Utah State Higher Education System--University Of Utah

NIH Research Projects · FY 2026 · 2026-01

Summary Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that cause dementia and represent a major public health concern. Both diseases primarily affect the elderly and are becoming increasingly prevalent as the aging population grows. These disorders are associated with pathological changes in the brain, including the deposition of abnormal proteins. TDP-43 (TAR DNA-binding protein of 43 kDa) was initially linked to FTLD and has since been found in up to 60% of brains with AD. One of the most significant challenges in understanding the role of TDP-43 in neurodegeneration and developing effective treatments for these disorders is the lack of reliable biomarkers that can predict TDP-43 pathology in living FTLD and AD patients. TDP-43 is clinicopathologically heterogeneous, and the relationships among clinical phenotypes, local neurodegeneration, and TDP-43 pathology remain unclear. This heterogeneity arises from the complex molecular composition of TDP-43 inclusions. A biomarker or antibody capable of revealing the relationship between TDP-43 pathology and neurodegeneration would significantly advance the field. Through the screening of over 5,000 monoclonal antibodies (MAbs), we identified an anti-TDP-43 antibody, MAb No. 9, which recognizes novel TDP-43 pathology in FTLD and AD. Furthermore, Meso Scale Discovery (MSD) immunoassays using this antibody detected elevated TDP-43 levels in the plasma extracellular vesicles (EVs) of FTLD and AD patients, suggesting its potential as a plasma biomarker for TDP-43 proteinopathies across different dementias. The main objectives of this project are to investigate the MAb No. 9-positive TDP-43 pathology and its association with neurodegeneration in FTLD and AD and to develop plasma biomarkers for TDP-43 proteinopathies. To achieve these objectives, we will examine how MAb No. 9-positive TDP-43 pathology contributes to neurodegeneration in FTLD and AD by analyzing the relationships between MAb No. 9 positivity, inclusion types, pathology subtypes, and local neurodegeneration in brain specimens from autopsy- confirmed FTLD and AD patients. We will also establish plasma biomarkers of TDP-43 proteinopathies by measuring plasma EV TDP-43 levels using MSD immunoassays in cases of neuropathologically confirmed FTLD-TDP, FTLD-tau (a subtype of FTLD), and AD, as well as in healthy aging controls. This study has significant

NIH Research Projects · FY 2025 · 2026-01

ABSTRACT Hematopoietic stem and progenitor cells (HSPCs), which include hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), give rise to all blood and immune cells across the lifespan. HSCs first emerge during gestation and ultimately becoming the adult hematopoietic compartment. Human studies have associated events during pregnancy such as maternal infection, diet, or exposure to microbes with increased risk of immune dysfunction in offspring; however, the mechanisms behind this are unknown. Since hematopoietic progenitors arise during gestation and seed the adult hematopoietic compartment, we hypothesize that prenatal inflammation reprograms the cellular output of distinct fetal HSPCs, thus influencing postnatal immune function. Recent data has suggested that fetal HSCs and fetal MPPs emerge independently from the intra-embryonic aorta during development. This suggests that fetal MPPs and fetal HSCs of distinct origin have specific functions and relative contributions to postnatal blood production at homeostasis and during inflammatory insults, but this has not been directly investigated. Our working hypothesis is that fetal MPPs drive the response to prenatal inflammation in order to preserve the HSC pool, shaping the postnatal hematopoietic compartment. We will test our hypothesis by integrating genetic fate mapping experiments, transplantation assays, transcriptomics, and early life infection models. Our preliminary data suggests independent emergence of fetal MPPs and fetal HSCs from the developing aorta and has revealed the first evidence of functional differences between fetal MPPs and HSCs. We have found that fetal MPPs are the first responders to Type II-IFN mediated prenatal inflammation and expand the pool of downstream myeloid cells, which remain expanded in the postnatal period. Our findings also support the idea that timing of emergence influences the functional output of fetal progenitors at steady state and in response to inflammation. The objective of this proposed work is to comprehensively examine the specific effects inflammation has on fetal HSCs and MPPs and will define the mechanisms by which prenatal inflammation shapes the adult hematopoietic system. We will determine how inflammation experienced in utero influences offspring immunity and response to postnatal immune challenges at the level of fetal HSPCs. We anticipate that the insights gained from this proposed work will help inform underlying causes of disease that may start during development.

NIH Research Projects · FY 2025 · 2025-12

Project Summary Arterial remodeling is a crucial pathological change in diseases like pulmonary arterial hypertension (PAH), which reduces the flexibility of arteries. Without treatment, PAH patients face a grim prognosis, with most dying within a year of diagnosis and only a 45% survival rate at three years. Current drugs only slow the decline in pulmonary function and do not stop or reverse the disease. It is essential to understand the biological processes behind the pathophysiology of PAH for new targeted therapeutics. We propose that pulmonary arterial cells, especially smooth muscle cells (SMCs), may migrate in response to changes in the stiffness of their extracellular matrix, a process called durotaxis, which occurs independently of chemical or substrate-bound signals. In vitro tests showed that PAH patient-derived pulmonary arterial endothelial cells, SMCs, and fibroblasts can migrate against a spatial hydrogel gradient (stiffness 1-10 kPa), with PAH-SMCs being the most migratory. Additionally, Bio- AFM-based nanoindentation of lung samples from a SUGEN/hypoxia PAH rat model revealed an extracellular matrix gradient in the pulmonary arterial bed. Our proposal aims to track the spatiotemporal ECM stiffening in the progression of PAH in mice and rat pulmonary arteries using Bio-AFM and to quantify matrix component accumulation and crosslinking through immunostaining and orientation analysis. We found that introducing the L994E FAK mutation in pulmonary arterial cells inhibited durotaxis in cell-based assays, confirming the need for FAK-Paxillin interaction for stiffness sensing. We have developed a novel CRISPR FAKL994E knock-in (FAKL994E KI) mouse model and a novel pulmonary arterial hypertension-on-a-chip (PulA-Chip) model to study the role of the FAK/Paxillin complex in mechanosensing and muscularization. Both models are ready for use. We will also investigate how actin-microtubule communication in PAH-SMCs affects ECM stiffness-directed durotaxis. Cell adhesions assess matrix stiffness by exerting traction forces on the ECM through integrins, mainly αvβ3. We will study the role of α-TAT1 in regulating the recycling of αvβ3/FAK/Paxillin complexes via clathrin-coated vesicles. Understanding these mechanisms will help us to develop therapies in the future to stop or even reverse arterial muscularization among PAH patients.

