Utah State Higher Education System--University Of Utah

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY / ABSTRACT Congenital cytomegalovirus (CMV) infection can lead to sensorineural hearing loss (SNHL) long after resolution of acute infection, implicating lasting alterations to tissue immunity, but the underlying pathogenic mechanisms remain poorly understood. The long-term goal of this project is to define the mechanisms by which congenital infection impinges on cochlear immune development to drive SNHL. The overall objectives in this application are (1) to determine the contribution of the fetal host immune cells, specifically resident tissue macrophages (RTMs) to normal cochlear development and (2) to determine how CMV shapes tissue immunity during perinatal development to drive cochlear dysfunction. The central hypothesis is that RTMs are crucial to normal cochlear development and that the response of fetal-derived RTMs to CMV infection is a critical mediator of cochlear damage that drives SNHL. Our preliminary data indicate that fetal macrophages of distinct ontogenetic origin seed the cochlea in a specific spatiotemporal pattern. Temporal blockade of CSF1R, a regulator of fetal macrophage development, causes cochlear impairment and SNHL. Together, these findings suggest that fetal- derived RTMs are critical regulators of normal cochlear development and tissue homeostasis, but the precise mechanisms have not been delineated. The central hypothesis will be tested by pursuing three specific aims: 1) Define the contribution of fetal RTMs to normal cochlear development; 2) Determine the effect of acute CMV infection on RTM development; and 3) Determine the immune drivers of progressive SNHL following acute CMV infection. In the first aim, we will employ fate-mapping and deletion of specific ontogenetic macrophage subsets to define the spatiotemporal seeding and function of distinct waves of RTMs in normal cochlear development. In Aim 2, we will investigate the effect of acute CMV infection in the perinatal period on seeding, transcriptional, and functional regulation of RTM development in the cochlea. In Aim 3, we will examine how replacement of fetal RTMs with adult BM-derived RTMs reshapes cochlear immunity and cochlear function, both under homeostasis and in response to acute infection. We will combine fate-mapping, transcriptomic analysis and genetic deletion models to define how replacement of fetal RTMs with BM-derived RTMs contributes to cochlear inflammation, immune cell infiltration, and hearing function. The research proposed in this application is innovative because it examines the origins of CMV-associated SNHL and cochlear dysfunction from the perspective of immune ontogeny and because it integrates state-of-the-art fate-mapping and deletion models with single-cell transcriptomics, advanced microscopy, and specialized hearing tests to perform highly detailed mechanistic studies over the course of CMV pathogenesis and associated SNHL. The proposed research is significant because it will contribute fundamental knowledge about the developing auditory system and provide strong scientific justification to examine RTMs as a potential novel therapeutic target for SNHL treatment.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY / ABSTRACT Although chronic pain (CP) affects over 20% of the U.S. population, little is known about associated physiological consequences, which likely contribute to the patients’ functional limitations and high risk for cardiovascular disease. It is therefore the goal of this project to explore the impact of CP on cardiovascular function and to evaluate the potential and underlying mechanisms of an innovative pain management strategy to improve circulatory control in this vulnerable patient group. Two disease-related characteristics predispose CP patients to cardiovascular abnormalities during exercise. First, an enhanced responsiveness of sensory nerve endings and dorsal root ganglia (DRG) and the resulting high afferent feedback to medullary cardiovascular centers may exaggerate the exercise pressor reflex (EPR; a sympatho-excitatory reflex). Second, arterial baroreflex sensitivity (BRS), a sympatho-inhibitory reflex, may be decreased in CP. By studying both patients with CP from lower limbs and well-matched controls, we will evaluate the impact of CP on these neurocirculatory control mechanisms and associated consequences for the hemodynamic and neuromuscular fatigue response to physical activities. We will use lumbar intrathecal fentanyl and both the Modified Oxford method and the neck pressure/neck suction technique to evaluate the role of the EPR in determining the hemodynamic response to exercise and to determine baroreflex function. We will also study the impact of neuromodulation therapy (NMT), an innovative therapeutic approach that manages pain by electrically stimulating the spinal cord or DRG and subsequently blocking sensory feedback from reaching the brain, on muscle sympathetic nerve activity (MSNA) and the hemodynamic and neuromuscular fatigue response to rest and exercise in patients with CP. We will use direct peroneal and radial nerve recordings to quantify MSNA during handgrip and leg exercise. This will allow us to evaluate a) the direct effect of NMT (comparisons between NMT turned on vs turned-off) on efferent sympathetic nerve activity, and b) whether NMT affects EPR-mediated increases in sympathoexcitation during physical activity. Finally, ~40% of all CP patients suffer from clinical hypertension. We will therefore conduct these studies in normotensive and hypertensive patients and determine the efficacy of NMT to normalize the well-known hemodynamic abnormalities, including exaggerated MSNA and BP, during exercise in hypertensive individuals. If this project can, as suggested by our preliminary data, confirm a significant impact of CP on the circulatory and fatigue response to physical activity and that NMT can improve these impairments, but also the hemodynamic abnormalities associated with hypertension, the proposed studies will provide the scientific basis required to associate NMT with significant functional and cardiovascular health benefits.

NIH Research Projects · FY 2026 · 2024-08

This project seeks to comprehensively understand how gene regulatory elements within rapidly evolving areas of the human genome, segmental duplications, influence human evolution and disease. Despite their potential significance, these regions have historically been challenging to study due to technical limitations. The specific aims of this project are: 1. Characterize segmental duplications across the human population by constructing a pangenome graph using thousands of high-quality genome assemblies. 2. Establish a statistical and computational methodology for mapping regulatory DNA within SDs using long-read chromatin fiber sequencing (Fiber-seq). 3. Identify conserved regulatory and genomic elements within segmental duplication loci by mapping genetic and epigenetic haplotypes into the pangenome graph. 4. Uncover the regulatory fate of multi-copy gene families by analyzing segmental duplication para logs with Fiber-seq across tissues, determining if these para logs have undergone changes in regulatory function. Research Design and Methods: In this work, I will create a comprehensive SD pangenome graph by integrating thousands of long-read haplotypes from multiple consortia, which will significantly enhance our understanding of human variation within SDs. Next, I will use long-read Fiber-seq in conjunction with the development of a machine-learning framework to detect regulatory elements within SDs and use that information to impute the results of other short-read epigenetic assays. My approach will also involve a conservation analysis that prioritizes SD genes and regulatory elements. I will introduce a novel 'loss-of-paralog intolerance' (pLPI) score to rank these genes based on their conservation levels across populations. Additionally, the regulatory trajectories of SD genes will be determined using Fiber-seq conducted on a range of human tissues. This will help me identify distinct patterns such as neofunctionalization, subfunctionalization, or pseudofunctionalization. This investigative approach will deliver an in-depth understanding of the regulatory mechanisms in SDs using cutting-edge genomic tools. The insights gained have the potential to highlight human-specific regulatory adaptations and could pave the way for discovering new therapeutic avenues in personalized medicine.

