate kinase stability that controls broad apicoplast metabolism. These studies will deeply advance understanding of metabolic mechanisms within the Plasmodium mitochondrion and apicoplast organelles that underpin evolutionary specialization for intracellular parasitism and lay a groundwork to support future treatment strategies.

NIH Research Projects · FY 2026 · 2026-03

Maternal morbidity and mortality is a growing public health crisis in the United States that disproportionately impacts pregnant and postpartum Native Americans (Native mothers) and, subsequently, their children and families. In Utah, the leading causes of maternal death are related to substance use, substance use disorder (SU/SUD), and mental health conditions, with many considered preventable. In response, the University of Utah has partnered with the Confederated Tribes of the Goshute Reservation to develop, implement, and evaluate CEREMONY, a perinatal clinical program for Native mothers with SU/SUD. CEREMONY is rooted in cultural practices and addresses additional structural and social barriers to engagement in care and recovery. Relationships strongly influence health behaviors and outcomes, and this is acutely pertinent for Native Americans whose traditional values and family structures emphasize community healing and kinship. However, there is a critical gap in our understanding of the social networks of Native mothers, which have not been previously well-characterized or studied, and how these networks might be important to recovery from SU/SUD. Longitudinal research on the evolution of social networks in Native mothers navigating SU/SUD could inform the development and guide the improvement of effective interventions. Through this project, I will: 1) characterize the social networks of Native mothers participating in a culturally integrated perinatal SU/SUD program, thereby enhancing my social network analysis skills; 2) assess the relationship between social network characteristics and SU/SUD and perinatal program outcomes, and 3) explore Native mothers’ perceptions of their social networks and how their networks impact their health behaviors and outcomes, further developing my qualitative and mixed methods skills. The completion of the aims outlined in this proposal will both contribute to a critical knowledge gap and provide me with an important research skill set in SU/SUD and maternal health research. Rigorous training in mixed methods design, social network analysis, qualitative methods, and biostatistics will accelerate my transition to a tenure-line independent investigator. My training plan was developed in collaboration with my Co-Sponsors to achieve the following goals: 1) form clinically relevant hypotheses and design rigorous experiments to test them, 2) develop skills in mixed methods design and social network analysis, 3) strengthen my skills in scientific writing and communication, 4) develop and demonstrate mentorship and leadership skills, and 5) maintain and strengthen clinical skills to better understand the clinical significance of my research. My interdisciplinary team of mentors will provide extensive guidance to achieve these goals, thus facilitating my progression into an independent physician-scientist researcher and leader. This fellowship will help me, a rising Eastern Shoshone physician-scientist, develop the skills required to conduct reciprocal, ethical research that honors Tribal sovereignty, knowledge, and traditions as essential tools for addressing health disparities.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Most human viruses originate from recent zoonotic spillover, but the upstream evolutionary processes in animal reservoirs that drive zoonosis-promoting traits remain poorly understood. Our long-term goal is to elucidate the evolutionary forces enabling animal viruses to acquire traits facilitating human spillover and adaptation, with a focus on viral entry receptor usage as a critical determinant of cross-species transmission. Toward this end, this proposal investigates the evolutionary dynamics underlying changes in receptor-binding specificity in beta-coronaviruses (CoVs) linked to past and potential future zoonoses: SARS-CoV-2, MERS- CoV, and HKU1 alongside their bat, rodent, and other animal relatives. Our central model is that long-term evolutionary arms races between viruses and wildlife hosts drive evolvable mechanisms of receptor- engagement promoting subsequent human spillover and adaptation. This model will be examined through three specific aims: (1) Identify mechanisms driving human receptor binding in bat SARS-related CoVs; (2) Dissect the origins and consequences of receptor-switching in bat MERS-related CoVs; and (3) Identify evolutionary origins of and functional constraints imposed by a newly discovered HKU1 CoV receptor. In each aim, we combine phylogenetic surveys across diverse animal CoVs with high-throughput mutagenesis screens to map the evolutionary, genetic, and structural mechanisms driving receptor-use transitions and their downstream evolutionary consequences. These studies will illuminate how host-virus dynamics shape receptor-binding architectures to enable zoonotic potential and post-spillover antigenic evolution. The resulting large-scale genotype-phenotype maps will inform computational models for assessing viral zoonotic risk and guide the design of broad-spectrum antibody and vaccine therapeutics for pandemic preparedness. Taken together, this work advances understanding of mechanisms of viral evolution while providing actionable insights for proactive ecological, diagnostic, and therapeutic interventions.