NIH Research Projects · FY 2025 · 2025-12

ABSTRACT Inflammatory bowel disease (IBD) affects over 3 million people in the United States alone. IBD is caused by excessive gastrointestinal tract inflammation and depends on the microbiota. The intestinal immune response to the microbiota must be regulated to prevent inflammatory diseases such as IBD. The intestinal immune system can interact with the microbiota via pattern recognition receptors (PRRs), including the inhibitory C-type lectin receptor, Clec12a. Previously, we have determined that Clec12a can bind specific commensals within the intestine. Clec12a has inhibitory capacities, making it a unique PRR for commensal recognition, as it could act as a brake on immune proinflammatory signaling in this microbe and microbial ligand-rich environment. Clec12a is downregulated in individuals predisposed to IBD, suggesting a role for Clec12a in disease development. Interestingly, Clec12a-/- mice have more proinflammatory macrophages and less reparative macrophages, emphasizing that in the absence of Clec12a, there is a dysregulation in the immune response. Further, Clec12a- /- mice exhibit worsened colitis that is microbiota dependent, exemplified by the microbiota being sufficient to drive worsened colitis in WT mice. A major feature of the Clec12a-/- microbiota is a significant expansion of the gram-positive bacteria Faecalibaculum rodentium. These data suggest that Clec12a might dictate microbiota composition by limiting the expansion of harmful bacteria. In fact, Clec12a binds F. rodentium in a species- specific manner. Due to Clec12a having the highest expression on macrophages and monocytes in the gut, we tested whether Clec12a functioned in phagocytosis and observed that Clec12a-/- macrophages phagocytosed F. rodentium at lower levels, and this was also species-specific. Therefore, this proposal aims to identify how Clec12a regulates intestinal inflammation (Aim1) and how Clec12a dictates microbiota composition (Aim2). I will use a novel Clec12a-floxed mouse, allowing for the deletion of Clec12a in a cell-specific manor, while analyzing the effects on inflammation and microbiota composition. This proposal will determine the mechanism by which Clec12a restrains intestinal inflammation and sculpts the microbiota. Our working hypothesis is that Clec12a on transepithelial sampling myeloid cells can control the outgrowth of potentially harmful members of the microbiota through phagocytosis while also constraining harmful inflammatory events. We will test this hypothesis by completing these two aims: AIM 1: Determine how Clec12a regulates intestinal inflammation. AIM 2: Resolve how Clec12a sculpts the intestinal microbiota. This proposal will lay the groundwork for targeting Clec12a, and its inhibitory capacity, to treat IBD. Clec12a is a unique mechanism the immune system employs to sculpt the microbiota without eliciting prototypical inflammation. This mechanism could unveil treatments for other diseases that are influenced by the microbiota.

NIH Research Projects · FY 2026 · 2025-10

SUMMARY Alpha herpesviruses are a subfamily of ubiquitous viruses that can cause a spectrum of clinically-significant diseases including blindness from acute retinal necrosis (ARN). Unfortunately, even with timely antiviral treatment, irreversible pathological changes occur within the retina and significantly increase the risk of vision- threatening complications to further compromise an already poor visual prognosis. Since the advent of acyclovir, there have been no major advances in the treatment of clinically-significant herpes infections despite the vision-degrading complications and very little is known in regards to the immune response to the virus within the retina. This proposal will provide a fundamental understanding of the innate immune response to HSV-1 within the retina, while developing critical skills in career development. The long-term goal of this project is to acquire the scientific skills needed to enhance our understanding and pursue novel therapies to preserve vision and reduce complications related to ARN as an independent clinician-scientist. The scientific objective of this K08 proposal is to test the hypothesis that type I interferons (IFNs) are central to host defense to viral infection of the retina and that toll-like receptor-3 within retinal microglia activate this innate immune response. We propose evaluating the innate immune response to herpes virus infections of the retina by utilizing several immune knock-out mouse lines, human retinal cell cultures, and vitreous specimens from patients with ARN to assess the role of IFNs and their role in neuroinflammation. Three focused specific aims will be utilized to test our hypothesis: 1) Identify pathways and cell types responsible for HSV innate immunity within the retina; 2) Determine the role of downstream IFNs in host defense against viral infection of the retina; 3) Identify the predominate IFN subtype and cellular source in acute retinal necrosis from human samples. The career development objective is to develop the mentorship and expertise needed to become a productive and independent clinician-scientist. The Department of Ophthalmology and Visual Sciences and the University of Nebraska Medical Center have state-of-the-art laboratory facilities and world-class faculty with expertise in neuroimmunology, viral infections, and innate immune signaling to serve as the mentoring team. The institutional resources, mentorship team, and career development plan have been developed to specifically promote scientific independence in the study of neuroinflammation of the retina.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY This project aims to improve the health of all people living in rural communities throughout the United States by improving the reach and engagement of evidence-based lifestyle change interventions (EB-LCIs). Component A focuses on developing and evaluating novel marketing strategies to improve perceptions of EB-LCI feasibility and motivation among rural populations. The activities within Component A include a landscape analysis to identify innovative LCI approaches, discrete choice experiments to determine the best program features to market to rural audiences, and a randomized controlled trial testing the use of bi-directional text messaging to test optimized strategies to improve enrollment in EB-LCIs. The project will leverage the Mountain West Family Healthy Weight Collaborative (MW-FHWC) and the CDC Prevention Research Center Network to engage community members and organizations across diverse rural regions in the U.S. Component B establishes the Lifestyle Change Implementation Research Network Coordinating Center (LCIRN-CC) to support and coordinate the dissemination and implementation of EB-LCIs. The LCIRN-CC will leverage leading-edge dissemination and implementation (D&I) science methods, community-engaged research processes, and will leverage and innovate on the Mountain States Partnership for Community-Engaged Dissemination & Implementation (MS-CEDI) Science Training Institute to include an implementation practitioner training track in addition to the effective implementation researcher training track the institute developed and evaluated over the last four years. The center will facilitate communication and collaboration across the Network, support sustainable communities of practice, and build capacity for the next generation of EB-LCI D&I practitioners and scientists. Additionally, the LCIRN-CC will provide technical assistance, mentorship, and resources to ensure the successful implementation and sustainability of EB-LCIs across the Network. The ultimate goal of Component A is to improve the reach and overall health of Americans living in rural areas. For Component B, the ultimate goal is to contribute to generalizable implementation strategies and frameworks for EB-LCIs and build researcher and practitioner capacity to contribute to sustainable improvements in population health.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT: Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD) are leading causes of dependence and disability in older adults, projected to impact ~153 million people worldwide by 2050. Hypertension (HTN) increases the risk of both AD and Vascular Cognitive Impairment and Dementia (VCID). Black and Hispanic adults have higher average blood pressure (BP) and nearly 1.5 to 2 times higher dementia incidence than white adults, despite having less brain β-amyloid (Aβ). The Systolic Blood Pressure Intervention Trial (SPRINT), which included 9,361 US adults, found that intensive vs standard systolic BP (SBP) treatment (<120 vs <140 mm Hg) reduced risk of combined emergent mild cognitive impairment (MCI) or dementia. Epidemiological evidence suggests a synergism between SBP and AD pathology; however, significant gaps remain in our understanding the role AD pathology plays in how intensive SBP control affects MCI/dementia risk overall and if there are differences by sex, race/ethnicity, and APOE ε4 genotype (ε4). Understanding the extent to which intensive SBP treatment affects dementia risk in the presence or absence of AD pathology and by age, race/ethnicity, and sex can refine HTN treatment strategies to lower dementia risk and inform future trial designs. We will assess AD/ADRD plasma biomarkers longitudinally using stored SPRINT plasma samples (4 time points; n=8,797; mean age at baseline 68 years; 40% Black or Hispanic; median 7 years follow-up). We will determine whether baseline AD pathology or ε4 modifies the effects of intensive SBP control on MCI/dementia; whether intensive SBP control reduces longitudinal change in AD biomarkers (ptau217, Aβ 42/40), neurodegeneration (neurofilament light; NfL), measures of vascular remodeling (placental growth factor; PlGF), or neuroinflammation (glial fibrillary acidic protein; GFAP); how this varies by baseline AD pathology, ε4, race/ethnicity, age, and sex; and which plasma biomarker(s), including novel biomarker candidates assessed on the NULISA platform, can predict dementia risk. The aims are: (1) Determine effects of intensive vs standard SBP control on MCI/dementia (primary) by baseline AD pathology (primary effect modifier) and by age, sex, race/ethnicity, and ε4 (secondary effect modifiers); (2) Determine effects of intensive vs standard SBP control on longitudinal AD/ADRD biomarkers, overall and in subgroups; and (3) Provide a shared public repository of AD/ADRD biomarker data to investigate the effect of other biological and non-biological risk modifiers in the diverse and well-characterized SPRINT trial. Exploratory work will use proteomics to identify additional plasma biomarkers that add to established AD/ADRD biomarkers in explaining the emergence of dementia. This project will help inform patient selection for particular therapies, create a shareable research resource, and examine how cross-sectional and longitudinal plasma biomarkers can be applied in a large, representative population of at-risk older adults.

