Utah State Higher Education System--University Of Utah

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT Among the 800,000 individuals who sustain a stroke annually in the United States, up to 65% continue to expe- rience chronic moderate-to-severe impairments in one upper extremity (UE), limiting their ability to perform daily tasks. These impairments, often characterized by limited arm and hand movements, prevent the use of the paretic UE in functional tasks. Functional electrical stimulation (FES)-assisted task-specific practice is the only viable option to promote use-dependent plasticity and improve UE impairment and function. However, the ben- efits are only modest and transient, indicating that FES-assisted task-specific practice alone is insufficient in improving UE impairment and function in this more impaired population. Non-invasive neuromodulatory tech- niques [e.g., repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS)] have also been applied to cortical motor areas to augment the effects of FES-assisted task-specific practice. However, there is limited evidence supporting the effectiveness of these approaches. Thus, there is a critical need for new evidence-based multimodal interventions for moderate to severely impaired individuals who con- stitute the largest cohort of stroke survivors. Transcranial random noise stimulation (tRNS) is a new type of non- invasive brain stimulation that can boost the weak neural signals via random currents applied to the lesioned hemisphere. tRNS is more effective in modulating brain excitability than other conventional neuromodulatory techniques. When delivered during FES-assisted task-specific practice, tRNS can enhance the excitability of the surviving neural pathways to promote use-dependent plasticity and improve UE impairment and function. Indeed, our preliminary data show a profound increase in brain excitability and significant improvements in UE impair- ment and function after 6-weeks of tRNS and FES-assisted task-specific practice. Building on our preliminary data, the specific objective of this proposal is to conduct a blinded, sham-controlled, randomized clinical trial to determine the efficacy of tRNS and FES-assisted task-specific practice to improve UE impairment and function after moderate-to-severe stroke. We will also comprehensively evaluate the effect of this intervention on cortico- spinal excitability by examining the changes at multiple anatomical levels (i.e., cortical, cervicomedullary, and spinal). Our central hypothesis is that tRNS delivered during FES-assisted task-specific practice will augment the effectiveness of FES-assisted task-specific practice. The specific aims of the study are: 1) Determine the effect of tRNS and FES-assisted task-specific practice on UE impairment, 2) Determine the effect of tRNS and FES-assisted task-specific practice on UE function, and 3) Determine the effect of tRNS and FES-assisted task- specific practice on corticospinal excitability. The expected outcomes of this project include a novel multimodal therapeutic paradigm for the largest cohort of stroke survivors who currently do not have any effective interven- tions, which directly aligns with the research priority of the NIH NCMRR to study multimodal approaches to promote plasticity and sensorimotor function.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Aging is the strongest risk factor for cancer, yet the mechanisms linking aging to tumor development remain poorly defined. Our work focuses on adrenocortical carcinoma (ACC), a rare but aggressive cancer with peak incidence after age 50 and limited treatment options. We developed the first ACC mouse model that mirrors the age dependence of the human disease and found that age-associated tumors retain long-lived senescent adrenal cortex cells. Senescence, a hallmark of aging, was traditionally viewed as tumor-suppressive due to its prolonged growth arrest. However, recent evidence indicates that some senescent cells can become protumorigenic, particularly when they persist long-term. This has important clinical implications given the widespread use of conventional chemotherapy agents that trigger therapy-induced senescence (TIS), including in ACC where the standard-of-care uses etoposide, doxorubicin, and cisplatin (EDP). Consequently, TIS may create reservoirs of tumor cells primed for recurrent growth, leading to worse patient outcomes long-term. To address this clinical problem, senolytic drugs that kill senescent cells could be repurposed for cancer therapy, but this has never been tested in ACC. Our overall objective is to determine how long-term senescent cells that accumulate with age promote adrenal tumor initiation and progression, and to develop senolytic strategies to kill senescent ACC cells following TIS. Our central hypothesis is that persistent senescent cells become protumorigenic through an age-dependent increase in the dosage of Wnt signaling, which is targetable using senolytics. In Aim 1, we will use genetic and pharmacological tools to selectively ablate senescent cells at different age-dependent stages and measure ACC tumorigenesis. We will then test whether hyperactivation of Wnt signaling facilitates senescence release and tumorigenesis. In parallel, we will use spatial transcriptomics to develop a high-resolution atlas of cellular senescence and the age-dependent changes in senescent cell states that enhance Wnt activation. In Aim 2, we will therapeutically target persistent senescent cells after TIS using senolytics. For these studies, we developed new ACC cell lines containing a live senescence reporter, which we will use to test the sensitivity and specificity of both novel and established senolytic strategies. We will then validate our results using human ACC models and an orthotopic tumor transplant model of primary ACC tumor growth and recurrence. Animal models are essential for this project because they uniquely enable the study of systemic, age-dependent physiological changes and immune interactions that regulate senescent cell behavior and tumorigenesis. To extend our findings to patients, we will use primary human ACC tumor samples to measure TIS clinically and identify predictors of high senescent burden where a senolytic has the highest potential benefit. Together, these studies will define how persistent senescence contributes to adrenal cancer, providing the preclinical rationale for senolytic therapies in ACC and helping to inform other age-related cancers.

NIH Research Projects · FY 2026 · 2026-06

SUMMARY Colorectal cancer (CRC) is the second leading cause of cancer death in the United States, with incidence rising alarmingly among younger adults and non-white populations. Chronic inflammation, driven in part by poor diet quality, is a key modifiable risk factor for CRC. However, current clinical tools lack the precision to identify individuals at elevated CRC risk due to pro-inflammatory diets. There is an urgent need for objective, scalable biomarkers that can quantify dietary inflammation and guide personalized prevention strategies. We developed the reversed Empirical Dietary Inflammatory Pattern (rEDIP) biomarker score—a novel, poly- metabolite blood-based biomarker that quantifies the inflammatory potential of diet. Derived from nutritional metabolomics and validated in over 20,000 adults across 12 global cohorts, the rEDIP score reflects habitual dietary intake and predicts CRC risk independent of traditional risk factors. This biomarker captures the synergistic effects of food combinations on systemic inflammation, offering a more precise and culturally adaptable measure than conventional dietary indices. This R01 application proposes to translate the rEDIP biomarker score into clinical practice through three specific aims. Our central hypothesis is that the rEDIP biomarker score is a robust indicator of dietary inflammation that is responsive to diet intervention. Aim 1 will evaluate the association between the rEDIP score and systemic and colon tissue-specific inflammation in 200 adults undergoing colonoscopy, and test for differences by colorectal adenoma severity. Aim 2 will test the efficacy of a 12-week randomized controlled trial of a precision nutrition intervention guided by the rEDIP score in 126 adults with high-risk adenomas, assessing changes in the biomarker and systemic inflammation. Aim 3 will externally validate the rEDIP score using already generated metabolomic data from a tightly controlled 14-day feeding study of habitual diet in 153 adults. This study will establish the rEDIP biomarker score as a clinically actionable tool for identifying individuals at elevated CRC risk due to diet-related inflammation. By integrating this biomarker into gastroenterology workflows and delivering personalized dietary interventions, we aim to intercept inflammation early, reduce CRC incidence, and advance precision nutrition in cancer prevention.