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY This project aims to investigate the interactions and impacts between a depleting antibody (D-aPD-1) that targets programmed death-1-expressing (PD-1+) cells and the autoimmune environment in type 1 diabetes (T1D). PD- 1+ cells are primarily effector lymphocytes that are diabetogenic in T1D.These PD-1+ cells could be a potential target for suppressing autoimmunity in T1D. Initial studies demonstrated that eliminating PD-1+ cells with a PD- 1-specific immunotoxin delayed hyperglycemia onset in NOD mice with late insulitis (L-insulitis). However, immunotoxins are not ideal for chronic disease management, leading to the development of D-aPD-1 as an alternative. Interestingly, when administered to mice with early insulitis (E-insulitis), D-aPD-1 delayed hyperglycemia onset, suggesting a protective effect. However, when given to L-insulitis mice, it unexpectedly accelerated hyperglycemia onset, indicating a pro-autoimmune response. Furthermore, unlike D-aPD-1, PD-1 immunotoxin delayed hyperglycemia onset in L-insulitis mice. These findings align with clinical observations that disease stages and therapeutic agens influences treatment outcomes, highlighting the need to elucidate the mechanisms driving these contrasting responses for better desing and application of T1D therapeutics. To address these questions, this project will investigate the hypothesis that both the immune milieu of T1D and the characteristics of PD-1+ cell-depleting agents play key roles in determining treatment outcomes. Aim 1 will uncover the immune determinants of D-aPD-1’s divergent treatment outcomes in E and L-insulitis by profiling pancreatic islets and systemic immune cells before and after D-aPD-1 treatment. We will use single-cell RNA sequencing (scRNA-seq) and flow cytometry to dentify changes in immune cell populations and pathways associated with pro- and -anti-autoimmune effects. Additionally, strategies to shift L-insulitis responses toward an E-insulitis-like profile will be explored through modulate certain immune cell types. Aim 2 will define the mechanism underlying differential responses to D-aPD-1 and PD-1 immunotoxin by comparing immune cell dynamics and gene expression changes following the treatments. We will identify key cellular mediators responsible for the pro-autoimmune response induced by D-aPD-1, while also investigating whether depleting these responsive cell populations can mitigate its adverse effects. Aim 3 will establish that Fc-free PD-1+ cell depleting agents protect L-insulitis mice from hyperglycemia. Specifically, we will assess whether the Fc-free PD-1+ depleting agents, including albumin-amended antibody-drug conjugate (A3DC) and bispecific killer cell engager (BiKE), can eliminate PD-1+ cells without triggering pro-autoimmune effects. This research could advance targeted PD-1+ cell depletion strategies, leading to safer and more effective antibody-based treatments for T1D. By addressing immune context and therapeutic design, the findings may tailor the design and application of therapeutics for T1D patients at different stages.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT Mutations in telomerase cause bone marrow failure in patients suffering with dyskeratosis congenita and other associated telomere biology disorders. While mutations in these patients are found in different components of telomerase, mutations in genes that regulate the processing of the RNA component of telomerase, TERC, are the most prevalent. Due to a lack of adequate models and intrinsic difficulties in studying human telomerase in physiologically relevant cells, the molecular pathways that control TERC biogenesis and decay during hematopoiesis remain largely unknown. Progress in the field has been hampered by species and even cell-type specific differences in telomerase biology that limit our understanding of the molecular mechanisms leading to the disproportionate role of TERC in hematopoietic failure when compared to other components of telomerase. A better understanding of the molecular regulation of TERC biogenesis and function in hematopoietic cells is essential for development of novel alternatives for patients, which remain without a cure. The focus of this proposal is to use different in vitro and in vivo approaches to decipher molecular pathways controlling TERC biogenesis and decay in blood cells, as well as the function of TERC during erythroid, myeloid and lymphoid development. We have developed unique models, including targeted hematopoietic differentiation of human pluripotent stem cells, transplantation of primary CD34+ human stem cells into sub-lethally irradiated mice, and studies in primary patient samples, that will allow a complete analysis of the pathways regulating TERC decay and function during hematopoietic development. For that, two specific aims are proposed that will both identify novel regulators of TERC decay in blood cells, as well as specific functions of TERC in the hematopoietic system. Aim 1 will determine the role of novel, recently identified 3'- end RNA deadenylases to TERC processing in the blood, and to which extent different RNA deadenylases prevent TERC degradation by the exosome. We will complement these experiments with the identification of the molecular effectors of a novel route for TERC decay, triggered by differential TERC capping on its 5'- end, and mediated by trafficking to the cytoplasm. We will investigate if modulation of these different pathways can rescue hematopoietic development in telomerase mutants. Aim 2 will investigate novel functions of TERC outside telomerase that can explain the disproportionate role that mutations that affect TERC levels show in bone marrow failure. We have created unique cellular systems where we can uncouple TERC expression from telomere length, and will utilize them during hematopoietic differentiation to study direct functions of TERC on DNA damage and regulation of hematopoietic gene expression programs. These studies will determine the molecular mechanisms controlling TERC decay and function in hematopoietic cells. Our unique cellular tools, combined with our expertise in telomerase, RNA decay, and stem cell biology puts us in an ideal position to make a significant impact in this field.