NIH Research Projects · FY 2025 · 2025-09

PUBLIC ABSTRACT Pregnant persons shoulder disproportionate burdens related to the US overdose epidemic. This burden is demonstrated by a quadrupling of births complicated by opioid use disorder (OUD) in the past two decades. This burden is also evident in that pregnant persons with OUD have elevated rates of HIV/HCV, psychiatric conditions, health-related social needs, and neonatal health challenges. Non-opioid substance use disorder, particularly stimulant use and disorder (StUD), is highly common and markedly increasing among pregnant per- sons with OUD. While recommended care for pregnant persons with OUD includes medication for opioid use disorder (MOUD) combined with behavioral health services—current research is unclear regarding which be- havioral health model(s) are optimal for addressing OUD with or without StUD (OUD±StUD), promoting treatment linkage/retention, and preventing overdose—while also addressing co-occurring psychosocial problems. One promising approach is patient navigation (PN), an evidence-based practice for a variety of medical and psycho- social conditions. Our preliminary studies have demonstrated that compared to Usual Care (UC), PN can pro- duce superior outcomes for MOUD adherence, drug treatment attendance, illicit opioid use, and overdose. Also, nearly all participants in our preliminary studies have been Medicaid beneficiaries, suggesting Medicaid pro- grams may be optimal partners to scale and sustain PN. Yet, while our PN model has robust preliminary evi- dence—it lacks tools to maximize benefit for co-occurring StUD. To enhance our PN model’s ability to address StUD for patients with OUD within Medicaid programs, we propose this mixed methods, type-2 hybrid implemen- tation study. First, we will further develop PN to target StUD in addition to OUD among pregnant persons. To do so, we will expand our PN model to include contingency management, a highly effective evidence-based inter- vention for addressing StUD. Completing this step positions our PN model for implementation planning and testing. Second, we will collaborate with Medicaid leaders, health care professionals/staff, and Medicaid benefi- ciaries to co-develop a PN implementation strategy for Medicaid. We will perform a contextual inquiry using qualitative interviews with Medicaid leaders (N=20) and four focus groups, two with obstetric/pediatric health professionals/clinic staff and two with persons with lived experience (6-8 participants per group). Results will be used to develop a Medicaid implementation guide for the current study and future real-world PN implementation in Utah Medicaid and other states. Last, we will implement and test PN vs. UC for opioid ± stimulant use reduc- tions/outcomes among pregnant persons. Partnering with Utah Medicaid, the University of Utah Health Plans, and Health Choice Utah Medicaid programs, we will conduct a powered randomized trial. Participants (N=429) will be assigned 1-1 to PN or UC. We hypothesize PN participants will have more opioid ± stimulant free days vs. UC. This study establishes needed evidence to aid pregnant persons to reduce illicit use, prevent overdose, and improve health outcomes.

NIH Research Projects · FY 2025 · 2025-09

This K01 award application is for Dr. Lindsey Palmer, a PhD-trained social worker whose overarching career goal is to become an independent violence prevention scientist, focused on promoting child health and well- being by advancing data-driven, evidence-based strategies to prevent maltreatment and its long-term consequences. This K01 will support three key areas of career development: 1) the application of machine learning approaches on violence prevention research, 2) cross-cutting violence prevention strategies, and 3) professional development and leadership. Dr. Palmer has assembled an interdisciplinary mentoring team comprised of Kristine Campbell, MD, MSc, a nationally recognized expert in pediatric child maltreatment with extensive experience collaborating with public agencies to develop cross-system prevention efforts; Fernando Wilson, PhD, an expert in the application of machine learning techniques on large-scale databases to examine health services and policy; Brooks Keeshin, MD, an internationally recognized expert in trauma assessment and suicide prevention; and Angela Fagerlin, PhD an expert in faculty enhancement, leadership and representation. Over the past decade, rates of self-directed violence (SDV) have risen sharply, particularly among 10- to 17-year-olds, with children and adolescents who have experienced maltreatment being at particularly heightened risk. A staggering 57% of children and adolescents who die by SDV have a history of alleged child maltreatment, which encompasses physical abuse, sexual abuse, emotional abuse, physical neglect, and exposure to intimate partner violence. These youths often face the compounded challenges of trauma, family dysfunction, and mental health issues. While child welfare system (CWS) involvement frequently signals heightened vulnerability, the pathways linking child maltreatment to SDV remain poorly understood. Contributing factors such as parental mental illness, substance use, overlapping forms of maltreatment, family instability are not well defined or understood. Additionally, there is limited evidence on the effectiveness of CWS interventions in reducing the risk of SDV for these children. This study’s Specific Aims include: 1) Determine the relationship between child maltreatment and SDV, specifically: Establish how the timing, type, and frequency of child maltreatment indicators are associated with SDV; and characterize the association between child maltreatment intervention and SDV; and 2) Leverage machine learning based approaches to identify direct and indirect pathways between child maltreatment and SDV, focusing on the progression of suicidal thoughts and behaviors over time. This study is significant and innovative because it will clarify the relationship between child maltreatment and SDV, identify high-risk subgroups, and examine if existing CWS interventions mitigate or exacerbate SDV risk, providing critical insights into the strengths and limitations of current maltreatment practices in reducing other forms of violence.

NIH Research Projects · FY 2025 · 2025-09

––– PROJECT SUMMARY / ABSTRACT –––––––––––––––––––––––––– Sleep Deficits Induced by Alcohol –––– Alcohol use disorders (AUD) are a public health problem for which few effective treatments exist. Alcohol drinking causes sleep disturbances, both acutely, as well as with chronic use. These long-lasting sleep deficits are often ‘alleviated’ by drinking yet more alcohol, thus reinforcing a vicious negative cycle. A large fraction of AUD patients in recovery will continue to experience sleep deficits, even after other physical withdrawal symptoms have subsided. That fraction of abstainers is most at risk for relapse. Despite its obvious clinical significance, very little is understood about the mechanistic links between alcohol consumption and the development of long-lasting sleep deficits, and how these sleep deficits might be addressed to reduce continued or relapsing alcohol use. This proposal aims to undertake a mechanistic investigation into the genes and neurons that regulate alcohol-induced sleep deficits, with the long-term goal of finding interventions to ameliorate these deficits. We use Drosophila as a model organism because of its economy of scale and face- valid behaviors, i.e. alcohol responses that ‘look like’ those in humans. We propose to build on our substantial foundational data showing that sedating alcohol exposures lead to long-lasting sleep deficits for days after alcohol exposure and clearance. This includes loss of total sleep amount, especially at night, an increase in sleep latency, which means that it takes flies longer to fall asleep after lights out, and poor sleep quality — all recapitulating human phenotypes. In Aim1 we will investigate behavioral correlates and predictors of alcohol- induced sleep deficits. In Aim2 we will investigate the genetic mechanisms of ethanol-induced sleep deficits based on our preliminary data from three genes, generated using three orthogonal approaches. We will investigate the role of the insulin receptor signaling pathway, which we have previously shown to regulate behavioral responses to alcohol. We will also test 216 candidate genes associated with sleep phenotypes in humans for their role in alcohol-induced sleep deficits. In Aim3 we will determine neurons and circuits that mediate ethanol-induced sleep deficits, based on our preliminary findings that different neurons have distinct effects on ethanol-induced sleep deficits. This necessary step will allow us to address mutants’ pleiotropy, affecting multiple alcohol responses, and it also paves the way to investigate the molecular changes induced by alcohol that might mediate persistent sleep deficits. Together, these data will provide first mechanistic insights into the long-lasting sleep deficits that are induced by alcohol. Because these deficits pose a significant risk factor for continued and relapsing alcohol use, our mechanistic investigation will also suggest potential interventional strategies.