NIH Research Projects · FY 2026 · 2026-06

PROJECT ABSTRACT Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma, providing durable, curative responses to a proportion of patients with advanced and metastatic disease. Nonetheless, there remains several obstacles that impact the clinical utility of ICI treatment, with most significantly a lack of understanding of which patients are at risk for treatment resistance and/or immune-mediated side effects. Over half of all patients receiving ICIs display resistance, and biomarkers to predict benefit from ICI treatment remain limited. To combat therapeutic resistance, combination approaches that target multiple immunoregulatory markers have been clinically approved. While combinations improve treatment efficacy, they also precipitate an increase in the frequency of severe side effects, known as immune-related adverse events (irAEs). These irAEs can impact nearly every organ system and lead to significant morbidity, discontinuation of cancer-curing treatments, and even death. Therapies used to combat irAEs, such as corticosteroids and cytokine inhibitors, have been increasingly suggested to limit the efficacy of ICI treatment, highlighting the need for irAE-specific options that uncouple side effects from anti-tumor immunity to improve treatment outcomes for patients with melanoma. One major limitation for understanding optimal treatment combinations is the lack of models that assess both therapeutic safety and efficacy in the same system. This is due to many preclinical melanoma models being developed in autoimmune-resistant or immunodeficient mice that do not develop irAEs following exposure to ICIs, or other immune-based and targeted treatments. Additionally, the ability to identify systemic interactions between tumor-directed and host immunity cannot be assessed using current in vitro and ex vivo approaches, due to the heterogeneity and inaccessibility of irAE-affected tissue. We will engineer syngeneic models of melanoma, initiated by oncogenic drivers, in autoimmune-prone non-obese diabetic (NOD) mice. A series of NOD melanoma cell lines will be evaluated for their genetic, transcriptional, and immune phenotypes to select for heterogeneity in melanoma models, consistent with diverse clinical features. Using these models, we will assess the efficacy and safety of ICI treatments, either with or without targeted therapies to the oncogenic drivers employed for melanomagenesis (namely mutant Braf and Nras) and will define novel anti-irAE treatments that do not compromise ICI therapeutic efficacy. Together, this first-in-class model system of melanoma will enhance our ability to understand and treat complex clinical problems, such as treatment resistance and toxicity, and lead to improved therapeutic strategies with enhanced safety and efficacy for patients with melanoma. By advancing mammalian mouse models through combining the etiology of melanomagenesis alongside diverse host immune responses that reflect clinical conditions, such as irAE susceptibility, we will enhance the translational applicability of preclinical systems to overcome the bottleneck in therapeutic innovation.

NIH Research Projects · FY 2026 · 2026-06

Cancer immunotherapy has become a pillar of cancer treatment, but fails to deliver benefit for many patients. There is thus a critical need to identify and understand the mechanisms that limit the efficacy of cancer immunotherapy, and how they can be overcome. Our lab previously set out to identify mechanisms by which tumor cells can impede the anti-tumor T cell response, as T cells are critical for the success of nearly all immunotherapy strategies. We identified tumor-produced CX3CL1 as one such mechanism, and showed it has a “dominant-negative” effect on tumor immunity: tumors comprised of as little as 10% CX3CL1high tumor cells exhibit a blunted T cell response. We further carried out a pan-cancer analysis of CX3CL1 across 12 human cancer types and found that, in patients, high CX3CL1 is associated with immune microenvironments that are low in T cells and rich in macrophages; features that also correlate with poor responses to ICIs. Mechanistically, we showed that ablation of CX3CL1 in tumor cells resulted in a tumor microenvironment (TME) that is rewired to be “hotter”, characterized by more T cells and fewer CD206high macrophages. Interestingly, dendritic cell (DC) numbers are also increased in both tumors and tumor-draining lymph nodes of CX3CL1KO tumors. Further, knock-out of CX3CL1 sensitizes tumors to ICI. We have additionally found, and recently published, that CX3CL1high tumor cells have a particularly pronounced effect on the TME in their immediate vicinity, creating spatial niches of immunosuppression within the TME. These CX3CL1high regions are characterized by increased CD206high macrophages, fewer T cells and diminished T cell functional activity, and we hypothesize these niches underlie the impaired anti-tumor immunity we observe even when CX3CL1 is heterogeneously expressed. In this proposal, we will use genetic tools, a novel series CX3CL1KO cell lines established by our lab, and spatial analysis of human tumors to dissect the local and systemic effects of CX3CL1 on the TME and on anti-tumor immune control of tumors. Aim 1 will interrogate the mechanisms by which a CX3CL1high TME impairs DC infiltration and activity in tumors, combining functional assays of DCs with genetic tools to define the cell types and signaling axes responsible for impairing DCs in CX3CL1high tumors. Aim 2 will interrogate how CX3CL1high tumor cells create local suppressive niches, using a combination of our novel mouse model of tumor heterogeneity and spatial transcriptomics analysis of human bladder cancer and melanoma samples. Aim 3 will test the ability of CX3CR1:CX3CL1 therapeutic blockade to remodel the TME of CX3CL1high tumors as well as of heterogenous CX3CL1high:CX3CL1low tumors, and to sensitize these tumors to ICI. Together, these experiments will provide critical insights into how CX3CL1 impairs anti-tumor immunity, providing both a foundational for future work targeting the CX3CR1:CX3CL1 axis therapeutically as well as a detailed understanding of how local CX3CL1high tumor regions create immunosuppressive niches that impact systemic anti-tumor immune control.