NIH Research Projects · FY 2025 · 2024-08

Project Summary Myeloproliferative neoplasms (MPNs) include primary myelofibrosis (PMF; characterized by the over- proliferation of megakaryocytes and granulocytes with abnormal collagen deposition in the bone marrow stroma), essential thrombocythemia (ET; increased megakaryocyte and platelet production), and polycythemia vera (PV; increased red cell production, hemoglobin, and hematocrit). Although all MPN driver mutations lead to constitutive activation of JAK/STAT signaling, targeted JAK inhibitors are not curative and fail to alter disease progression. Therefore, there is a great unmet need to identify novel curative therapies for MPNs. Mutations in calreticulin (CALR) represent the second most common genetic abnormality in MPN. The CALR gene encodes a calcium (Ca2+)-binding chaperone protein that primarily resides in the endoplasmic reticulum (ER). All CALR mutations share an identical neomorphic C-terminal peptide, which permits binding to the thrombopoietin receptor MPL and the subsequent activation of pathogenic JAK/STAT signaling. The majority of CALR mutations are classified as either type 1 or type 2 based on the extent of homology to the wild type protein, where type 1 proteins exhibit complete loss of C-terminal Ca2+ binding sites that are retained in type 2. Despite their shared mutant C-terminus and ability to bind and activate MPL, type 1 and 2 CALR mutations engender significant phenotypic and prognostic differences. Type 1 mutations are more common in PMF, and are associated with increased risk of myelofibrotic transformation from ET. Conversely, type 2 mutations are primarily associated with ET, exhibit low incidence of myelofibrotic transformation, and are rarely found in PMF. The mechanisms underlying these divergent clinical phenotypes remain unknown. We discovered that the IRE1a/XBP1 pathway of the unfolded protein response (UPR) is differentially activated in type 1 versus type 2 mutant CALR cells, and that type 1 mutant CALR cells are dependent on this pathway for survival and to drive ET. We found that IRE1a/XBP1 is activated only by type 1 and not type 2 mutant CALR due to a loss of calcium binding function specific to the type 1 protein. More recently, we found that the ATF6 pathway of the UPR is differentially up- regulated in type 2 compared to type 1 mutant CALR cells, and that type 2 mutant proteins exhibit loss of molecular chaperone function. These data support the central hypothesis that type 1 and type 2 CALR mutations activate and depend on different arms of the UPR based on their respective losses of function, and that these pathways promote distinct disease phenotypes. Thus, targeting different arms of the UPR based on mutation type may represent a novel, individualized treatment strategy for type 1 versus type 2 CALR+ MPN patients. To test this hypothesis, we will dissect the role of the UPR in type 1 mutant CALR-driven fibrosis (Specific Aim 1) and type 2 mutant CALR-driven ET (Specific Aim 2), and determine if each is uniquely sensitive to therapeutic targeting of different arms of the UPR (Specific Aim 3).

NIH Research Projects · FY 2026 · 2024-07

Project Summary The human polycystin family of membrane proteins consists of versatile cellular censors classified as PKD1-like 11-transmembrane (TM)-spanning receptors (PKD1, PKD1L1, PKD2L2, and PKDREJ) and PKD2-like 6-TM- spanning cation channels (PKD2, PKD2L1, and PKD2L2). PKD1 and PKD2 were first identified as the two cul- prits that are mutated autosomal dominant polycystic kidney disease (ADPKD). ADPKD is the most common monogenic disorder and fourth leading cause of kidney failure. PKD1 and PKD2 assemble into a heteromeric receptor/ion channel complex at primary cilia in the kidney where they sense mechanical and/or chemical stimuli and contribute to the development and maintenance of the exquisite tubular architecture of nephrons. PKD2 additionally functions co-dependently with PKD1L1 at vertebrate embryonic node cilia to mediate Ca2+ influx, which initiates a transcriptional program that determines left-right asymmetry of internal organs and the vascu- latures. Mutations in PKD1L1 lead to development of heterotaxy, biliary atresia (BA), and congenital heart de- fects (CHD). PKDREJ and PKD2L2, two understudied polycystin members, likely participate in Ca2+ signaling in sperms and are crucial in male reproduction. Polycystin proteins have been historically studied using human genetics and functional analyses in model organisms, but we still do not fully understand their assembly princi- ples, structure-function relationships and channel properties. Furthermore, kidney cells secrete PKD1/PKD2 into urine in form of membrane-bound extracellular vesicles (EVs), sparking intense efforts to translate total urinary EVs as a non-invasive biomarker for prognosis/diagnosis of ADPKD but with limited success due to their inherent impurity. In this application, our goals are to: 1) determine structures and stoichiometry of the PKD1/PKD2, PKD1L1/PKD2, and PKDREJ/PKD2L2 complexes and define their channel properties that underlie their diverse roles in a range of sensory processes; 2) develop PKD1/PKD2-containing EVs into an ADPKD biomarker, profile their molecular cargo, and determine a PKD1/PKD2 structure embedded in EVs. Overall, our holistic and com- parative studies of various polycystin complexes will clarify the currently obscure mechanistic roles of these disease-associated channel proteins, provide a basis to understand the impact of disease-associated mutations, and inform future efforts to develop novel therapeutics to treat ADPKD, BA, and CHD.