NIH Research Projects · FY 2025 · 2025-09

7. Project Summary Atypical atrial flutter ablation outcomes are poor, with high recurrence rates following ablation procedures. Patient-specific computational models have recently shown promise as a tool for pre-ablation planning, with the ability to locate all possible reentrant circuits before a procedure. However, such models suffer from a lack of parameter optimization and high computational costs. The goal of this project is to apply state-of-the-art computational methods to improve the parameterization of patient-specific models of atypical atrial flutter. Aim 1 will investigate the effect changing input parameters has on the flutter circuits observed. By systematically varying these parameters, we will establish a quantitative relationship between model inputs and outputs. This will help us quantify the uncertainty in the models and identify the most critical parameters that influence the accuracy of the predictions. Aim 2 will look to increase the accuracy of scar detection from LGE-MRI using deep learning. Accurate detection of scar tissue from late gadolinium enhancement magnetic resonance imaging (LGE-MRI) is crucial for creating precise models. We will develop and test an overcomplete convolutional neural network (CNN) to improve scar segmentation, addressing challenges posed by image quality and scan variations. Aim 3 strives to personalize the electrophysiology parameters of the model. By tuning electrophysiology parameters to match patient-specific data, we will compare the accuracy of personalized versus generalized models in predicting clinically observed circuits. This personalization is expected to significantly enhance the predictive power of the models, making them more useful for clinical decision-making. Success in this project will improve the personalization of patient-specific atypical atrial flutter models, allowing for more accurate prediction and further clinical utilization. This project will also provide me with the technical expertise and scientific training required to be an independent research scientist in the field of cardiac electrophysiology and computing.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract This proposal investigates metabolite transport modulation in the setting of myocardial ischemic-reperfusion (I/R) injury. I/R is a consequence of the standard of care for heart attack patients and leads to heart failure (HF). The overall aim of this grant is to develop novel interventions to mitigate injury to the heart by focusing on metabolite transport modulation. The experiments focus on the inhibition of monocarboxylate transporter 4 (MCT4), which is crucial for lactate excretion, and potentially other metabolites from cardiomyocytes. My previous research has shown the potential for cardioprotection with MCT4 inhibition. The four specific aims that are proposed in this grant are as follows: K99-Aim 1: Define metabolite transport and utilization in response to I/R with and without MCT4 inhibition in vitro. K99-Aim 2: Determine metabolite transport in vivo during I/R injury with MCT4 inhibition. R00-Aim 1: Test whether MCT4 inhibition is sufficient to protect against development of ischemic cardiomyopathy. R00-Aim 2: Determine roles for MCT4 inhibition in preserving human myocardium in ex vivo injury models. By uncovering how MCT4 inhibition influences myocardial biology, my research offers a therapeutic approach to alleviate cardiac injury. Continued training will add new dimensions to my knowledge base that will be broadly applicable to my goal of leading a lab at a top-tier research institution studying protection from cardiovascular diseases (CVD). These avenues of research have the potential to alter our understanding and approaches to cardiovascular medicine, and my long-term vision is to develop novel approaches in the fight against CVD that will improve quality of life. To accomplish this, I have a team of supportive faculty mentors who are experts in cardiovascular and metabolism research. The UofU has exceptional researchers who collaborate through institutional organizations such as the Nora Eccles Harrison Cardiovascular Research & Training Institute and the Diabetes and Metabolism Research Center. This award is foundational for my scientific career, bridging in- depth research with practical, clinical utility in cardiovascular medicine. These experiments will lay the groundwork for new therapeutic approaches during cardiac injury. Under the guidance of my co-mentors and my team of collaborators during this K99/R00, this grant will allow me to eventually transition seamlessly from my current mentored position into an independent research group leader at an R1 institution.

NIH Research Projects · FY 2025 · 2025-09

Although the American Diabetes Association (ADA) guidelines help clinicians choose medications for type 2 diabetes based on comorbidities, they primarily offer broad class-based recommendations. However, more granular decisions are needed to account for intra-class drug differences, considering factors like HbA1c reduction, weight impact, hypoglycemia risk, cost, and side effects. Thus, it is crucial to explore whether real-world data could provide insights beyond what is currently available in the ADA guidelines to support personalized clinical decisions. This K01 project aims to address these gap by developing Diabetes Recommendations Enhanced with AI Models (DREAM), a set of predictive models leveraging large, cross-institutional electronic health record (EHR) datasets, including Epic Cosmos, TriNetX, and AHEAD datasets. These models will predict HbA1c, weight, and hypoglycemia events 6 months into the future for each ADA-guideline compliant medication option. The project has three specific aims: (1) Develop DREAM 1.0, a set of predictive models to estimate individualized outcomes for pharmacotherapy options, including HbA1c, weight, and hypoglycemia; (2) Characterize variation in diabetes pharmacotherapy across patient subgroups using clustering methods to identify prescription patterns by demographic and clinical characteristics; and (3) Improve predictive model performance across patient subgroups. In addition to the research aims, this K01 award will provide Dr. Polina Kukhareva with training in diabetes pharmacotherapy, artificial intelligence, and subgroup-specific performance evaluation. Her four key career goals are: (1) gaining expertise in diabetes pharmacotherapy through specialized courses and clinical experiences; (2) acquiring advanced AI skills for EHR data analysis, including deep learning and clustering, and learning bias mitigation techniques; (3) strengthening understanding of clinical variability and its implications for AI development; and (4) building research leadership and grant-writing skills to lead multidisciplinary research teams and prepare for NIH funding. Dr. Daniel Malone, a recognized leader in pharmacotherapy and pharmacoepidemiology, will serve as Dr. Kukhareva’s primary mentor, supported by an interdisciplinary team of experts in AI and diabetes management. This mentorship, combined with the University of Utah's strong research environment, will equip Dr. Kukhareva with the tools and expertise to become a leader in developing AI solutions for personalized type 2 diabetes care.