NIH Research Projects · FY 2026 · 2026-06

SUMMARY. Regulating the timing of meals and snacks to re-align the body’s circadian clock and improve metabolic health is emerging as a promising approach for cancer prevention in early animal and small clinical studies. Yet, a major barrier to studying meal timing and cancer is that large population studies rarely measure meal timing, which makes it impossible to conduct epidemiological studies of meal timing and cancer risk on a large-scale and across individuals with different biological and environmental characteristics and varied meal timing practices. Although obesity and its related metabolic dysregulation are important risk factors for at least 13 cancer types, weight management is notoriously difficult in the long-term. Behavioral strategies are needed that can improve metabolic risk factors for cancer but that do not necessarily rely on weight loss. Herein, we propose to discover and then externally validate novel objective biomarkers of meal timing practices, then test their relationship with incidence of breast (BC), endometrial (EC), and colorectal (CRC) cancers, three of the most prevalent obesity-linked cancers. Our central hypothesis is that meal timing is associated with perturbations in blood metabolomic profile, and with obesity-related cancer incidence in free-living humans. We will test our hypothesis with unique data from large-scale cohorts with validated measures of meal timing and sleep and longitudinal metabolomics data measured on the same metabolomics platform to facilitate data harmonization. In Aim 1, we will Identify biomarkers of meal timing patterns using a discovery and external validation design in the Cancer Prevention Study 3 Diet Assessment Sub-study (DAS) (n=750) and the Interactive Diet and Activity Tracking in AARP (IDATA) Study (n=718) and measure their association with risk of obesity-related cancer in the Cancer Prevention Study 2 (CPS-2, 782 BC matched sets; 517 CRC matched sets with 16-year follow-up time) and CPS-3 cohorts (1695 BC patients, 1983 controls, 3-year follow-up). In Aim 2, we will examine whether there is large-scale, real-world evidence that meal timing patterns are associated with obesity-related cancer risk among 185,000 US adults in the CPS-3 cohort. The proposed study will answer critical, outstanding questions about which meal timing practices are associated with cancer- relevant metabolic factors and risk of obesity-related cancers in a real-world scenario and identify objective biomarkers of meal timing behaviors that will facilitate large-scale investigations of meal timing and cancer risk at the population level. These meal timing biomarkers could also be used to assess response to meal timing interventions in clinical studies. Following successful completion of this project, we plan to apply the resulting biomarker profiles to study meal timing and cancer risk across international cohorts in the Consortium of Metabolomics Studies (COMETS). Epidemiological research stemming from our study findings will be vitally important prior to issuing public health guidance on meal timing for cancer prevention.

NIH Research Projects · FY 2026 · 2026-06

ABSTRACT (PAYNE) Breast cancer is the second most common cancer among American women, and most of these women (~64%) will be diagnosed at an early stage when the cancer is still localized to the breast. Surgery is often the treatment of choice for most early-stage breast cancer patients, as it is typically a curative treatment option when combined with radiation, chemotherapy or hormone therapy as indicated by the tumor subtype. Treatment selection by the patient and clinical team encompasses many factors, including surgical side effects such as aesthetic outcomes and pain. There remains a need for more conservative, more efficacious, and less invasive breast cancer treatment options for early-stage breast cancer patients. This proposal seeks to address these issues through the development of a magnetic resonance guided focused ultrasound (MRgFUS) system that can non-invasively treat breast cancer through both thermally ablative and non-ablative techniques. This proposed system re-envisions the potential of breast MRI and MRgFUS with the goal of achieving efficacious thermal ablation under diagnostic-quality MRI, while prioritizing the patient’s experience and comfort. The goal of construction and validation of a patient-specific, next generation breast MRgFUS system will be achieved in three specific aims. Aim 1: Construct a patient-specific next generation breast MRgFUS system that enables an individualized experience, with the required signal-to-noise ratio to support high accuracy and precision MR temperature imaging and MRgFUS thermal ablation treatment monitoring. Aim 2: Optimize and validate a MRgFUS hyperthermia controller specifically for breast cancer patients. Aim 3: Evaluate imaging and treatment of the new breast MRgFUS system in a treat and resect feasibility clinical trial where both ablative and non-ablative conditions will be evaluated. The successful achievement of the defined aims will result in a breast MRgFUS system that can deliver highly controlled ablative and non-ablative thermal exposures and has undergone the validation required for future phase II clinical trials.

NIH Research Projects · FY 2026 · 2026-06

Project Abstract Alternative promoters are increasingly recognized as critical regulators in cancer, enabling the expression of isoforms with distinct functions, often supporting oncogenic activity. Beyond initiating transcription, promoters have been shown to serve as cis-regulatory elements, enhancing or compensating for the expression of neighboring genes. 3D genomics assays show that alternative promoters of the same gene interact with each other at the chromatin level. However, it is unknown whether this chromatin interaction plays a functional cis-regulatory role in the transcriptional expression of the host gene. Our analysis of TCGA and ENCODE data shows that minor alternative promoters exhibit enhancer-like histone modification signatures and cancer-specific chromatin accessibility. Preliminary studies further reveal that minor alternative promoters of oncogenes, such as EGFR, interact with the major alternative promoter, and show both enhancer and compensation activity in a cancer-type specific manner, indicating their cis-regulatory potential. However, the prevalence and mechanism of cis-regulatory alternative promoters in cancer remains largely unexplored. Our hypothesis is that minor alternative promoters serve as cis-regulatory elements that can enhance or compensate for major promoters, representing a common mechanism to ensure robust expression of cancer-related genes. Aim 1 will assess the enhancer role of minor alternative promoters for cancer-related genes. Focusing on genes that harbor enhancer-like minor promoters, we will use CRISPR interference (CRISPRi) and CRISPR activation to manipulate minor promoter activity and assess the impact on major isoform expression. We will also evaluate the role of cancer-type specific transcriptional master regulators in governing this enhancer activity and further determine the functional relevance of this enhancer activity on cancer cell fitness. Aim 2 will evaluate the compensatory role of minor promoters by repressing the major promoter with CRISPRi and assessing minor isoform expression. We will use HiChIP assays to assess whether shifts in enhancer interactions contribute mechanistically to the compensation. Currently the field lacks understanding in how alternative promoters function as cis-regulatory elements, limiting our ability to comprehend how cancer cells exploit alternative promoters to promote oncogenic activity in cancer cells. These studies will define a mechanism by which alternative promoters regulate oncogenic gene expression through enhancer-like and compensatory functions. Our findings will generate a resource of cancer-type specific genes with alternative promoters that exhibit cis-regulatory functions, offering potential targets for cancer therapy and providing a new approach to modulate oncogene expression in cancer cells.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY During sickness, the immune system and central nervous system coordinate to generate physical and behavioral changes, such as lethargy, anorexia, anhedonia, and social withdrawal, that can vary significantly in severity between individuals. While these symptoms help aid in sickness recovery, severe responses can be harmful and possibly life-threatening. What drives this symptomatic variation in sickness manifestation is still unclear, however, external factors such as social support may be a contributing factor. Prolonged social isolation not only impacts the immune response but is also associated with adverse physical and mental health outcomes. Previous studies have identified bi-directional interactions between immune signals and the central nervous system, suggesting a direct link between immune-activated neural circuits and sickness outcomes. Moreover, social isolation can have a dramatic effect on neuronal activity in specific brain regions. My preliminary studies demonstrate that social isolation exacerbates symptoms of sickness, such as body temperature and appetite, and increases circulating levels of immune factors known to mediate sickness state. Using activity pattern analysis, I found that activity in the insular cortex (IC) is dependent on both sickness and social isolation, suggesting integration of both social and immune signals. Therefore, I hypothesized that social isolation increases the severity and recovery time of sickness through specific neuronal and circuit mechanisms that integrate social behavior and sickness. I will address my central hypothesis by inducing sickness in isolated or group-housed mice through peripheral administration of bacterial lipopolysaccharides (LPS). In Aim 1, I will employ cell-type-specific functional manipulation approaches, including chemogenetic activation and permanent neuronal silencing, to determine the function of the “sickness neurons” in the IC. In Aim 2, I will identify the upstream neuronal inputs that convey social context to sickness-activated IC neurons using retrograde tracing and determine how these social inputs modulate sickness symptoms and behaviors using projection-specific activation. Together, the completion of this project will determine how the social environment influences sickness manifestation and recovery, revealing critical insight into long-standing observations linking isolated social environments with poor health.