NIH Research Projects · FY 2026 · 2026-02

Falls are the leading cause of injury in older adults, leading to costly injury, high stress on the healthcare system, reduced quality of life and fatality. With a rapidly aging population, fall rates are growing exponentially. Thus, there is a critical need for high-efficacy fall prevention interventions. Among various strategies, volitional stepping-based exercise interventions are promising due to their low-cost, accessibility, and fall rate reduction. Despite the demonstrated benefits of volitional step training in reducing fall risk and improving cognitive and motor functions, not all older adults benefit uniformly. This variability is linked to heterogeneity in the age-ability and task complexity of these training paradigms. Regardless of an individual’s age or the complexity of the stepping task, effective stepping relies on cognitive-motor processes. Currently, there is a critical gap in the knowledge of these processes in the context of effective stepping. This is limiting our ability to optimize fall prevention interventions to greater efficacy rates. Today, this gap can be overcome with innovations in mobile electroencephalography (EEG). Thus, this study will quantify the cognitive-motor processes of effective stepping across age groups (younger and older adults) and task complexity (simple and complex cues). This knowledge will provide essential data to guide the optimization of volitional step training design parameters, making them population-specific and more effective in reducing fall rates. We will recruit 30 healthy younger and 30 healthy older adults to complete a clinically validated step training paradigm. This will involve volitional stepping in response to visual cues while standing in place, with electrocortical activity recorded via high- density mobile EEG and stepping performance monitored via motion capture. Our first aim is to characterize the electrocortical activity of effective stepping by age group and task complexity. This will provide the fundamental knowledge to aid the optimization of intervention design parameters to elicit necessary cognitive- motor processes for training benefits across diverse age populations. Our second aim is to discover new biomarkers for fall prevention in older adults via cognitive-motor processes of effective stepping. Identifying individual cognitive-motor processes of effective stepping has the potential to provide objective biomarkers of fall risk and forecast individual benefits from step training interventions. Success in these aims will lead to transformative knowledge for fall prevention research and clinical practices for older adults.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT Members of the IL-17 family (IL-17A-F) and its cognate receptors (IL-17RA-RE) mediate physiologically important immune responses, however, they can also drive inflammatory diseases, such as allergic asthma in case of IL-25. Despite its emerging clinical need, no drugs against IL-25 or its signaling pathway are currently clinically available. Our long-term goal is to identify small molecule inhibitors of the IL-25 pathway to probe and prevent IL-25-mediated diseases. The goal of this exploratory R21 application is to establish and validate a high throughput screening (HTS) system as well as relevant orthogonal assays that will enable successful IL-25 small molecule drug discovery using HTS-based hit identification and a defined hit advancement strategy. One major barrier for small molecule drug (SMD) development targeting IL-25 (and other members of the IL-17 family) is that the defined part of the signaling cascade relies on a series of hierarchically acting protein interactions that are inherently difficult for targeted drug development: IL-25 initiates signaling via binding and dimerization of IL-17 receptor RA- and RB-chains, which leads to recruitment/ dimerization of the common IL- 17R adaptor ACT1, followed by recruitment/ dimerization of TRAF6. IL-25 and IL-17RA/RB define the IL-25- specific signaling pathway, while ACT1 defines the common IL-17R family pathway. TRAF6, in turn, defines the boundary between various IL-17R family members and common, IL-17R-non-specific downstream pathways. Thus, signaling events up-stream of ACT1 represent a ‘drug target window’ that defines IL-25-specific inhibitors. Signaling events between ACT1 and TRAF6 represent a ‘drug target window’ that defines common inhibitors of the IL-17 family, including IL-17A as major driver of Th17 immune responses and inflammatory diseases. To overcome limitations related to targeted drug development, we developed a unique, cellular high throughput screening (HTS) platform that retains the advantages of phenotypic screening, i.e. the testing of complex responses in the natural environment of cells and, at the same time, eliminates non-specific compounds, thereby mitigating the major disadvantage of phenotypic screening. In this application, we propose (i) to validate already established reporter cell lines on robots in HTS/ 386 well- format and perform a small 3.6k pilot screen to test and calibrate our screening tool and (ii) to establish and validate a set of orthogonal assays that are suitable to advance IL-25-inhibitory compounds in a full-scale drug discovery campaign. We expect that establishment of these key components of HTS-based drug discovery (along with medicinal chemistry, pharmacology and clinical support by collaborators) will put us in an ideal position for future work to (i) identify specific IL-25-inhibitory small molecule compounds and (ii) develop them towards lead compounds with suitable drug-like properties to be used as probes and starting point for future drug development.