NIH Research Projects · FY 2025 · 2025-09

Boyu Hu, MD is an Associate Professor at the Huntsman Cancer Institute (HCI) and a clinical investigator whose research has focused on discovering novel and combination treatments for patients with lymphoid malignancies. His portfolio of clinical trials for lymphoma and chronic lymphocytic leukemia (CLL) addresses key areas of unmet need and includes National Cancer Institute (NCI)-sponsored trials whose results will have practice-changing implications. The scope of this program is significant and aims to improve the local, national and international care of lymphoma patients through drug discovery and reduction of treatment toxicities. Due to Dr. Hu’s participation in the SWOG cooperative group and the National Clinical Trials Network (NCTN), he dedicates 40% of his time to performing and promoting NCI-sponsored clinical trials. This includes Dr. Hu’s efforts as the national co-chair and lead adult principal investigator (PI) for the early-stage Hodgkin lymphoma (HL) cooperative group study, AHOD2131 (NCT005675410), and national PI for the upcoming SWOG-led NCTN trial for relapsed/refractory marginal zone lymphoma, MOZART MZL (NCT pending). As Director of Lymphoma and CLL at HCI, he has been a strong champion of NCTN-based studies leading his group to open almost every NCI-sponsored lymphoma/CLL study, which has resulted in HCI being top 10 nationally for accrual in several of the studies on which he is the site PI including S1826 (HL), EA4151 and EA4181 (both mantle cell lymphoma). Dr. Hu also sponsors the HCI lymphoma/CLL group to engage in the NCTN by sponsoring his lymphoma/CLL faculty to participate in the Lymphoma Committees for SWOG and ALLIANCE. Due to his extensive leadership experience and participation within the NCTN, he was selected as the SWOG co-PI for HCI’s UG1 grant (5UG1CA233178). All of Dr. Hu’s efforts within the NCTN are currently unfunded. At HCI, he serves on several committees dedicated to hematology clinical research including his role as a physician leader for both the hematology clinical trials research group and HCI clinical trials office, and member of institutional protocol development committee. Furthermore, he is the primary mentor for multiple junior faculty within the lymphoma/CLL group as well as a pediatric oncologist at Primary Children’s Hospital of Utah. Each of his mentees have received prestigious foundational career development awards under his mentorship. The R50 Award would support Dr. Hu to continue his work at HCI and within the NCTN, which in turn would aid in achieving the long-term goals of NCI-funded clinical research including: 1) utilization of results from HCI investigator-initiated studies to develop new cooperative group studies and advocating for promising junior faculty to lead these national trials, 2) expand access to clinical trials for all patients within HCI’s catchment area, especially for those in rural areas, and 3) increase clinical trial enrollments through utilization of HCI’s Patient Navigation and Patient & Public Education Programs.

NIH Research Projects · FY 2025 · 2025-09

More than 10% of U.S. households have experienced food insecurity (FI) every year for the past two decades. FI is associated with depression, hypertension, obesity, and type 2 diabetes and costs the U.S. healthcare system $53 billion annually. Therefore, addressing FI can have a significant impact on public health. Progress in reducing FI is hampered because FI is a dynamic problem: people can experience it multiple times throughout a year; individual- and community-level disruptions contribute to local and temporal surges of FI; and these disruptions can impact people who have never experienced FI. This dynamism creates unexpected local surges in FI, while our current food system is not equipped to deal with these sudden surges in FI. Federal nutrition assistance programs, while necessary and impactful, cannot provide immediate assistance as their application processes can take up to a month. They also fail to reach all low-income individuals with FI and to provide enough benefits to their clients. This has led to an influx of food demands for emergency food providers (e.g., food banks/pantries, Soup Kitchens). However, we still do not know when and where these resources are most needed. This leads to an inability to meet the local food demands promptly, and thus, people experiencing unmet food needs will face the health consequences of FI. Without addressing this gap, FI will continue to contribute to health differences. A local, real-time understanding of FI can inform timely interventions. One potential early warning metric for local surges of FI is the 2-1-1 network (211). 211 is a nationwide, free public referral system that responds to >20 million requests for help each year from U.S. residents. Service navigators at 211 direct callers to resources that can address unmet needs. For instance, navigators connect callers with food needs to nearby food pantries. Our objective in this project, to be conducted in Utah, is to gauge the usefulness of 211 food-related calls to be used as a local, real-time surveillance system for FI. Using the CDC’s guidelines for public health surveillance systems, we will determine the timeliness and validity of 211 food-related calls in detecting FI aberrations. Based on preliminary analyses and literature, we hypothesize that the system can quickly detect statistically significant ZIP Code-level FI aberrations (timeliness) and can replicate external sources of FI-related trends (validity). The rationale for our project is that FI is a dynamic problem and requires prompt responses, yet we do not know when and where surges in food demands happen to intervene. Using advanced geographic information system and aberration detection methods, our Specific Aims are to: (1) Determine the timeliness of 211 food-related calls in detecting FI aberrations; and (2) Determine the validity of 211 food-related calls for FI surveillance. The expected outcome of this project is a scalable, timely, and valid surveillance system to detect local FI aberrations, which can enable place-based, timely FI interventions.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Colorectal Cancer (CRC) is a significant burden on human health and in need of better diagnostics and treatments. Microbes have been implicated in ~20% of all human cancers, and recent studies have shown strong associations of CRC with bacteria residing in the gut. The gut microbiota has well-established roles in modulating intestinal immune responses that can exacerbate or alleviate inflammation, however, the ways in which members of the gut microbiota modulate pro or anti-tumor immune responses remain largely unknown. Colonic tumors are infiltrated by surrounding immune cells and disease outcome is heavily influenced by which immune cells are recruited to tumors and their roles within the tumor microenvironment (TME), therefore, understanding the mechanisms of how gut bacteria can modulate those infiltrating immune cells is critical in designing new and more improved diagnostics and interventions. In my work investigating human microbiotas from CRC patients, I discovered a human gut commensal, Bacteroides uniformis, protects against disease by enhancing anti-tumor immunity. This protection is dependent on Natural Killer (NK) cells and is effective in multiple pre-clinical mouse tumor models. I found that B. uniformis directly activates NK cells, and this effect is independent of adaptive immunity. However, the bacterial factors recognized by NKs are still unknown, as are the dynamics within the NK cells after B. uniformis stimulation in the gut and TME. B. uniformis and other Bacteroides spp. can modulate immune responses via their unique capsule polysaccharides, but their impact on anti-tumor immunity is unknown. Therefore, I hypothesize that B. uniformis directly activates NK cells, through its capsule molecules, resulting in remodeling of the immune landscape in the tumor microenvironment, and enhancing anti- tumor immunity to protect against CRC. I will investigate this hypothesis along three lines of interrogation. Specific Aim 1: Identify the bacterial factor by which B. uniformis modulates NK cell activation and cytotoxicity. Specific Aim 2: Determine how strain level genetic variations in B. uniformis influences immune activation and CRC development. Specific Aim 3: Investigate how bacterial induced NK activation in the tumor microenvironment promotes anti-tumor immunity. By completion of this proposed work I will have a more nuanced understanding of the mechanisms by which B. uniformis prevents tumor formation via NK cells in the TME, which will lead to translational progress in innovative diagnostics and novel therapies for patients with CRC.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Preeclampsia (PE) is a pregnancy-specific syndrome of progressive vascular dysfunction that leads to escalating hypertension and extensive maternal organ damage, which can ultimately result in death. Occurring in 5-8% of pregnancies worldwide, PE is a leading cause of both maternal and perinatal mortality. Beyond the short-term risks, PE survivors suffer a 2-6-fold increase in lifelong risk of future hypertension (HTN), heart failure, stroke, and cardiovascular (CV)-specific mortality. Despite its high incidence, the underlying genetic and environmental contributions to PE is lacking. Recent advances now allow for the simultaneous analysis of multiple types of omics data (“multi-omics”), offering new opportunities to identify risk factors for PE and its long-term CV effects. In this project, we will use TOPMed- supported omics data from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be Heart Health Study (nuMoM2b-HHS) as well as supplementary data from its parent study, nuMoM2b. Both cohorts possess extensive phenotyping variables. These variables were collected in a standardized manner throughout the course of pregnancy and the postpartum period, providing an unparalleled level of depth in a large cohort with long-term follow-up. The nuMoM2b and nuMoM2b-HHS cohorts, with their diverse sample types, large cohort size, comprehensive clinical and psychosocial phenotyping, and long-term CV follow-up, provide an unparalleled platform for a holistic analysis of the factors contributing to the increasing burden of CV morbidity associated with PE. The long-term goal of our study is to identify risk variants, gene targets and pathways for PE and its associated long-term CV effects. Our current objective is to perform a first-time analysis of whole genome sequencing (WGS) data in the nuMoM2b-HHS cohort together with an integrated analysis of multidimensional data from the nuMoM2b-HHS cohort. To achieve our objective, we propose the following aims. Aim 1: Determine the genetic architecture of PE (and its long-term CV effects) and gene environment interactions. Aim 2: Determine the role of placental trophoblast gene expression in the development of PE and long-term CV effects and perform in- depth multi-omics data integration to provide molecular insights into PE. Aim 3: Optimize predictive models for PE (and long-term CV effects) through machine learning and integration of clinical, environmental, and multi- omics data. Completion of these aims will provide one of the most comprehensive models of PE to date, that integrates data from both the maternal cardiovascular system and placenta-fetal interface. This work will lay the groundwork for further investigation of the reproductive origins of PE, CV morbidity and health across the lifespan.