NIH Research Projects · FY 2026 · 2026-06

Platelets are key cells involved in coagulation and have been recognized as effector immune cells with significant contributions to infectious and inflammatory syndromes. While capable to de novo protein synthesis, platelets are anucleate and must have mRNA invested into them by a parent megakaryocyte prior to being released into circulation. We have previously shown that bone megakaryocytes alter the transcriptome of circulating platelets in a mouse model of sepsis. My NHLBI K08 focused on the role of FcγRIIA, a low affinity IgG immune receptor, impacted platelets function in sepsis. We have found that FCGR2A transcript was one of the most differentially expressed transcripts in platelets from patients with sepsis. I aimed to interrogate how FcγRIIA upregulation impacted platelet function and increased sepsis-induced mortality. After my K award was initiated the COVID-19 pandemic shuttered all research with the exception of those studies that were directly related to COVID-19. I quickly pivoted my research towards investigating the impact of acute COVID-19 infection on the platelet transcriptome and alterations in platelet function. During the COVID-19 pandemic we found that the platelet transcriptome was significantly altered in those patients with acute hypoxemic respiratory failure. Furthermore, we found that platelets and neutrophil extracellular traps (NETs) were found in small lung vessel of patients deceased from COVID-19. We found plasma markers of NETs were significantly correlated with severity of respiratory failure and mortality. Suggesting that immunothrombosis is a significant contributor to hypoxemic respiratory failure. Sepsis is the most common cause of acute hypoxemic respiratory failure, termed acute respiratory distress syndrome (ARDS). ARDS is a common cause of ICU admission that continues to carry significant morbidity and mortality. Moreover, others have shown that megakaryocytes are found in both the lung and the spleen and produce platelets that express markers suggesting an immune phenotype. We hypothesized that the population of megakaryocytes found in the lung will contribute to lung injury. We have found that lung megakaryocytes are present and produce platelets in a murine model of LPS- induced acute lung injury. We aim to study how both the lung megakaryocyte and lung megakaryocyte-derived platelet increase both early and late-stage lung injury.

NIH Research Projects · FY 2026 · 2026-06

Abstract The brain is highly susceptible to aging, with a notable decline in multiple brain functions. To empower strategies that restrain the influence of age on the brain, we must identify the brain- regulatory factors that undergo age-associated decline and, more importantly, identify those amenable to being boosted or rebounded in the setting of advanced age. We identified such a factor: the brain-regulatory, gamma-delta T cell (γδT) that resides in the meninges. This proposal presents several fundamental discoveries regarding the influence of age on meningeal γδT cells, their regulation by gut microbes, and gut-centric interventions that drive their rebound in advanced age. Figuring out how to fortify γδ17 cells to support brain health will have a transformative impact on human health, particularly as it relates to advanced age. This collaborative proposal endeavors to make strident leaps toward this long-term goal.