NIH Research Projects · FY 2025 · 2024-07

PROJECT ABSTRACT This is an application for the NIAMS K01 Mentored Research Scientist Development award for Dr. Stephan Bodkin, an Assistant Professor in the Department of Physical Therapy and Athletic Training in the College of Health at the University of Utah. Dr. Bodkin is establishing himself as an emerging leader in sports medicine research, specifically in advancing clinical decision making in returning patients to activity following traumatic joint injuries. This K01 award will provide Dr. Bodkin the support necessary to accomplish the following career development goals: 1) Obtain training in molecular techniques of skeletal muscle cellular remodeling, especially relating to the quantification of intramyocellular lipids and fibrosis, 2) Expand my knowledge in age-related changes to skeletal muscle and cartilage degradation within the lifespan of osteoarthritis diagnosis, 3) Develop expertise needed for clinical interpretation of MRI as it relates to skeletal muscle and cartilage, and 4) Strengthen leadership and research skills required to conduct clinical trials successfully. To achieve these goals, Dr. Bodkin has assembled a mentoring team comprised of a Scientific Mentor, Dr. Micah Drummond, a translational researcher experienced in biological mechanisms of aging skeletal muscle atrophy and regrowth, a Career Mentor, Dr. Jennifer Majersik, a clinical neurologist with a proven track record of mentoring junior faculty members, and 5 advisors with expertise in aging medicine (Dr. Mark Supiano), biostatistical design and analysis (Mr. Greg Stoddard), clinical imaging (Dr. Glenn Morrell), orthopedic surgery (Dr. Travis Maak), and skeletal muscle function following joint injury (Dr. Lindsey Lepley). Dr. Bodkin’s work has well documented skeletal muscle weakness following anterior cruciate ligament reconstruction (ACLR) and the inability to restore strength despite undergoing traditional post-operative rehabilitation. This work and others suggest potential physiological contributors to skeletal muscle weakness following ACLR. Based on recent evidence, Dr. Bodkin’s central hypothesis is that ACL injury and reconstruction promotes the infiltration and development of muscle adiposity which thus impairs muscle strength. He will test this hypothesis by serially quantifying intramuscular adipose tissue (IMAT) and intramyocellular lipids (IMCL) in patients undergoing ACLR and relating measures of muscle adiposity to strength. These outcomes will be collected in young and middle-aged adults, exploring potential interactions of age and traumatic injury on skeletal muscle remodeling. By pursuing the following specific aims, the applicant will test his hypothesis and gather data for a subsequent R01 application to investigate rehabilitation interventions on skeletal muscle biology following traumatic joint injuries. Specific Aim 1 will determine the influence of ACLR on quadriceps adiposity by quantifying IMAT and IMCL pre-ACLR, 2 weeks post-ACLR, and 3 months post-ACLR. Specific Aim 2 will determine the relationships between IMAT and IMCL to quadriceps muscle strength 3 months post-ACLR. Specific Aim 3 will evaluate the difference in age related changes in muscle adiposity following knee surgery by comparing serial changes in IMAT and IMCL post-ACLR between young and middle-aged adults. The proposed research is significant because traditional strength training may fail to overcome the skeletal muscle weakness that presents following ACLR. Investigations into physiologic contributors to skeletal muscle weakness are a priority research area to personalize healthcare and aligns with the NIAMS strategic plan, “to turn discovery into health”. My proposed study will determine acute changes in skeletal muscle remodeling following ACLR and establish relationships between cellular changes and muscle strength.

NIH Research Projects · FY 2025 · 2024-07

SUMMARY This proposal explores the hypothesis that very long chain ceramides serve as a causal mediator in the structural and functional changes which underlie diastolic heart failure (HF). Moreover, this suggests a rare therapeutic opportunity for diseases such as heart failure with preserved ejection fraction (HFpEF), which have few evidence- based therapies. The idea is predicated upon data presented herein showing that the genetic deletion of a ceramide synthesis enzyme, dihydroceramide desaturase 1 (Des1), prevents hypertrophy and impairments in diastolic function in 2 distinct mouse models of diastolic HF. The theory is further supported by untargeted lipidomics from HFpEF patients, which demonstrate ceramides as the most upregulated lipids in serum. Moreover, biopsies obtained from hearts with diastolic failure show elevated ceramides compared to control. Cardiac-specific ablation of acid ceramidase, is sufficient to drive ceramide accumulation and diastolic dysfunction without overt changes in systolic function. Administration of a pharmacological inhibitor of ceramide biosynthesis to rodents preserves diastolic function and prevents fibrosis and hypertrophy, suggesting therapeutic potential if safe, effective ceramide synthesis inhibitors are identified. We will determine if ceramides are necessary and sufficient mediators of diastolic heart failure that can be targeted for therapeutic intervention. We will evaluate our hypotheses through the following Aims: • First, we will determine the effects of genetic induction or reduction of ceramides selectively in cardiomyocytes in mouse models of diastolic HF. • Second, we will determine the efficacy of Des1 antagonism or ablation as a therapeutic approach for the treatment or prevention of diastolic HF. • Third, we will elucidate the mechanisms linking ceramides to cardiac fibrosis and mitochondrial dysfunction using cells, mice, and human tissues. Findings obtained from these studies could uncover new nutrient-sensing regulatory mechanisms that modulate mitochondrial function, cardiomyocyte survival, fibrosis, and hypertrophy. Moreover, the translational component of this work could propel the development of promising therapeutics for preventing or treating diastolic HF.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY Inadequately managed symptoms caused by their disease and its treatment result in unnecessary suffering for children with cancer that interferes with their quality of life and may impact survival. Communication that emphasizes the child’s self-report and is actionable by the child’s parents and the clinical team is key to effective symptom management. The early cancer treatment period (ECTP) is a key time to implement interventions targeting symptom-related communication. Digital health tools, including mobile health (mHealth) apps are emerging as proposed solutions to support health-related communication between patients and clinicians. The Office of the National Coordinator for Health Information Technology prioritizes the routine use of patient-generated health data (PGHD), data recorded by patients that complement clinical data, in clinical care. Achieving the larger goal of integrating PGHD from mHealth apps into clinical care requires attention to data security, interoperability standards for data exchange, and representation of data within the electronic health record (EHR). Integrating PGHD in clinical care also requires attention to facilitators and barriers such as patient/family adherence to reporting, accessibility of PGHD in the EHR, and clinician engagement. Our interprofessional team engaged school-age children (6-12 years) with cancer, parents, and clinicians to co- design Color Me Healthy, a child-centric app that provides an evidence-based structure for children to report eleven common symptoms, and demonstrated its feasibility and acceptability. Our next critical step to advance Color Me Healthy to scalable implementation is to develop and evaluate a clinician-facing app that is interoperable with electronic health record (EHR) systems to integrate review and discussion of children’s data as part of the clinical workflow. The project will be conducted as an early phase Behavioral Intervention Development Trial to define and refine key components of implementing Color Me Healthy during the ECTP with attention to underlying mechanisms of the intervention and to identify and address facilitators and barriers from perspectives of children, parents, and clinicians. During Aim 1, we will employ user-centered design methods to develop a Web-based, clinician-facing version of the Color Me Healthy app for EHR integration as a SMART on FHIR app. Aim 2 will allow us to optimize implementation of Color Me Healthy as an implementable communications-support intervention in the clinical setting during the ECTP by engaging children, parents, and clinicians to define and refine key components of the intervention. During Aim 3, we will conduct a single-site repeated measures trial to evaluate the efficacy of implementing Color Me Healthy in the ECTP to improve symptom communication. The immediate expected outcome is successful implementation of an interoperable, scalable SMART® on FHIR app to improve symptom communication during the ECTP. The proposed work will build a chain of evidence to meet our long-term goal to deliver timely, evidence-based care to alleviate symptoms and promote quality of life for children with cancer.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY/ABSTRACT This is an application for a K23 award for Dr. Kathleen M. Job, a clinical pharmacologist and young investigator pursuing patient-oriented clinical research into how pregnancy and chronic disease influences drug disposition and action. This K23 award will provide Dr. Job with support necessary for career development in the following areas: (1) advanced pharmacometric techniques; (2) pregnancy and maternal-fetal science; (3) clinical trial design and management in pregnant populations; and (4) leading an interdisciplinary research program. By acquiring these skills, Dr. Job will fulfill her career goal of becoming an independent investigator who advances clinical care by integrating physiology and pharmacology into approaches for designing, conducting, and interpreting clinical trials in pregnant individuals. To achieve these goals, Dr. Job has assembled a mentoring team comprising a primary mentor, Dr. Kevin Watt, an expert in PBPK modeling in special populations, and co-mentors, Dr. Torri Metz, a specialist in maternal-fetal medicine and clinical research, Dr. Christina Chambers, an expert in epidemiology of drugs during pregnancy and health outcomes, and Dr. André Dallmann, a leader in physiologically-based pharmacokinetic (PBPK) modeling in pregnant populations. Asthma is the most common chronic condition associated with pregnancy and affects up to 300,000 pregnancies every year in the United States. Asthma drugs are critical for achieving and maintaining proper control of asthma symptoms. The pharmacokinetics of these drugs can be affected by the altered physiology and lead to unacceptable drug-related toxicity or treatment failure. Progressive changes to physiology occur throughout pregnancy. In the current proposal, Dr. Kathleen Job will determine optimal dosing of two common asthma medications in pregnant individuals. In Aim 1, she will develop maternal-fetal PBPK models for these asthma medications. In Aim 2, she will evaluate model predictions with data from prospective clinical pharmacokinetic studies in pregnant individuals with asthma. In Aim 3, she will develop pharmacodynamic models for the drugs of interest in pregnant individuals with asthma with data collected as part of the prospective clinical pharmacokinetic studies in pregnant individuals. Findings will inform a Phase II/III Phase II/III safety and efficacy trial in pregnant individuals with asthma and build a platform that can be applied to dosing of any drug at any stage of pregnancy. This research will prepare Dr. Job to design and implement scientifically rigorous and ethical drug trials in pregnant populations.