NIH Research Projects · FY 2025 · 2025-09

PROJECT ABSTRACT Treatment of children with sepsis-induced multiple organ dysfunction syndrome (MODS) requires optimal dosing of drugs. Drug dosing may need to be adjusted in these children because of altered drug pharmacokinetics (PK) and pharmacodynamics (PD), resulting from: 1) inflammation and capillary leak leading to increased volume of distribution; and 2) organ dysfunction causing decreased drug clearance. The impact of these alterations can be quantified using physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) modeling. Anakinra is an interleukin-1 receptor antagonist (IL-1Ra) that is FDA approved to treat hyperinflammatory syndromes in children. The use of anakinra in children with sepsis-induced MODS is currently being evaluated in the Personalized Immunomodulation in Pediatric Sepsis-Induced MODS (PRECISE) trial, a multi-center randomized control trial wherein children are randomized to receive anakinra or placebo if they have sepsis-induced MODS with hyperinflammation. In this population, optimal dosing of anakinra is unknown. In addition, the role and kinetics of endogenous IL-1Ra is unknown. These gaps in the understanding of anakinra PK and PD place these children at risk for treatment failure and toxicity. The objective of this proposal is to leverage the PRECISE trial to evaluate the impact of sepsis-induced MODS on the kinetics of endogenous IL-1Ra and anakinra. Based on these results, we will use a PBPK-PD modeling approach to determine a safe and efficacious anakinra dosing regimen. Specifically, the proposed work will 1) characterize the kinetics of endogenous IL-1Ra in children with sepsis-induced MODS who receive placebo in the PRECISE trial; 2) incorporate relevant drug and population specific factors into a PBPK-PD model to predict anakinra disposition and efficacy; 3) validate the model using prospective data obtained from children receiving anakinra in the PRECISE trial and establish a model- and biomarker-informed anakinra dosing regimen. Training will take place at the University of Utah under the mentorship of a pediatric trialist and leading expert in PBPK modeling. Through my training plan, I will develop the necessary skills for a career as an independent physician scientist including training in advanced pharmacology, clinical trial design, scientific communication, and sophisticated modeling and simulation techniques.

NIH Research Projects · FY 2025 · 2025-09

PROJECT ABSTRACT Inflammatory bowel diseases (IBDs), which entail debilitating gastrointestinal symptoms, affect millions of people worldwide. Interestingly, IBD patients suffer from anxiety & depression more often than the general population. Gastrointestinal symptoms of human IBDs are typically chronic and relapsing, but the co-occurring psychological abnormalities are relatively constant. Some studies have investigated the effect of active intestinal inflammation on the brain, but little work has been done to characterize changes to the brain during relapsing intestinal disease remission, when behavioral symptoms remain. Thus, the long-term goal is to understand colitis-induced neuroinflammatory dynamics and the mechanism through which they are conveyed. Neuroinflammation can be deleterious to the brain and contributes to the progression of many psychological & neurological diseases. The Round lab has identified two major neuroinflammatory phenotypes that may be contributing to the intestinal inflammation-induced psychological manifestations: (1) Calprotectin is elevated in the brain early and persistently during relapsing intestinal insult, and (2) monocyte and neutrophil infiltrate the brain ten days after colitis induction. Calprotectin can stimulate inflammation, leukocyte recruitment, and apoptosis in a variety of tissues and disease contexts; however, it is not well understood how calprotectin contributes to persistent colitis-induced neuroinflammation or what the functional role of the infiltrating immune cells is. Aim 1 will determine what cell type in the brain is responsible for the elevated calprotectin and its necessity for immune cell recruitment. Aim 2 will determine whether these cells are facilitating brain tissue repair or destruction. Finally, the mechanism of gut-brain communication during colitis still needs elucidation. It has been demonstrated that colitis can increase bone marrow granulopoiesis; thus, Aim 3 will test if changes in bone marrow during colitis are persistent and contribute to brain immune cell infiltration. Overall, this proposal will test the hypothesis that relapsing intestinal insult leads to elevated brain calprotectin levels that recruit multifunctional immune cells borne of persistently reprogrammed progenitor cells. In conclusion, this work will significantly enhance our understanding of the gut-brain axis during intestinal disease which can be leveraged for therapeutic benefit. This proposed research will facilitate the training of the applicant, Michaela Murphy, to prepare her for her career goal of becoming an independent scientific investigator in the gut-microbiota-brain axis field. It will develop her skills in 4 areas: (1) Knowledge & Experimental Design, (2) Technical Research Skills, (3) Science Communication, (4) Teaching & Mentorship, and (4) Leadership & Collaboration. Her sponsor, Dr. June Round, has the mentoring experience, supportive environment, and scientific expertise to ensure the successful execution of Michaela’s training plan, and the University of Utah provides ample resources to facilitate the efficient completion of this project and Michaela’s professional development.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Leukoencephalopathy with Vanishing White Matter (VWM) is a rare neurodegenerative leukodystrophy that presents with ataxia, seizures, and progression to death. There are no clinicaltreatments for VWM, and our ultimate goal is the development of a therapy for VWM. VWM is caused by autosomal recessive mutations in the five subunit genes of the Eukaryotic Initiation Factor 2B (EIF2B) complex, which is necessary for regulation of the integrated stress response (ISR). VWM has abnormal, persistent activation of the ISR. Current dogma in the field has settled on astrocytes as responsible for VWM pathophysiology. We developed adeno-associated virus (AAV)- mediated EIF2B5 gene (the most commonly mutated subunit) replacement therapy for VWM with targeted astrocyte expression. In both the classic R191H mouse model and a more severe I98M mouse model, we showed rescue of VWM-disease related phenotypes (Herstine et al., 2024). However, we observed waning efficacy in treated VWM mice. Interestingly, our preliminary data showed recrudescent ISR activation that mirrored presence of activated microglia. Further, we found that untreated mice have extensive infiltration of Iba1+/CD68+ microglia into the CNS. Activated microglia secrete cytokines which induce reactive astrocytes in vitro and in vivo. Our hypothesis is that activated microglia contribute to VWM pathophysiology, and that transplant of wild-type microglia is necessary for full gene therapy rescue of VWM by interrupting the cycle of microglia-driven reactive astrocyte activation.To test our hypothesis, we propose first, to Characterize microglial phenotypes in wild-type, mutant, and AAV9-treated mutant VWM mice. We will characterize the timing and extent of activated microglia involvement in the CNS, in R191H and I98M mice, at defined ages; in comparison to wild-type and AAV9-treated VWM affected mice. Histological, molecular, and biochemical targets include CD68 and Iba1 (for activated and stable microglia); and CNS tissue markers (GFAP, astrocytes; NeuN and neurofilament light, neurons; and Olig2, fluoromyelin, oligodendrocytes and myelin). Second, we will Perform microglia replacement using circulation-derived myeloid cells (CDMCs) in VWM mice in conjunction with or without AAV9 gene therapy. Since dysregulated microglia may interfere with gene therapy rescue, we will test a combination approach of microglia transplantation and gene therapy. We will use a published protocol, which we have demonstrated in preliminary data is effective for VWM mice at our lab (busulfan ablation of endogenous hematopoietic cells, followed by bone marrow transplant with donor circulation derived myeloid cells (CDMC)). With use of PLX5622 (a CSF1R inhibitor required for native microglia), the CDMC cross the blood-brain barrier and replace endogenous microglia. Our experiments will include 3 mouse groups: VWM mice; VWM mice receiving CDMC replacement and AAV9-EIF2B5 gene therapy; and VWM mice with CDMC only (no gene therapy).