NIH Research Projects · FY 2026 · 2026-06

Project Summary/Abstract Methamphetamine use disorder afflicts millions of Americans and precipitates a debilitating withdrawal syndrome marked by hypodopaminergia, anxiety, and somatic distress, yet our ability to interrogate its neuropeptidergic underpinnings is hindered by a lack of versatile, high precision chemical probes in neuroscience. We hypothesize that corticotropin releasing factor (CRF) mediates negative affect and stress responsivity, neuropeptide Y (NPY) promotes resilience within reward circuits, and orexin (ORX) governs motivational and somatic outputs during withdrawal. To test this, we will engineer a modular library of cyclic, photolabile caging scaffolds that render CRF, NPY, and ORX both inert and proteolysis resistant (enhancing in vivo stability and bioavailability), thereby enabling multiplexed interrogation of multiple peptide systems reducing the need to generate or maintain multiple mouse lines to modulate each peptidergic system. Each probe will undergo a rigorous validation pipeline: biophysical photolysis and binding assays to quantify release kinetics and receptor engagement, cell culture studies to confirm receptor specificity and downstream signaling, and acute brain slice experiments in both naïve and methamphetamine-withdrawn mice (focused uncaging on genetically identified cell types with whole cell electrophysiology and two photon calcium imaging) to verify functional efficacy and altered peptide responsiveness. We will then deploy genetically encoded peptide sensors to dynamically monitor CRF in the bed nucleus of the stria terminalis (BNST), NPY in the ventral tegmental area (VTA), and ORX in the nucleus accumbens (NAc) both before methamphetamine exposure and during withdrawal in behaving mice, an approach that will reveal how peptide activity in discrete circuits drives specific withdrawal features. Separate experiments using time locked uncaging manipulations will test causality by modulating peptide signal and assessing effects on withdrawal phenotypes. Behavioral endpoints will include quantitative somatic withdrawal scoring (for example, jumps and tremors), validated anxiety assays (elevated plus maze and open field), and reward related paradigms (sucrose preference and conditioned place preference), analyzed in both male and female mice to uncover sex specific peptide mechanisms. Because CRF, NPY, and ORX, along with their respective brain circuits, are conserved across mammals, these mechanistic insights will be directly relevant to human neurobiology and withdrawal physiology. Leveraging these findings will pave the way to rationally design peptide-based agonists and antagonists as prototype therapeutics to restore neuropeptide balance and ameliorate withdrawal symptoms. Finally, we will disseminate our chemical reagents, protocols, and data through open access repositories, empowering the broader neuroscience community to apply these spatiotemporal control strategies across diverse research domains and accelerate development of targeted treatments for substance use disorders.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Broadly neutralizing antibodies (bnAbs) that target the CD4 binding site (CD4bs) on the HIV envelope glycoprotein (Env) are an attractive target for an HIV vaccine and antibody-based therapy for HIV protection. However, eliciting CD4bs bnAbs in a vaccine is challenging, and current CD4bs bnAbs are insufficient to provide long-term HIV suppression. This difficulty in CD4bs bnAb-mediated treatment stems from Env mutations near the CD4bs referred to as “loop D,” including the gain of a glycan at N276 that has yet to be dependably overcome in vaccine regimens. Although improvements in antibody isolation have provided mechanistic and evolutionary insight into some CD4bs bnAbs, it remains poorly understood how CD4bs bnAbs evolve breadth and potency from their naïve precursors, complicating attempts to elicit them via vaccination. To address this issue, high-throughput deep mutational scanning (DMS) techniques will be used to characterize the effect of all possible single-amino acid mutations at each position in the variable domains of the VRC01 and IOMA CD4bs bnAbs that represent two stereotyped mechanisms of Env CD4bs recognition. VRC01 and IOMA variant libraries will be expressed on the cell surface of yeast. Using this yeast-surface display (YSD) platform, both VRC01 and IOMA variant binding affinities will be measured against various Env proteins using fluorescence-activated cell sorting and high-throughput sequencing (FACS-seq), facilitating the measurement of the binding properties of these bnAb libraries in parallel. Aim 1 will determine the mutations in CD4bs bnAbs that enable HIV Env N276 glycan accommodation. DMS, YSD, and FACS-Seq will be performed on libraries of mature VRC01 and its naïve precursor to determine their binding affinities to two closely related donor-autologous Env proteins that contain and lack the N276 glycan. These experiments will reveal routes to overcome common barriers in CD4bs bnAb development and illuminate how the next generation of immunogens will better elicit broad and potent bnAbs. Aim 2 will map the mutational landscape that confers CD4bs bnAbs breadth and potency. DMS, YSD, and FACS-seq will be performed on mature VRC01 and IOMA to measure the impact of all single mutations on binding to a previously established panel of 12 heterologous Env strains that comprise a reference of global Env diversity. These results will illustrate how mutations in these antibody scaffolds confer binding to divergent Env strains versus promoting strain-specific binding, fully defining the functional constraints and flexibilities of these CD4bs bnAb classes. The results of this proposal will illustrate a new approach to investigate the evolution and engineering of HIV CD4bs bnAbs, setting the stage for the development of improved immunogens and therapeutic antibodies against HIV. More broadly, the methodological innovation herein will provide a new platform for antibody engineering for the treatment and prevention of various infectious diseases.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Chronic postsurgical pain (CPSP) is a potentially devastating outcome from an otherwise successful surgical procedure. It affects millions of patients every year, with pain lasting for months to years, resulting in patient suffering and economic hardship. Attempts to prevent CPSP have largely been unsuccessful, with no change in the incidence despite increased use of regional and multimodal analgesia. This illustrates that there is much we still don’t understand about what causes the transition from acute to chronic pain and that further research is needed to understand the mechanism of this transition and to identify ways to prevent and treat it. Descending pain facilitatory circuits via cells in the rostroventral medulla have been proposed as a key mechanism in the acute to chronic pain transition. However, it is unclear if this is a defining feature or just one of many mechanisms responsible for central sensitization. We have identified three strains of consomic rats that develop persistent pain-like behaviors following a hind paw incision; both male and female SS-5BN rats, and male but not female SS-6BN and SS-13BN rats. This indicates that genes on Brown Norway (BN) chromosomes 5, 6 and 13 lead to CPSP-like behaviors when substituted into the Dahl salt-sensitive (SS) rat genetic background. We will use these strains to test the hypothesis that a defining feature of the acute to chronic pain transition is the recruitment of pain faciliatory “on” cells in the RVM. Our overall objective is to use these consomic strains to identify and link the effects of gene(s) to ion channel and receptor profiles, and to physiological pathways (descending pain modulation) which result in changes in our behavioral endpoints (mechanical nociceptor thresholds), thus leading to a greater understanding of the mechanisms responsible for the acute to chronic pain transition. This will be accomplished in three projects: Project 1 will test the hypothesis that the recruitment of pain facilitatory rostral ventromedial medulla (RVM) neurons drives the acute to chronic pain transition in SS-5BN, SS-6BN and SS-13BN rats using a Targeted Recombination in Active Populations (TRAP) approach for targeted expression of inhibitory DREADDs in a select subpopulation of RVM neurons; Project 2 will use a cell-based high-content phenotypic- screening platform to elucidate the cell-specific combinations (constellations) of key signaling proteins that define specific cell types. Differences in these profiles between the strains will be used to help identify pathways underlying the pain-like phenotypes exhibited by SS-5BN, SS-6BN and SS-13BN rats; Project 3 will use congenic SS-13BN rats to narrow chromosomal regions to help identify the gene polymorphism(s) responsible for this strain’s CPSP-like behaviors. We expect our studies to provide a better mechanistic understanding of the acute to chronic pain transition and may identify genetic or biochemical biomarkers that will guide future research on the causes of chronic postsurgical pain.