NIH Research Projects · FY 2026 · 2024-07

PROJECT ABSTRACT. About 75% of the newly diagnosed colorectal cancer patients are ≥70 years old and have the lowest 5-year relative survival (61%) due to comorbidity and frailty. Current clinical care guidelines for older cancer patients only partially address specific challenges experienced by them, thus resulting in large variations and inconsistency in their standard cancer care. Evidence surrounding complications after colorectal cancer surgery, treatment toxicity, and their impact on patients’ quality of life (QoL) in older colorectal cancer patients is inconsistent, and relies heavily on the chronological age of the patient. Thus, there is an urgent unmet need to evaluate predictors of clinical and patient-reported outcomes in older colorectal cancer patients in order to aid clinical decision-making and tailor treatment regimens that coincide with patients’ level of risk, while minimizing complications and toxicities, and improving QoL. The current project is prepared in response to NIH NOSI NOT-CA-21-031, and will help inform the role of aging-related functional decline on various clinical and QoL outcomes in cancer patients. The overall objective of this project is to evaluate whether physical function (Aim 1), a multidimensional brief geriatric assessment tool (Aim 2), and pre-operative biomarkers of aging (telomere length, mitochondrial DNA copy number), inflammation, nutritional status and a biological aging score (Aim 3) are associated with postsurgical complications, treatment toxicity, survival, QoL, and cognitive outcomes in geriatric colorectal cancer patients. Our central hypothesis is that outcomes in geriatric colorectal cancer patients are associated with physical, functional, emotional, and cognitive status, irrespective of patients’ chronological age. We propose to recruit a prospective cohort of newly diagnosed stage I-III colorectal cancer patients (n~462) ≥70 years of age recruited ~2 weeks prior to their cancer surgery. At study enrollment, we will assess patients’ physical function through Short Physical Performance Battery and Handgrip testing, and administer a brief geriatric assessment tool developed by Hurria et. al. Biomarkers of biological aging, inflammation, and nutritional status will be measured in stored blood collected prior to surgery using well-validated assays. Associations of these exposures with surgical complications (at 30 days), treatment toxicity, QoL and cognitive function (at 12 months), and clinical outcomes such as survival (at 24 months) will be measured. Our proposed study design is cost-effective as it builds upon a well-established unique cohort currently recruiting colorectal cancer patients <70 years of age, the ColoCare Study. The healthcare of older cancer patients extends beyond the traditional management of cancer, and requires addressing the multifactorial health concerns of this expanding population, making it a significant public health priority. Information gained in this project may ultimately inform precision geriatric oncology approaches to improve clinical and patient-reported outcomes in patients at a higher risk of chemotoxicity and death, and to tailor risk stratification for cancer surveillance in this growing population of geriatric colorectal cancer survivors.

NIH Research Projects · FY 2025 · 2024-07

This K01 award application is for Dr. Victoria L. Tiase, a PhD-trained nurse informaticist with a commitment to improving the systems, structures, and policies that support the nursing workforce. Her overarching career goal is to become an independent nurse researcher focused on obtaining a broad understanding of nursing workload, specifically in relation to reducing nurse burnout, through the application of electronic health record (EHR) data and data science. This K01 will support three key areas of career development: (1) strengthen existing knowledge of EHR audit log data for use in research; (2) acquire advanced knowledge and skills in data science and computational modeling; and (3) transition from a mentored researcher to independent investigator. The training and research will be conducted at an institution with a strong record of providing excellent support and rich training and educational resources. The candidate’s department is committed to the success of this early-stage researcher, providing any additional resources necessary to complete the proposed career development and research aims, and ensuring ongoing protected research time. The coursework and mentoring will be overseen by a complementary team of experienced researchers and experts in these fields. Nurse burnout is persistent in the U.S. with nurses reporting concerns over their work environment, particularly those working in primary care and community clinics. Increased workload is reported as the main contributor. Although nurse burnout has been studied for decades, little has changed in the organization of clinical care, and the measurement of nursing workload is not well understood. Workload measurement has traditionally taken the form of self- report, surveys, and time and motion studies which are time-consuming, expensive, and difficult to scale. Gathering sufficient data that are reliable, reproducible, generalizable, and that represent nursing contributions within the context of work activities remains a complex, unsolved problem. Advances in informatics and electronic health record (EHR) audit log data have shown promise in measuring clinician work activities. State-of-the-art data science paradigms are needed to fully understand the complexity of nursing work activities and their relevance to workload. Thus, this study’s Specific Aims include: (1) Characterize and extract features from EHR audit log data and develop a data representation amenable to state-of-the-art data science techniques; and (2) Develop realistic and reproducible computational models of nursing EHR interactions. The proposed research is innovative because it will extend an existing untapped data source to nursing activities and will create a model to quantitatively measure workload influencers. This research lays the groundwork to test scalable interventions that mitigate nurse burnout, improve nurse wellness, reduce costs, and ultimately, improve health for all.