NIH Research Projects · FY 2025 · 2025-09

Project Summary: Cardiovascular disease has consistently been the leading cause of death in the US for the last century with resultant heart failure (HF) accounting for nearly 800,000 deaths per year. Despite substantial advancements in clinically available interventions, the incidence of HF continues to rise with a staggering estimated economic burden of >$900 billion per year by 2030. Virtually all etiologies of cardiovascular disease leading to both heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) involve pathological remodeling of the left ventricle characterized by excessive deposition of extracellular matrix (ECM) proteins that impair ventricular compliance and perpetuate HF pathogenesis. The primary cell type responsible for synthesizing and secreting ECM proteins are resident cardiac fibroblasts (CFBs) that become activated by diverse stimuli during HF. As a testament to the secretory potential of CFBs, a single fibroblast can produce >500,000 procollagen chains per hour which necessitates the presence of a robust network of protein folding machinery in the endoplasmic reticulum to maintain cellular proteostasis and allow for the proper processing of nascent ECM proteins. Such protein folding demands trigger activation of the unfolded protein response (UPR), an adaptive component of the proteostasis network to facilitate proper protein quality control. Our long-term goal is to determine the mechanistic contributions of the UPR in regulating chronic CFB activation and reactive cardiac fibrosis in response to HFrEF and HFpEF. Our preliminary data support the notion that the IRE1 arm of the UPR plays a pivotal role in protecting against fibrotic remodeling in the heart via targeted mRNA degradation of transcripts encoding proteins required for CFB activation, namely Tmem100. We’ve also characterized a novel small molecule activator of IRE1 with potential to ameliorate functional decline in a preclinical model of HFrEF. In this proposal, we will focus on IRE1 and whether tactile control of the endonuclease activity of IRE1 could alter CFB activation and ECM deposition with the hypothesis that IRE1 protects against pathological cardiac fibrosis in HF via regulating the selective degradation of Tmem100 and a pro-fibrotic transcriptome. We will address this hypothesis using fibroblast-specific gene targeting in complimentary mouse models of HF, as well as mechanistic studies in primary CFBs, in the following Specific Aims which are to: (Aim 1) determine the cardiac fibroblast transcriptomic profile regulated by IRE1 using a mouse model of HFrEF, (Aim 2) determine the functional significance of IRE1-mediated degradation of Tmem100 mRNA in fibrotic remodeling using a mouse model of HFrEF, and (Aim 3) evaluate the therapeutic efficacy of novel small molecule activator of IRE1 in mitigating fibrotic remodeling using mouse models of HFrEF or HFpEF. These studies are significant as they present the opportunity to identify novel mechanisms contributing to CFB activation and ECM deposition as well as to test new therapeutic strategies with potential to ameliorate fibrotic remodeling associated with both HFrEF and HFpEF.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Squamous cell carcinoma (SCC) is one of the most common cancers worldwide, with over one million deaths annually. While treatments such as chemotherapy and radiation are available, their severe side effects highlight the need for targeted therapies. SCCs from diverse tissues often share the overexpression of the transcription factor SOX2, which has been implicated in tumor initiation and maintenance. Despite its central role in SCC, therapeutic targeting of SOX2 remains challenging, necessitating a deeper understanding of its oncogenic transcriptional program and regulatory mechanisms. Our preliminary work demonstrates that SOX2 acts primarily as a transcriptional activator in SCC, binding promoters and distal enhancers to upregulate cancer- relevant genes via chromatin loops. Interestingly, many SOX2 binding sites are co-occupied by the oncogenic transcription factor TP63, a known master regulator in SCC. TP63 also functions as a pioneer factor, opening chromatin to facilitate binding by other factors including SOX2. Despite their established co-regulatory role, little is known about the mechanisms by which SOX2 and TP63 interact to regulate target gene expression in SCC. We hypothesize that SOX2 and TP63 co-occupy enhancers and upregulate target genes driving oncogenic pathways in SCC. This study aims to elucidate the functional regulatory role of SOX2 in SCC by addressing two key aims. First, characterizing the cancer-specific transcriptional program regulated by SOX2. Using an integrated genomics approach combining CRISPR-Cas9-mediated SOX2 knockout RNA-seq, SOX2 ChIP-seq, and H3K27ac HiChIP, we will identify direct SOX2 target genes. We will then prioritize genes relevant to human SCC using data from the Cancer Genome Atlas. We will evaluate the role of these prioritized target genes in cell proliferation and tumor growth using an in vitro competition assay and in vivo xenograft models. Second, we will explore the interplay between SOX2 and TP63 at shared enhancer binding sites. We hypothesize that TP63 facilitates chromatin accessibility, enabling SOX2 binding, and together, they regulate critical oncogenic pathways. This will be tested using CRISPR Cas9-based enhancer motif disruption, and RNA-seq and ATAC-seq following TP63 knockout to assess changes in chromatin accessibility and gene expression. This work will reveal SOX2 target genes, and how SOX2 along with TP63 drives SCC, providing insights into cancer-specific pathways that could serve as therapeutic targets. Furthermore, the insights gained may extend to other cancers where SOX2 activation is implicated, broadening the impact of this work.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Widespread deficits in ambulatory capacity (e.g., reduced walking speed and increased metabolic cost) with age have far-reaching health impacts and are strongly associated with older adult life expectancy. Recently, the foot’s muscles and joints have been implicated in regulating gait propulsion, an important variable for maintaining walking capacity. Older adults have substantially weaker foot muscles, deficits that are associated with diminished walking speed, highlighting the foot as a key new target for mitigating age-related mobility deficits. However, traditional analysis techniques which have formed the basis of our modern understanding of gait propulsion misattribute the foot’s mechanical contribution to the ankle joint and its associated musculature. This fundamental misunderstanding of gait propulsion thereby sets the stage for elucidating the foot’s role in age- related gait impairment and highlights new targets for restoring older adult ambulatory capacity. I posit that age- related toe flexor weakness results in impaired foot joint and muscle function, contributing to mobility deficits which can be mitigated using low-cost assistive devices. Across both of the proposal’s aims, I will for the first time leverage state-of-the-art biomedical imaging, gold standard indwelling electromyography, and high-fidelity musculoskeletal computational simulation to assess age-related differences at the foot that contribute to gait deficits. Aim 1: I will capture differences in foot bone motion, foot strength, and foot muscle behavior between healthy younger and older adults to define mechanistic linkages between foot muscle weakness, foot joint and muscle behavior, and hallmark age-related propulsion deficits. Aim 2: I will then examine how low-cost assistive devices (i.e., carbon fiber shoe insoles) directly influence foot bone motion, foot muscle dynamics, and clinical measures of walking ability. Using advanced bone motion and muscle measurement in conjunction with high- fidelity musculoskeletal simulation, this proposal will substantially improve our understanding of age-related mobility impairments by uncovering the role of foot-based deficits arising from pervasive toe flexor weakness that plagues the older adult population. As such, my findings will have an immediate clinical impact on targets for future therapeutic intervention as well as ideal device design to restore older adult ambulatory capacity. Through the research training plan I have developed, I will acquire novel training in biomedical measurement modalities (i.e., computed tomography, biplane fluoroscopy, cine B-mode ultrasonography, and indwelling electromyography), clinical gait analysis, and assistive device implementation. These new skills, along with my previous expertise in whole-body motion capture and high-fidelity computational simulations, will prepare me well to embark on an independent career as a principal investigator at a research-intensive university. Specifically, I will leverage this postdoctoral training to deploy in vivo and in silico approaches to examine mechanisms underlying efficient and inefficient human movement in health and disease.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The transformative discovery of immune checkpoint inhibitors (ICIs) has unlocked antitumor immune responses in a wide range of cancer patients. Nonetheless, alternative treatment options are critically needed for the majority of patients who are non-responders to ICIs. Even cancer types known to have the highest response rates such as Hodgkin lymphoma can cause relapsed or refractory disease in a subset of patients. Among the key factors hindering the clinical benefit of ICIs are T cell exhaustion and suppressive myeloid cells. Exhausted T cells can be locked in a dysfunctional state by multiple redundant mechanisms including the suppressive action of myeloid cells. Despite the documented clinical relevance of suppressive myeloid cells, however, targeted therapies remain in clinical development. The Research Plan addresses the hypothesis that JAK inhibitors in conjunction with checkpoint inhibitors convert myeloid cells from a suppressive into an immunostimulatory state, inducing clinical responses in ICI monotherapy-resistant patients. The proposed studies leverage concordant preliminary preclinical and clinical preliminary data from preclinical cancer models and a clinical trial in Hodgkin lymphoma patients with high efficacy. In Aim 1, key mechanistic features of the effects of the JAK inhibitor ruxolitinib will be determined. Aim 2 focuses on the identification of cellular and molecular correlates of response to the combination therapy of ruxolitinib with the ICI nivolumab in Phase 1b and II clinical trials of relapsed or refractory Hodgkin lymphoma, including evaluation of the hypothesis that responders exhibit more baseline circulating suppressive myeloid cells than non-responders. In Aim 3, the cell- intrinsic role of JAK1 and JAK2 in this combination therapy will be established, and the hypothesis that MHC class I-independent responses are preferentially enhanced will be tested. The principal investigator Dr Zak is an immunologist with expertise in chemical biology, computational biology and clinical studies, possessing a comprehensive toolkit to execute this translational project. His long-term goal is to establish an independent research program centered on identifying and targeting immunosuppressive pathways in cancer. Dr Zak has established a clinical collaboration enabling the development of a novel combination therapy. A comprehensive career development plan addresses four key areas of training to enhance the launch of his research program: (1) utilizing relevant models of cancer, (2) design, management and analysis of collaborative clinical studies, (3) grantsmanship and progression towards independent grant submission and (4) establishing a laboratory, hiring, mentoring and management. The career development activities will forge the skills needed to launch and sustain an independent academic research program in cancer immunology.