NIH Research Projects · FY 2026 · 2026-05

Project Summary: Cell migration is a critical aspect of normal development, as cells are often not born in the location of function, and migrate long distances to their final destination. But this process is often co-opted in disease states such as cancer. Much of our understanding regarding cell migration stems from work in 2D cell culture models, in which many types of cells exhibit a net forward movement through cell protrusion at the front and cell retraction at the back. Central to this form of migration is the ability of the cell to physically attach to its underlying substrate through the formation of focal adhesions. in vitro 2D and 3D approaches offer numerous advantages to dissect focal adhesion biology in terms of high-resolution image acquisition, control over matrix properties, and quantitatively assessing biophysical properties. While these studies have been immensely valuable, despite the years of research, it is still unclear what the organization and dynamic regulation of focal adhesions are during single cell migration in complex in vivo systems. Furthermore, pharmacological inhibitors have been developed against components of focal adhesion machinery for the treatment of disease without a clear understanding of how focal adhesions form and function during cell migration in animals. To meet this need, we developed a system in which we can directly visualize the formation and dynamics of focal adhesion structures of highly migratory single cells on a relatively planar surface of the zebrafish larval skin. Our recently published work challenges dogma established by in vitro studies, showing that phosphorylation of a key focal adhesion component, Paxillin, is greatly reduced in migrating cells in vivo, and that lack of Paxillin phosphorylation promotes focal adhesion disassembly rates and single cell migration in vivo, despite inhibiting cell migration in culture. This contradiction emphasizes the need for additional work in understanding focal adhesion regulation in complex in vivo environments (Aim 1). Furthermore, we found that the expression of the upstream kinase, FAK, is significantly reduced in cells in vivo compared to cells in culture. Given that FAK inhibitors are currently being developed in the clinic under the premise that part of FAK's function is for focal adhesion regulation, it is important to definitively determine whether FAK activity is required for focal adhesion regulation during single cell migration in vivo (Aim 2), and how Paxillin promotes cell migration in the absence of FAK phosphorylation (Aim 3). Identifying new proteins that interact with Paxillin in vivo will also begin to unravel why focal adhesion regulation is different in vivo versus in culture. Thus, our work has the potential to re-define the roles for focal adhesion proteins during single cell migration in vivo.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY / ABSTRACT Memory formation is thought to involve long-lasting changes in the synaptic connections between neurons to form memory circuits, but the precise molecular mechanisms remain poorly understood. One key player in memory is the immediate early gene Arc, which is critical for memory consolidation. The Shepherd lab discovered that Arc self-assembles into virus-like capsids that can traffic RNA and protein between cells in extracellular vesicles. We recently found that when Arc is transferred between primary cultured neurons, recipient neurons exhibit changes in synaptic neurotransmitter receptors. This suggests a novel form of intercellular synaptic plasticity, where Arc transfer modulates the activity of surrounding neurons. However, the significance of this mechanism in memory formation is unknown. My preliminary data suggest 1) Arc intercellular transfer occurs in vivo and 2) the fear memory deficit in Arc knockout (KO) mice can be rescued by expression of wildtype Arc in adulthood. This proposal will test whether Arc intercellular transfer facilitates memory consolidation in vivo. To investigate the role of Arc intercellular transfer in memory, I will evaluate its dynamics and necessity in vivo. In Aim 1, I will directly characterize intercellular Arc transfer in the brain using a novel molecular reporter to visualize Arc donor and recipient cells. I will determine the spatiotemporal dynamics of intercellular Arc transfer during memory consolidation. I will also evaluate the cell-type specificity of recipient cells and determine whether Arc intercellular transfer captured with our tool is behaviorally induced. In Aim 2, I will express Arc mutants that either disrupt intercellular signaling or Arc-dependent regulation of synaptic receptors in Arc KO mice, using a “rescue” approach to restore memory deficits. This experiment will inform which of Arc’s molecular functions are necessary for fear memory. These experiments may reveal a novel form of brain plasticity that uses viral-like intercellular signaling, shedding light on how memories are formed, stabilized, and stored in the brain. Elucidating the molecular mechanisms of Arc in normal memory stands to inform potential points of failure in neurological disorders.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT The prevalence of early-onset dementia is higher in autistic adults than the general population. While there is some evidence that the hippocampus may be smaller in autistic adults, there are no longitudinal studies of hippocampal changes across the lifespan in this population to identify when these differences emerge. Published longitudinal work by our group shows that brain developmental trajectories differ based on modality and region, with some differences present in early childhood and some appearing by late adolescence or early adulthood. This proposal is a first step in establishing lifelong developmental trajectories in autism spectrum disorder (ASD) of brain areas known to be involved in dementia. We will utilize a retrospective dataset collected over 23 years, with up to seven timepoints of data for some participants, in a well-characterized cohort of 125 autistic adults and 150 age-matched non-autistic participants. Our first aim will measure and describe longitudinal changes in hippocampal volume from childhood into adulthood. We will examine total hippocampal volume and hippocampal subregions and use advanced statistical methods that allow for flexible modeling, or unique nonlinear developmental trajectories, separately for participant groups. These methods will identify when group differences emerge in certain regions/subregions, vulnerable windows of development, and regions with persistent group differences. Our second aim will investigate the relationship between hippocampal volume, memory function and longitudinal changes in cognitive performance. We will examine current mental status and how longitudinal hippocampal changes differ in autistic participants who are impaired on dementia screening measures. We will also examine individual trajectories to further characterize aging-related changes within the ASD group. These aims will provide important pilot data for examining an established biomarker for dementia, hippocampal volume and change, throughout adulthood in a population at increased risk. Understanding the interplay between biological and cognitive changes will enable a more accurate characterization of aging and dementia in autistic adults. Consequently, appropriate diagnostic instruments can be developed, and targeted interventions and therapeutics can be implemented to best support autistic adults as they age.

NIH Research Projects · FY 2026 · 2026-05

This is a K01 award application for Dr. Peter Taber, a sociocultural anthropologist and clinical informaticist to address ethical challenges related to secondary findings in whole genome sequencing. A K01 award will provide Dr. Taber with time to gain expertise in four areas: i) ethical, legal and social implications of pediatric genomic medicine; ii) healthcare partner-engaged implementation science in genomic medicine; iii) clinical informatics and health communication approaches in genomic medicine suitable for all populations; and iv) research leadership and management. These skills will enable Dr. Taber to meet his career goal of becoming an impactful independent investigator using social science and informatics to address ethical, legal and social implications of genomic medicine. Dr. Taber is supported by an interdisciplinary NIH R01-funded mentoring team, including: Dr. Guilherme Del Fiol, an expert in health informatics; Dr. Martin Tristani-Firouzi, a pediatric cardiologist and expert in pediatric genomic medicine; Dr. Sara Knight, a clinical psychologist and leading expert in engagement methods in genomic medicine; and Dr. Kimberly A. Kaphingst a leader in health communication in genomic medicine. Dr. Taber is also supported by advisors, including clinicians, genetic counselors and a bioethicist working with the whole genome sequencing program of interest.    Whole genome sequencing is now a guideline-recommended first-tier test in pediatric medicine. Compared to conventional genetic testing, whole genome sequencing has a higher likelihood of returning findings unrelated to the indicator condition (“secondary findings”). Real-world guidance for ethically managing secondary findings is limited, because relatively few clinical whole genome sequencing programs have been implemented. Management of secondary findings that fails to recognize patient communication needs, cultural orientations and resource constraints risks exacerbating poor health outcomes. Addressing these challenges requires approaches that are context sensitive, and that engage healthcare partners. This project uses ethnography (the study or people in context) and human-centered design (design processes that emphasize input from end-users) to address secondary findings in whole genome sequencing. In Aim 1, ethnography will be used to understand families’ lived experiences with whole genome sequencing and receipt of secondary findings. In Aim 2, Healthcare Partner Panels consisting of healthcare staff and families will be used to design interventions and implementation strategies addressing secondary findings. In Aim 3, a prototype tool for patient education about secondary findings will be created. In addition to the general population, each aim will include two groups at risk of poor health outcomes in Utah: Spanish-speaking and rural residing families. A future National Human Genome Research Institute R01 will test strategies designed by healthcare partners (Aim 2), and a tool for patient education about secondary findings (Aim 3).