NIH Research Projects · FY 2025 · 2024-07

Chimeric Antigen Receptors (CARs) are a combination of an extracellular single-chain variable fragment region (scFV) that recognizes tumor protein antigens in an MHC independent manner and an intracellular region that transduces extracellular stimuli similar to T Cell Receptor (TCR) signaling. Optimization of CAR constructs is of high importance as current CAR therapies have significant drawbacks including CAR T cell toxicity from severe cytokine release syndrome, neurotoxicity and lack of CAR T cell persistence in vivo and expansion in vitro. There is a new focus on tuning CAR intracellular signals via the immunoreceptor tyrosine-based activation motifs (ITAMs) to increase effector function and persistence. Each of the 3-zeta chain ITAM sequences are unique with distinct kinetics of phosphorylation including a hierarchy of specificity for Zap-70 upon phosphorylation. Our previous work determined that ITAM diversity was necessary for T cell development and attenuating TCR signaling. Importantly, ITAM diversity has also been shown to be necessary for TCR-driven proliferation and cytokine production. However, the role of CAR zeta chain diversity in CAR signaling, persistence and function has not been fully explored. Interactions between TCR and pMHC occur at the interface of two cells in a two-dimensional (2D) membrane microenvironment. Initial binding events including affinity and kinetics of the TCR/pMHC interaction, and the CAR/protein epitope interaction, will dictate binding stability and downstream signaling events including phosphorylation of the ITAMs. We have found that CARs expressing specific ITAM sequences (zeta-AAA, zeta- BBB or zeta-CCC) generate differing amounts of Force and bond lifetime after interacting with CD19. Therefore, a CAR may act as a mechanosensor similar to a TCR discriminating the quality of the interaction with antigen as cellular derived forces are applied to the bond. Mechanistically, we hypothesize that finetuning the combination of ITAM sequences will differentially regulate bond lifetime, phosphorylation and signal transduction leading to differential immune activation depending on the ITAM motif. Understanding the biology of ITAM specificity has important implications in “tuning” the activation of a CAR T cell without changing specificity.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY/ABSTRACT Nearly half of U.S. adults have or are at risk of developing type 2 diabetes. Lifestyle intervention is efficacious and the first line of prevention among adults at high risk for type 2 diabetes. Unfortunately, outcomes in real- world settings do not approach the initial efficacy trial findings, in part due to low rates of retention in the intervention. Real-world programs have particularly struggled to retain participants who identify as members of racial/ethnic groups that are disproportionately affected by type 2 diabetes, potentially exacerbating health disparities. Given the strong influence romantic partners have on one another and the shared environment in which couples typically live, lifestyle interventions that systematically include romantic partners have the potential to address the research-practice gap. The purpose of this project is to examine the efficacy of PreventT2 Together, a couple-based lifestyle intervention our team developed. The specific aims of the research are: (1) to determine the efficacy of PreventT2 Together in a single-center, randomized clinical trial, (2) to examine baseline relationship satisfaction as a moderator and perceived partner support as a mechanism of lifestyle change, and (3) to quantify intervention retention and describe reach across recruitment methods. We will recruit 162 couples (i.e., adults at high risk for type 2 diabetes and their romantic partners) from community and healthcare settings, oversampling members of racial/ethnic minority groups. We will randomize participating couples to individual (PreventT2; delivered only to partners at high risk) or couple- based (PreventT2 Together; delivered to couples) lifestyle intervention conditions. HbA1c and objectively measured moderate to vigorous physical activity (MVPA) will be collected from all participants at baseline (Pre) and at the end of the 1-year intervention (Post). Participants will also report on lifestyle factors, health outcomes, and relationship functioning at each of 13 time points (Pre, monthly during the intervention, and Post). We focus on the patient-centered minimum clinically important difference (MCID) in outcomes, including objectively-measured MVPA (primary outcome), as well as other aspects of lifestyle (nutrition, sleep), health outcomes (HbA1c, weight loss, stress), and relationship functioning (perceived partner support) (secondary outcomes). Situating lifestyle intervention within the romantic relationship context in which lifestyle change occurs is likely to increase reach and improve retention and lifestyle change outcomes in real-world settings. Our community-engaged approach to the development of the intervention and design of the proposed project will ensure broad applicability and dissemination of results across communities, including racial/ethnic minority groups that have not been effectively reached and retained. CDC review and approval of PreventT2 Together for use as an alternate curriculum in the National Diabetes Prevention Program (National DPP) delivered across the U.S. underscores the scalability of the intervention. If efficacious, PreventT2 Together has the potential to impact individuals and their romantic partners’ quality of life and ultimately improve real-world outcomes of lifestyle intervention to prevent type 2 diabetes.