NIH Research Projects · FY 2025 · 2025-09

Hepatocellular carcinoma (HCC), the predominant primary cancer of the liver, is 4th leading cause of cancer deaths, and the fastest growing malignancy in the US. Advanced-stage HCC remains largely incurable due to a dismal response rate (<20%) and therapeutic resistance. The current obesity epidemic has been associated with the rising prevalence of metabolic (dysfunction) associated fatty liver disease (MAFLD) and its inflammatory component, non-alcoholic steatohepatitis (NASH), which can lead to HCC. MAFLD-HCC incidence is increasing dramatically, underscoring an unmet medical need for new diagnostic and treatment strategies. Here, we describe a novel tumor suppressor role of the Hypoxia-Associated Factor, HAF, in MAFLD-HCC. Both global haploinsufficiency and hepatocyte-specific deletion of HAF in mice result in HCC with hallmarks of NASH including severe steatosis with hepatocyte degeneration (hepatocyte ballooning), fibrosis, and increased inflammatory cell infiltration. HAF loss in both mouse models or by siRNA transfection in HCC cells is associated with decreased activation of the p65/p50 NF-κB transcriptional subunits, and in decreased levels of their upstream regulators, TAK1 and NEMO. Endogenous HAF forms a complex with NEMO and TAK1, suggesting that HAF modulates the NF-κB pathway by directly modulating the stability of these proteins, potentially through HAF’s E3 ubiquitin ligase activity. HAF knockdown was associated with increased spontaneous apoptosis, whereas HAF overexpression protected cells against TNF-induced cell death, suggesting that HAF may play a tumor suppressor role by protecting cells against death associated with liver inflammation (hepatitis) that can lead to HCC. Indeed, HAF levels are suppressed by conditions prevalent during hepatitis such as hypoxia and elevated TNF or TGF-β, whereas HAF are increased by DNA damage, suggesting that HAF may contribute to NF-κB activation in response to genomic instability in pre-neoplastic hepatocytes. Significantly, HAF was highly expressed in most cases of human hepatitis but was undetectable in 94% of human HCCs examined (65 cases). Thus, our hypothesis is that HAF plays a novel tumor suppressor role in HCC by facilitating NF-κB activation that promotes the survival of hepatocytes during hepatitis. Suppression of HAF by hypoxia or inflammatory cytokines during hepatitis results in increased cellular turnover that drives progression to NASH and HCC. Our overall goal is to identify new predictive/prognostic biomarkers or therapeutic targets for HCC, particularly those relevant to MAFLD-HCC. In Aim 1, we will test the hypothesis that HAF activates the NF-κB pathway by modulating the stability of TAK1 and NEMO, and thus identify the molecular mechanisms regulating the HAF- NF-κB axis. In Aim 2, we will test the hypothesis that HAF protects cells from excessive cell death during hepatitis, thus preventing progression to NASH and HCC. In Aim 3, we will test the hypothesis that HAF deregulation is associated with progression to HCC by investigating HAF expression in > 500 patient samples, to determine the association of HAF and its downstream targets to HCC initiation and progression or to treatment response.