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY / ABSTRACT This MPI R21 proposal directly addresses the objectives of the INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project, emphasizing the creation of innovative biological resources to advance Down syndrome (DS) research. DS is linked to widely dysregulated immune responses, including susceptibility to autoimmunity and infections, but most current research has focused on B cell hyperactivity and interferon-driven pathways, leaving the role of inadequate thymic selection—marked by reduced thymic output and premature thymic involution—largely uncharacterized. Our proposal posits that a fundamental gap in DS research is the absence of a comprehensive understanding of how these thymic defects drive peripheral immune dysfunction. To address this, we will build a well-annotated, deeply profiled biorepository of thymic samples from individuals with trisomy 21 and age-matched disomic controls, enabling a systematic examination of thymic education processes that may underlie the broader immunopathology seen in DS. Although murine models of DS have offered important insights into the genetics and pathology of trisomy 21, they are inherently limited by the fact that the extra copy of human chromosome 21 cannot be fully and precisely replicated in mice. Thymic development, in particular, depends heavily on self-antigens specific to each species, as immature thymocytes are “educated” through interactions with the host’s unique set of self-genes. By establishing a biorepository of human DS thymic tissue, we will circumvent these issues, enabling precise investigations into how an extra copy of chromosome 21 disrupts thymic selection and predisposes individuals with DS to immune dysfunction. To this end, we propose the following two goals. First, through a close collaboration with the Primary Children’s Hospital in Salt Lake City, we will create a comprehensive repository of thymic samples from infants with trisomy 21 and age-matched controls. All samples will undergo HLA genotyping, biological sex determination, and a thorough phenotypic analysis of both T-lineage and non–T- lineage cells, evaluating each thymocyte subset’s responsiveness to T cell receptor (TCR) stimuli at critical developmental checkpoints. Second, we will sequence the TCR repertoire at each developmental stage— evaluating both diversity and amino acid composition—and then compare these results with our existing in- house TCR datasets from individuals with autoimmune diseases and carriers of polymorphisms in genes critical for TCR repertoire formation. This approach will help us pinpoint meaningful similarities or differences among these groups. By filling critical knowledge gaps related to T-lineage ontogeny, our findings may reveal whether this underexplored aspect of thymic development in DS contributes to the documented immune dysfunction.

NIH Research Projects · FY 2025 · 2026-02

Project Summary It has been well established that small non-coding RNAs, such as microRNA (miRNA) and small interfering RNA (siRNA), act as potent regulators in numerous biological processes. MiRNA, for instance, modulate gene expression by targeting mRNA based on sequence complementary via the RNA Induced Silencing Complex (RISC). This allows miRNA to regulate key cellular events including cell differentiation, proliferation, and apoptosis. Consequently, when expression levels of miRNAs are dysregulated or alterations to the miRNA sequence occur, individuals can become more susceptible to the development of a variety of disease types, such as cancer, immune-related and neurodegenerative diseases. In response, researchers have been using a combination of techniques to identify the mechanism(s) behind points of dysregulation to guide future RNA- targeted therapeutics. Towards this goal, extensive studies have been carried out to identify and characterize the proteins involved in the miRNA biogenesis pathway, which include the endoribonuclease III protein Dicer. Dicer performs the final cleavage reaction to remove the hairpin loop region of precursor miRNA (pre-miRNA) to produce mature miRNA strands. While in humans, Dicer’s role is centralized around miRNA maturation and regulation, exploration into Dicer proteins from other species has revealed a highly dynamic and multifunctional activity, which includes the cleavage of siRNAs, a key component in antiviral defense. Differences in substrate specify are seemingly dependent on the ATP hydrolysis activity of Dicer’s N-terminal helicase domain. To further investigate this functionality and determine its connection to substrate specificity, structural and biochemical studies have been implemented to uncover the mechanisms behind ATP-independent vs ATP-dependent helicase activity. However, these approaches have been unable to capture the conformational heterogeneity associated with this functionality. Therefore, this proposal puts forth a new approach that combines results from a series of molecular dynamics simulations used to investigate Dicer’s flexibility (Aim 1) with published experimental observations from biochemical, kinetic, and structural studies to create data-informed predictive simulations (Aim 2). These predictive simulations will be used to investigate the central hypothesis of this proposal which is that the overall flexibility of Dicer’s helicase domain is dependent on whether it can hydrolyze ATP, and that in the absence of this activity, the helicase domain is unable to maintain one stable structure and samples a variety of conformational states. Overall, with the extensive resources offered by the University of Utah and expert guidance provided to me by my mentors, I am confident that this proposal will not only generate the first comprehensive integrative dynamic model of Dicer function, but also introduce a novel workflow to explore hypotheses and predict related functional outcomes of other disease-associated RNA interactions.