NIH Research Projects · FY 2025 · 2024-07

PROJECT ABSTRACT Patients with type 2 diabetes (T2DM) are at increased risk (~50%) relative to non-diabetic individuals of suffering sudden cardiac death (SCD), most often due to fatal ventricular arrhythmias such as torsades de pointes (TdP). However, the underlying molecular mechanisms are unknown. Therefore, there is the critical need to identify and validate novel cellular proarrhythmic mechanisms in T2DM. In that regard, we have identified and validated a proarrhythmic lipid mediator, leukotriene B4 (LTB4), that is elevated in diabetes compared to non-diabetic patients suggesting that risk for ventricular arrhythmias may be highest for patients with high levels of LTB4. LTB4 inhibitors are a class of FDA-approved drugs that have been shown to confer major cardiovascular benefits. Recent evidence showed that LTB4 receptor (LTB4R) knockout or LTB4 inhibitor treatment of myocytes, prevented LTB4-related metabolic defects, supporting the results of a separate report indicating reduced LTB4 biosynthesis prevented ischemia/reperfusion-induced arrhythmias. Our pilot studies revealed that LTB4 is increased in multiple diabetes mouse models (ob/ob and PANIC- ATTAC), induces a profound prolongation of ventricular action potential duration, triggers cellular arrhythmogenesis, and severely depresses the repolarizing rapidly activating delayed rectifier K current (IKr) density in guinea pig ventricular myocytes but not in healthy heart cells, consistent with TdP vulnerability. We have further found that guinea pigs challenged with LTB4 displayed prolonged QT interval, and that this can be prevented with LTB4R inhibition, suggesting that preventing such LTB4-LTB4R effects may be therapeutically beneficial in T2DM ventricular arrhythmias. Our long-term goal is to accelerate the rational development of clinically useful anti-LTB4 agents as treatments for malignant ventricular arrhythmias. The overall objective for this application is to determine how the LTB4R signaling axis promotes arrhythmia and its usefulness as a preclinical drug target. Our central hypothesis, based on preliminary data described above, is that LTB4 through the LTB4R drives adverse remodeling of ventricular myocyte electrical activity and propensity for ventricular arrhythmias by promoting impaired IKr biophysics and preventing its functional expression. The rationale for the proposed research is that a science-based determination of the preclinical in vitro proarrhythmic effects of LTB4 and associated mechanisms of LTB4R inhibition is likely to support the development of new and promising therapeutic strategies in patients with T2DM. Our experimental studies will combine optical (FRET, photo-switchable fluorescent proteins, quantum dot labeling, 3D reconstruction), electrophysiology, genetic and pharmacological tools in guinea pig and human ventricular myocytes. Our expectation is that, if we understand T2DM ventricular electrical remodeling from a perspective of LTB4 and downstream pathways, we may be better equipped to provide new opportunities for the development of novel therapies for arrhythmia progression and prevention in patients.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY Spermatogonial stem cells (SSCs) maintain male fertility, but not all SSCs are created equal. Here, I propose to lineage trace the contributions of individual SSCs to sperm production across the fertile lifespan of an animal. My central hypothesis is that SSCs compete for dominance and that Paternal Age Effect (PAE) mutations in the RAS-MAPK pathway can confer autonomous advantage to SSCs at the cost of offspring health. In Aim 1, I will identify the contributions of individually labeled SSC clones to spermatogenesis throughout zebrafish adulthood using serial sperm sampling of male zebrafish from sexual maturity through the “elderly stage” when fertility begins to decline. In Aim 2, I will investigate whether PAE mutations drive the selection of individual SSCs. I will overexpress mutated PAE genes in a subset of SSC clones within the zebrafish testis and determine the consequences to clonal dynamics, measuring non-neutral clonal competition in a living animal. In Aim 3, I will determine the potentially “selfish” influence of PAE-containing clonal dominance by measuring mutation transmission and consequences for the next generation. Together, this proposal will illuminate developmental mechanisms that underlie male reproductive aging and may aid future efforts to design male-oriented reproductive interventions that improve birth outcomes. My interdisciplinary team of mentors will provide training in stem cell population analysis, genetic engineering, and modeling human disease in animals, complemented by clinical mentorship and shadowing in pediatrics and reproductive endocrinology. The training plan was developed in collaboration with my Sponsors to complete the central goals of conducting independent, collaborative research; advancing communication and grant-writing skills; learning how to effectively mentor and teach trainees in a supportive environment; and honing clinical skills in preparation for the return to medical school. This training is ideal for a future physician-scientist with the goal of improving patient care at the intersection of basic research and clinical reproductive interventions.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY / ABSTRACT Understanding the mechanisms that underlie learning and memory formation has been a goal of modern neuroscience. Moreover, investigating these processes is of critical importance to determine how they go awry in neurological disorders. Arc is an immediate early gene (IEG) that is dynamically expressed in response to learning and genetic ablation of this gene in rodents leads to severe long-term memory deficits. Recently, the Shepherd lab discovered that Arc evolved from an ancient Ty3 retrotransposon and has maintained its virus-like properties. In particular, Arc protein is capable of self-assembling into virus-like capsids that can encapsidate genetic material. These capsids can be transferred between neurons in extracellular vesicles (EVs) and deliver nucleic acids in the process, similar to retroviruses. However, the function of Arc mediated intercellular communication and the role of virus-like capsids in memory formation is entirely unknown. My current work has demonstrated that 1) Arc capsids are assembled and released from neurons during long-term potentiation (LTP) through direct interaction with I-BAR protein IRSp53. 2) EV transferred Arc reduces surface AMPA receptor levels via translation of delivered Arc mRNAs. Together, these results suggest that Arc mediates a novel form of intercellular synaptic plasticity through a virus-like signaling mechanism. The synaptic mechanisms of memory storage are poorly understood. Furthermore, why evolution exploited viral machinery to alter synaptic strength is unknown. This research plan will focus on how Arc’s virus-like properties have been co-opted to encode learned experiences and store information. To date, I have combined molecular and biochemical assays with various imaging techniques to elucidate how the Arc virus contributes to memory formation. I have used a novel Arc reporter system that dually labels both nascent Arc protein and mRNA to visualize Arc trafficking and release from living neurons during LTP. I have demonstrated that transferred Arc mRNA is translated in recipient neurons to induce AMPAR loss. The precise mechanisms governing how Arc virus-like signaling alters recipient cell function has yet to be determined. During the F99 phase, I propose to determine the intracellular trafficking and kinetics of Arc mediated viral signaling. In Aim 1.1, I will determine the intracellular trafficking of transferred Arc protein and mRNA. In Aim 1.2, I will determine the kinetics of transferred Arc EV uptake and AMPAR loss. During the K00 phase, I will study how activity-dependent release of extracellular vesicles alters the neuronal circuits that store memories. I hypothesize that neurons encoding learned experiences release EVs in an activity-dependent manner to shape the neuronal circuitry that will store memories. To test this, I will combine my current in vitro skillset with behavioral paradigms, the development of novel molecular tools, imaging techniques, and large scale sequencing.