NIH Research Projects · FY 2026 · 2026-05

This proposal seeks external funding for a recently launched internship program for undergraduate trainees who are passionate about improving metabolic health. Our program aims to help outstanding undergraduates achieve their goals of becoming the next generation of nurses, physician assistants, physicians, and scientists by providing research experience, clinical exposure, career development training, and community outreach opportunities over the course of a 10-week summer program. Our training offers exposure to the metabolic underpinnings of chronic kidney disease (CKD), diabetes, obesity, hypertension, heart failure, cardiovascular disease and stroke. These comorbid conditions have increased in parallel with the epidemic proportions of diabetes and obesity, which are strong risk factors for these chronic health conditions. With overwhelming support from UofU administration, colleagues, and community leaders, we created and implemented the Utah Summer Undergraduate Mentored Metabolism Immersive Training (SUMMIT) Program, a 10-week summer research internship which provides: i) hands-on research experience (basic, clinical, or translational) with established scientists; ii) professional and career development; iii) clinical shadowing; iv) cultural mentoring; and v) community outreach. With NIH support, we aim to continue annual research experiences and educational training in metabolic disease (with an emphasis on diabetes, obesity, endocrinology, and metabolism) through the Utah SUMMIT Program. We will: 1) Execute a summer research internship centered on metabolic health for undergraduates that includes comprehensive and lifelong academic, career, and educational support through mentored research and the development of a strong, supportive cohort experience; 2) provide Summit Scholars outreach opportunities with Utahns at high risk for metabolic disease; and 3) Evaluate the effectiveness of the SUMMIT Program on increasing trainee trajectories toward STEM careers and the endocrine-related biomedical workforce.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Dysfunction of the Wnt signaling pathway has been associated with mental ilness, but the underlying molecular and cellular mechanisms remain elusive. Our laboratory has discovered an evolutionarily conserved role for the Wnt transcriptional effector Lef1 in generating hypothalamic neurons and innate behaviors linked to stress. LEF1 variants could thus contribute to human stress-related mood disorders, and we propose that the distinct expression and function of two highly conserved protein isoforms could provide a way to separate this role from the other essential roles of Lef1 in development. We will use zebrafish to test the hypothesis that isoform- specific control of Lef1-dependent transcription regulates hypothalamic neurogenesis and stress- related behavior. In Aim 1 we will determine how the Lef1 N-tail and B-tail isoforms affect protein function, and in Aim 2 we will determine whether each isoform is specifically required for neurogenesis and behavior. Our goal is to establish an evolutionarily conserved model that we can eventually translate to human mental health.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Many endemic viruses, such as HIV-1 and Ebola, hijack the host ESCRT pathway to bud and spread infection. Most host-pathogen interfaces rapidly evolve to evade infection, but ESCRT subunits remain highly conserved across eukaryotes, as adaptations that block viral piracy also disrupt essential cellular functions such as cytokinetic abscission. This evolutionary constraint has allowed a broad class of ESCRT-dependent viruses to bud unchallenged. However, we recently discovered retroCHMP3, a species-specific ESCRT subunit that selectively inhibits ESCRT-dependent viral budding while permitting essential host functions. RetroCHMP3 arose independently in primates (~45 million years ago) and mice (~7 million years ago) as the truncated retrotransposition of the ESCRT subunit, CHMP3. Curiously, previous studies revealed CHMP3 truncation alone is cytotoxic due to dominant-negative inhibition of both host and viral ESCRT functions. These observations raise questions about the selective pressures driving the convergent evolution of retroCHMP3 and how ancestral retroCHMP3 precursors were detoxified while retaining antiviral properties. This project aims to understand the evolutionary mechanism for the detoxification of retroCHMP3, a non- inflammatory restriction factor in its evolutionary infancy. Traditional genetic and mechanistic studies of retroCHMP3 have proved challenging; the sensitivity of ESCRT complexes result in low expression levels of aberrant subunits and inviable stable cell lines and animal models. To overcome these barriers, I’ve established MEDUSA, an experimental evolution system in the budding yeast, Saccharomyces cerevisiae, that allows stable expression and adaptive evolution of mammalian retroCHMP3 under selection. S. cerevisiae is an ideal system to study retroCHMP3 considering its conserved ESCRT machinery, genetic malleability, and tolerance to subunit modifications. My primary hypothesis is that novel immune functions first mitigate cytotoxicity before optimizing antiviral effector properties. Testing this hypothesis will inform us on 1) the adaptive strategies that mitigate its cytotoxicity while preserving its ability to inhibit viral budding, and 2) the compensatory host changes in response to a novel antiviral mechanism. Aim 1 will determine the mechanism of detoxifying retroCHMP3 and its tradeoffs to host function. Aim 2 will determine evolutionary steps for tolerating a nascent ESCRT-dependent restriction factor in a new host. Together, these aims will reveal adaptive pathways for detoxifying emerging immune processes and provide insight into how hosts rapidly evolve in real time to disruptions to core cellular functions. RetroCHMP3 has broad implications for targeted therapeutics for HIV/AIDS and many other viral infections. This fellowship proposal will explore the possibility of a new class of non-inflammatory restriction factor by understanding mechanism for detoxification of a nascent immune pathway and its evolutionary host-pathogen dynamics. As such, this project is ideally suited for a training physician-scientist, as it combines innovative infection biology with comparative and evolutionary studies of emerging immune functions.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Immunotherapy has transformed cancer treatment, yet patients with endocrine tumors, including adrenal and ovarian cancers, rarely benefit due to poor immune infiltration and activation in steroid-rich environments. Androgens, traditionally viewed as cancer-promoting, may enhance anti-tumor immunity. High androgen receptor expression correlates with improved outcomes in adrenal, ovarian, and select breast cancers; however, the mechanisms underlying these effects remain poorly understood. Using a mouse model of adrenal cancer, my work revealed a sex bias in tumor incidence, with males exhibiting lower tumor burden, which was associated with androgen-driven immune activation. Androgen-secreting adrenal tumors in the clinic show better prognosis and greater immune infiltration, while androgen deprivation in our mouse model reduces intratumoral myeloid and lymphoid cells. Androgen supplementation increases circulating inflammatory monocytes, suggesting a tumor-protective role via immune activation. Similar androgen-driven immune responses occur in the ovary, paralleling clinical data linking androgens to reduced ovarian cancer risk. These findings support a translational potential for androgen-mediated immunity across endocrine malignancies. In the K99 phase, I will investigate how androgens enhance myeloid and lymphoid immune responses to improve ICB efficacy in ACC. Aim 1 will assess how androgens modulate myeloid cell function and recruit the adaptive immune response to promote anti-tumor immunity. I will use a syngeneic ACC mouse model with immune cell depletion and ICB, real-time ultrasound tumor tracking, and Xenium transcriptomics to dissect androgen-driven immune mechanisms. Findings will be validated in androgen-secreting ACC patient tumors. In the R00 phase, I will extend this work to ovarian cancer, a leading cause of gynecologic cancer mortality. Aim 2 will examine how androgen signaling enhances immune infiltration in the ovary and whether this can improve ICB efficacy in ovarian cancer. I will use AR-deficient myeloid mouse models, syngeneic ovarian tumor injections, and Xenium transcriptomics to define androgen-mediated immune effects. This will establish a potential rationale for androgen-based immunotherapeutics in ovarian cancer. My career development plan includes training in tumor immunology, Xenium transcriptomics, and ovarian cancer biology, supported by mentorship from leaders in the field. The research environment at Huntsman Cancer Institute offers state-of-the-art resources and collaborative opportunities to achieve these goals. The K99/R00 award will enable me to establish my independent research lab, where I aim to advance our understanding of how hormones impact the tumor immune environment and ultimately use this to improve therapeutic strategies.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Metabolic and bariatric surgery (MBS) has become an increasingly common weight loss treatment for severe obesity, but its impact on oral health remains poorly understood. Evidence based research evaluating oral health complications and associated oral healthcare costs following MBS is lacking. Addressing these important clinical gaps, this study proposes to leverage the integration of multiple unique data sources in conjugation with advanced causal inference and machine learning tools to systematically evaluate the comparative effectiveness and treatment costs between MBS and non-MBS surgical oral health management. Using the Utah Bariatric Surgery Registry, 13,713 patients with severe obesity who underwent MBS between 2014 and 2023 have been identified. These surgical records will be linked with the Utah Population Database (UPDB), a comprehensive resource covering over 11 million individuals and connecting 85% of Utah residents to vital statistics, demographic data, claims data, statewide facility databases, and medical records. These linked data will provide statewide follow-up information, enabling the assessment of changes in oral health outcomes and associated healthcare costs among obese patients with and without MBS. Results of these analyses will help inform patients and physicians about potential oral health risks associated with MBS as a treatment option for severe obesity and provide the basis of clinical recommendations on post-surgical oral health care.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Smoking remains a leading cause of cardiovascular disease (CVD), responsible for millions of deaths worldwide. Despite its widespread impact, the precise mechanisms linking smoking to CVD risk, particularly in relation to genetic factors, remain incompletely understood. One such genetic variation, ALDH2*2, affects approximately 540 million individuals globally and may interact with tobacco smoke to exacerbate CVD risk. However, the addictive nature of smoking, compounded by social and cultural influences, complicates efforts to reduce smoking prevalence in this population. Consequently, understanding the role of ALDH2*2 in smoking-induced CVD is crucial for advancing precision medicine for individuals affected by this genetic variation. Our previous research, which utilized induced pluripotent stem cell (iPSC)-derived endothelial cells (iPSC-ECs) from individuals carrying the ALDH2*2 variant, revealed significant endothelial dysfunction. These cells demonstrated elevated oxidative stress and inflammation, along with reduced nitric oxide production and tube formation capacity (Guo et al., Science Translational Medicine, 2023). Our recent findings further suggest that the endothelial dysfunction associated with the ALDH2*2 variant is exacerbated by exposure to cigarette smoke in both human iPSC and transgenic mouse models. Despite these findings, the specific mechanisms by which tobacco consumption exacerbates CVD risk in individuals with the ALDH2*2 variant remain unclear, impeding the development of tailored approaches for ALDH2*2 smokers. The overarching goal of our proposal is to utilize a multidisciplinary approach that integrates stem cell biology, molecular biology, toxicology, vascular physiology, and endothelial mechanobiology to elucidate the molecular mechanisms underlying ALDH2*2- and smoking- induced endothelial dysfunction. We will pursue two specific aims. In Aim 1, we will examine the ROS-FOXO1- KLF5→IL-18/IL-1β signaling axis in modulating endothelial dysfunction in both human iPSC and mouse models carrying the ALDH2*2 variant. Additionally, we will screen small molecules targeting the ROS-FOXO1-KLF5 axis in cigarette smoke-exposed ALDH2*2 iPSC-ECs to evaluate their effects on endothelial function. In Aim 2, we will examine NUP210’s interaction with the LINC complex in mediating the shear stress response in ALDH2*2- and smoking-induced endothelial dysfunction. We will utilize RNA-seq, ATAC-seq, ChIP-seq, and single-cell RNA-seq to gain mechanistic insights into how NUP210 interacts with LINC complex and regulates the H3K27me3 modification of extracellular matrix genes in response to mechanical forces. Our proposal is supported by robust preliminary data, and the successful completion of this research will identify two novel molecular mechanisms—KLF5-mediated inflammation and NUP210-mediated shear stress response—through which smoking exacerbates CVD risk in the ALDH2*2 carriers. Additionally, the study will provide insights into potential prognostic biomarkers and therapeutic targets to mitigate CVD in smokers with the ALDH2*2 allele.