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT Increased Treg T cell receptor (TCR) signaling is correlated with increased Foxp3+ regulatory T cell (Treg) function in organ specific autoimmunity. In the context of autoimmunity, both Tregs and autoimmune T cells target similar self-antigens, potentially increasing competition for TCR ligands. We propose that Tregs possess cell-intrinsic features that can increase their competition for antigen. Our preliminary data suggest that Tregs have higher levels of cholesterol within their cell membrane compared to conventional effector T cells, which correlate with tetramer binding, TCR signaling, and might increase relative Treg antigenic sensitivity and competition for antigen in vivo. It is well established that Tregs exhibit distinct metabolic profiles skewed towards fatty acid oxidation. Our intriguing new observations suggest that cholesterol metabolism impacts plasma membrane composition and TCR activation in Tregs. Furthermore, our data suggest that lipid metabolism could be manipulated to improve Treg function. This proposal will test the hypothesis that cholesterol metabolism is regulated by the transcription factor Foxp3 and can be increased to boost regulatory T cell function. We will begin addressing this hypothesis by pursuing two specific aims: 1) Test the specific role of recently identified regulator of cholesterol metabolism Spring1 in Treg function, and 2) Assess the impact of exogenous cholesterol uptake on Treg suppressive function. The objective of this proposal is to establish whether we can manipulate Treg function through cholesterol metabolism. The proposed research is significant, because it will determine Treg- specific regulation of cholesterol metabolism and its effect on Treg function in autoimmune and inflammatory models with implications for cancer, metabolic and heart disease.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Macrophages play paradoxical roles in cancer: They can be tumoricidal, but in many cancers, macrophages promote metastasis. There has been growing evidence that macrophages can modulate cell behavior via unconventional cell contact-mediated communication in development and homeostasis. We have recently extended these paradigms by discovering that macrophages laterally transfer mitochondria to breast cancer cells, promoting cancer cell proliferation. Mitochondria are dynamic organelles that perform a variety of essential cellular functions. Mitochondria have been shown to transfer to tumor cells in vivo, restoring their respiration and ability to form tumors. While these elegant “proof of principle” studies demonstrated that mitochondrial lateral transfer can occur in the tumor microenvironment, it was unclear how a relatively small population of exogenous mitochondria changes the behavior of the recipient cancer cell, particularly if the recipient cancer cell already has a functional endogenous mitochondrial network. In now recently published work, we found that transferred macrophage mitochondria are dysfunctional and accumulate reactive oxygen species. Accumulated reactive oxygen species at transferred mitochondria then promotes breast cancer cell proliferation in an ERK-dependent manner. These results suggest that transferred mitochondria do not promote cancer cell proliferation via restoration of bioenergetics. Rather, transferred mitochondria act as a signaling source, promoting cancer cell behaviors. These unexpected findings led us to ask whether this form of communication is specific to macrophages and cancer cells, or whether mitochondrial transfer between other cells in the tumor environment use this process to regulate proliferation. This question forms the basis of the extension period of the R37 award. Our preliminary results suggest that mitochondrial transfer between cancer cells may use different strategies, and thus, in updated aim 1, we propose to determine the mechanism by which mitochondrial transfer between cancer cells promotes cancer cell proliferation. We will also determine whether mitochondrial transfer from highly metastatic cancer cells promote metastatic behaviors of recipient weakly metastatic cells in vitro and in vivo. Furthermore, in updated aim 2, we have excitingly built a new tool to detect mitochondrial transfer with higher sensitivity, allowing us to delve into new mechanisms underlying mitochondrial transfer. Taken together, these experiments will reveal how mitochondrial transfer instructs breast cancer cells to become more robust and metastatic. Our goals are to define how immune cells function in the tumor microenvironment, and to provide a basis for developing future immunotherapies that limit metastasis.