NIH Research Projects · FY 2025 · 2024-07

Summary Coronary artery disease (CAD) is a major healthcare problem that affects over 20 million Americans and costs an estimated $82.8 billion each year. Atrial Fibrillation (AFIB) is a related epidemic that is estimated to affect 12 million Americans by 2030 with costs of ~$26 billion each year. Up to 38% of AFIB patients also have CAD and they have a worse prognosis than patients with CAD alone. In order to prioritize and treat this vulnerable population, clinicians need clear diagnostic tools that point toward specific treatments. Computed Tomography Angiography (CTA) can be used to detect anatomical blockages in the coronaries; however, the hemodynamic significance of the blockage cannot be accurately determined. Myocardial perfusion imaging is a proven tool to detect and characterize CAD by determining the hemodynamic significance of coronary blockages on the myocardium. While Single Photon Emission Computed Tomography (SPECT) perfusion imaging is widely used in the U.S., the specificity of SPECT is low in patients with AFIB and CAD. Positron Emission Tomography (PET) perfusion imaging is less widely available for CAD assessment but offers quantitative myocardial blood flow maps and has superior image resolution compared to SPECT. Magnetic Resonance Imaging (MRI) offers myocardial perfusion imaging with in-plane spatial resolution superior to PET imaging and without the ionizing radiation. However, MR imaging has a few limitations in the context of AFIB patients, (1) MRI relies on good and consistent ECG-gating signals to achieve diagnostic quality images. AFIB patients’ inconsistent R-R intervals result in poor image quality with randomly changing cardiac phases for a given slice and hence are often excluded from MR studies. (2) Quantifying MR perfusion images requires accurate measurement of the arterial input function with a high temporal sampling rate, something challenging in AFIB patients due to changing R-R intervals. (3) MR perfusion has limited slice coverage compared to SPECT and PET and is exacerbated in AFIB patients. Increased slice coverage is desirable for improved confidence and accuracy in perfusion defect assessment. A myocardial perfusion MRI method that (i) does not rely on ECG gating, (ii) has whole-heart coverage and (iii) is quantitative would be extremely valuable in AFIB patients to detect CAD. Specific aims of the project are (I) to develop a flow and motion insensitive steady-state (FAMISS) ungated quantitative simultaneous multi-slice acquisition methods along with novel constrained and deep learning reconstruction techniques for rapid, whole-heart quantitative perfusion MRI, (II) to rigorously compare the quantitative flow values from the FAMISS framework with existing dual-bolus quantitative MRI measures, and (III) to validate the FAMISS framework by comparing it to the gold standard for quantification, PET imaging, and the gold standard for diagnostic accuracy using invasive fractional flow measures. Our team and institution have deep cardiac MRI and PET experience and the technology needed to successfully execute all aspects of this project. The success of our project will deliver a game-changing MRI technology for AFIB patients with suspected CAD.

NIH Research Projects · FY 2025 · 2024-07

Consequences associated with obesity can be miƟgated by shiŌing adipose Ɵssue expansion from hypertrophic to hyperplasƟc expansion; the former increases overall size of exisƟng adipocytes and correlates with increased inflammaƟon, insulin insensiƟvity, and fibrosis, while the laƩer differenƟates new adipocytes from resident preadipocytes through adipogenesis. Remedying the expansion of our adipose Ɵssue to favor healthier hyperplasƟc expansion is of the upmost importance to combat the obesity epidemic, as western diets high in fat and carbohydrates have shown to shiŌ the balance of fat expansion to the more consequenƟal hypertrophic expansion. All preadipocytes have primary cilia, which are criƟcal for their differenƟaƟon into mature adipocytes. These organelles are typically rich in signaling components, specifically G protein‐coupled receptors (GPCRs), though liƩle is known about ciliary protein composiƟon in preadipocytes. Thus far only one receptor has been discovered in the cilium of preadipocytes, and its acƟvaƟon increases ciliary cAMP and subsequent adipogenesis. Increases in cellular cAMP are necessary for ex vivo adipogenesis, but it is unknown what role compartmentalized ciliary cAMP has in adipogenesis, though ciliary cAMP in other cell types has been shown to have differenƟal funcƟons than whole cell cAMP. I hypothesize that cAMP in the cilium is necessary and sufficient to induce adipogenesis in preadipocytes, and that a suite of ciliary GPCRs acts to influence this process in a cilia‐dependent manner. My first aim will define the role of ciliary cAMP in adipogenesis, using chemogeneƟc and optogeneƟc tools to control the generaƟon or depleƟon of ciliary cAMP during adipogenesis to define its sufficiency and necessity in preadipocyte differenƟaƟon. My second aim will idenƟfy GPCRs that localize to preadipocyte cilia and invesƟgate their physiological roles in adipose expansion and prevalence in healthy versus unhealthy adipose Ɵssues. This work will be conducted at the University of Utah under the guidance of my sponsor, Dr. Keren Hilgendorf, and co‐ sponsor, Dr. Jeremy Reiter, both of whom specialize in ciliary signaling. My thesis commiƩee is composed of interdisciplinary researchers with a range of specialƟes all pertaining to different porƟons of this proposal, such adipose Ɵssue, signaling metabolites, GPCRs, and primary cilia signaling. Together, these mentors will provide expert guidance in all facets of this project. In addiƟon, this project will be supported by the work of mulƟple university core faciliƟes, including those that offer services in cellular microscopy, flow cytometry, mass spectrometry, and metabolomics. These faciliƟes offer excellent support and training services to facilitate my growth as a researcher. The training plan presented was developed to ulƟmately prepare me for a future in academia as an independent researcher in the field of ciliary signaling and cell fate determinaƟon. In addiƟon to the technical skills this project will provide, it will also further my development as a mentor and teacher through university‐supported training programs and laboratory opportuniƟes. Dr. Hilgendorf has fostered a supporƟve research environment that encourages scienƟfic exploraƟon and my development as a researcher. She has demonstrated dedicaƟon to my training and catered her mentorship to reflect my career goals.

NIH Research Projects · FY 2025 · 2024-07

Project Summary/Abstract The brain ECM constitutes about 10-20% of the brain’s volume and plays a critical role in diverse brain functions. In particular, the brain ECM regulates neuronal plasticity and behavior. Unlike collagen-based peripheral ECMs, the structure of brain ECM is highly flexible and dynamically regulated by experience. However, due to the technical limitations, the mechanism by which the brain’s ECM is organized and regulated is poorly understood. We have developed a novel live-cell probe that labels hyaluronan-based brain ECM, named H-Link. Sparse H-Link imaging shows that clustered ECM, such as perineuronal net (PNN), is not limited to a specific neuronal type (PV interneurons) but also elaborately coats excitatory neurons in vivo and in vitro. Furthermore, the application of H-Link to cultured neurons shows a striking specificity in ECM clustering among different types of neurons and reveals its organization process on the neuronal surface, providing an excellent platform for loss-of-function screens. Using this novel approach, we will identify cell-autonomous neuronal ECM organizers and reveal the homeostatic and activity-dependent remodeling process of the brain’s ECM. The tools and knowledge obtained from the proposed study will be a foundation for understanding the cell-type-specific role of the brain’s ECM in neuronal plasticity and behavior.