NIH Research Projects · FY 2026 · 2026-04

Although the rate of suicide death across the U.S. has risen dramatically over the past two decades, prevention of mortality remains challenging. This proposal will continue discovery efforts leveraging unique genetic data, comprehensive health records, and deep genealogical records. The variation in responses to environmental and social risks due to underlying genetic vulnerabilities creates an opportunity for discovery of subtypes of individuals at particularly high risk for mortality to lead to future clinical translation. Thus far, genetic discoveries associated with suicidality remain largely removed from translational utility, and are additionally primarily focused on the outcome of suicide attempt. Among individuals with evident suicidality, fewer than 10% go on to die by suicide, and roughly half of suicide deaths occur with no prior evidence of suicide attempts, suggesting that suicide attempt may be a poor proxy for determining risks leading to mortality. Data resources in the Utah Suicide Mortality Risk Study (USMRS) offer much needed opportunities to bridge this knowledge gap, including >12,000 suicide deaths linked to statewide electronic health records; ~9,000 with genotyping, and 1,053 selected for high extended familial risk with whole genome sequencing. All data linkage, subsequent de-identification, and analyses are possible via the Utah Population Database (UPDB); this comprehensive statewide resource also includes unique knowledge of familial risk through genealogical records that go back to the 1700s. In the previous award period, we used the WGS resource, prioritizing genomic regions using 43 very extended families at high risk of suicide death. We pursued non- synonymous variants in the NRXN1 gene which is important for synaptic function, demonstrating the utility of the familial approach. We more broadly characterized suicide deaths with significant extended familiality, finding significant reduction in age at death and significant increase in polygenic risk specific to suicide. We expanded our sequencing sample from N=281 to N=1,053, prioritizing suicide deaths in extended high-risk families. In addition to familial prioritization, we prioritized brain-related expression quantitative trait loci in the deaths with WGS, finding significance associated with RFPL3S (a gene important for arousal), in addition to implicating other gene pathways. We characterized non-transmitted genomic deletions using a conservative strategy of internal replication and rigorous bench validation. Our large sample of genotyped suicides provides information regarding background common genetic risks of hundreds of diagnoses and traits via polygenic scores. Additional ongoing work has also strongly implicated underlying transdiagnostic risks above and beyond psychiatric risks, driving new research directions. We propose to target discovery of mechanistic genomic change within homogeneous subtypes. Extended families provide one method of reducing heterogeneity. We also propose complementary strategies of risk discovery within extreme subtypes of physiological stress response and of brain-related function.