NIH Research Projects · FY 2025 · 2024-07

Hedgehog Signal Transduction from the Cell Surface to the Nucleus during Vertebrate Eye Development The Hedgehog (Hh) pathway is essential for eye development, controlling a diverse array of fundamental patterning, morphogenesis, and differentiation events during oculogenesis. Misregulated Hh signaling instigates a spectrum of human developmental eye disorders, including holoprosencephaly, cyclopia, uveal coloboma and retinal dystrophy. This signaling pathway is therefore a prime therapeutic target for eye development disorders and for regenerative medicine efforts. During Hh signal transduction, the cell surface atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO) communicates with GLI transcription factors in the nucleus, via a mechanism that has remained enigmatic for decades. We recently found that SMO directly binds to the catalytic subunit of protein kinase A (PKAcat) and physically blocks its enzymatic activity. As a result, PKAcat cannot phosphorylate and inhibit GLI, leading to GLI activation. Thus, our work highlights two potential routes – traditional G protein coupling and our new direct PKAcat inhibition pathway – for Hh signal transduction from the cell surface to the nucleus during oculogenesis. How these two pathways regulate different stages of eye development, and how to target each of them optimally for therapeutic purposes, remains largely unknown. We hypothesize that SMO controls eye development by deploying the G protein coupling and PKA-binding pathways in a spatiotemporally distinct manner. Here we propose to combine organoid, and animal models, along with protein structure approaches, to uncover how SMO orchestrates eye development. We will: (1) learn how the SMO G protein coupling and PKA-binding pathways controls retinal development, using human retinal organoid development and retinal ganglion cell (RGC) differentiation as outputs for Hh pathway-dependent signaling processes in the human retina; (2) assess the impact of each SMO-dependent pathway on ocular Hh signaling in a whole animal context, using zebrafish to define the spatiotemporal contributions of each SMO-dependent pathway to optic fissure formation and RGC differentiation in vivo; (3) solve the structure of a vertebrate SMO / PKAcat complex using X-ray crystallography and cryo-electron microscopy, to learn how SMO engages PKAcat at the atomic level, enabling precise manipulation of this interaction for therapeutic purposes. To carry out the proposed studies, we have assembled a team of experts in biochemical / cell biological mechanisms of Hh signal transduction (Myers), structure / biophysics of PKA (Taylor), human cellular and organoid retina models (Wahlin), and zebrafish eye development (Kwan). The knowledge gleaned from our work will be vital in the development of therapeutics for a range of debilitating eye disorders, as well as for production of specific ocular cell types in regenerative medicine. It will also foster the development of drugs that selectively modulate either the SMO-G protein or SMO / PKAcat signaling pathways, enabling more precise generation of desired ocular cell types for regenerative medicine and more effective treatments for ocular conditions in the future.

NIH Research Projects · FY 2025 · 2024-07

ABSTRACT This is a K08 award application for Dr. Nathan Blue, a Maternal-Fetal Medicine physician and young inves- tigator pursuing translational and clinical research to improve risk stratification approaches to fetal growth re- striction (FGR). A K08 award will provide him with the means to acquire critical skills in three key career devel- opment areas: 1) programming skills to carry out analyses and visualizations (Unix, R, Python), 2) novel bio- medical informatics approaches to quantify risk of adverse outcomes, and 3) interdisciplinary research leader- ship and management. By acquiring these skills, Dr. Blue will fulfill his career goal of becoming an independent investigator who can improve prenatal recognition of fetuses at risk of adverse outcomes. To pursue this goal, Dr. Blue has assembled the mentoring team of Dr. Robert Silver (primary mentor), a Maternal-Fetal Medicine physician and international authority on obstetric complications, Dr. Mark Yandell (co-mentor), a human genet- ics scientist, expert in computational biology, and developer of medical risk assessment software tools, and Dr. Martin Tristani-Firouzi (co-mentor), a Pediatric Cardiology physician and widely recognized leader in applica- tion of new informatics tools to complex clinical problems such as congenital heart disease. Fetal growth restriction (FGR) is a leading cause of preventable stillbirths, postnatal complications, and re- sults in a lifelong increased risk of cardiovascular disease. Based on his own published data, Dr. Blue’s central hypothesis is that current fetal assessment tools function poorly because they assume all fetuses should be the same size and fetal growth ultrasounds are interpreted in isolation of other factors that could be useful to inform risk. He will test this hypothesis by analyzing maternal genetic variants and using a novel explainable artificial intelligence (AI) method to develop individualized prediction models for expected fetal growth and risk of perinatal morbidity. This will uncover insights into normal fetal growth as well as produce a new neonatal morbidity risk calculator. By pursuing the following aims, Dr. Blue will test his hypothesis and lay the ground- work for refining his new tools prior to application to fetal growth in a prospective cohort (to be proposed in an R01 application during the K08 award period). Specific Aim 1 will test the hypothesis that maternal genetic information can be used to individualize birth weight prediction in uncomplicated pregnancies. Specific Aim 2 will test the hypothesis that genetics, specific clinical variables, and social determinants of health interact syn- ergistically to increase the risk of poor outcomes in FGR, which can be captured by new explainable AI. The proposed research is significant because despite FGR’s enormous global burden, current approaches to fetal growth assessment continue to perform poorly, forcing clinicians and families to make plans without appropriately individualized information. The proposed research is innovative because of its use of 1) maternal genetic rather than clinical data such as height, weight, and race to predict healthy birth weight, and 2) explain- able AI for risk stratification rather than black-box AI techniques that are too opaque for trustworthy application.

NIH Research Projects · FY 2025 · 2024-07

Project Summary/Abstract Over the last decade, suicidal ideation and suicide death have increased significantly across all age groups, but have shown the most dramatic rise in teens and young adults. There is clear evidence that greater access to mental health care is associated with reduced suicide risk, but increasing mental health care using conventional models faces multiple barriers; ensuring access to mental health care in rural areas is especially challenging. Accordingly, innovative approaches to provide mental health care, and especially crisis intervention, to teens are essential. SafeUT is a text-messaging app developed in conjunction with state government agencies that links Utah teens who have a mental health crisis to a counselor who can provide support, assess suicide risk, triage to emergency services, and refer for additional treatment. Our project will utilize a large, rigorously anonymized repository of text-message data (>130,000 encounters and >2.3 million messages) contained within SafeUT to predict important outcomes of using the app, such as being referred to emergency services, staying engaged with the counselor, and receiving a thorough risk assessment. We will examine SafeUT data with cutting-edge machine-learning techniques, including natural language processing, to develop ways of predicting SafeUT users’ outcomes. These predictive systems will, ultimately, be used to produce real-time feedback systems that monitor and help improve the quality of SafeUT services. The current proposal squarely addresses Notice of Special Interest NOT-MH-22-110 (Priority Research Opportunities in Crisis Response Services), which emphasizes the importance of projects addressing crisis care in children and which requests applications focused on the development of “assessment strategies and decision-making aides (e.g., predictive algorithms) that incorporate demographic, clinical…and contextual data…to guide tailored strategies for resolution of distress, referral, and engagement in appropriate follow-up services.” These are precisely the goals of the project described here. Evaluating SafeUT’s impact is essential to improving the service over time through counselor training, policy changes, and in future, the development of real-time decision-support systems that enhance counselors’ interventions.

NIH Research Projects · FY 2026 · 2024-07

PROJECT SUMMARY Riboswitches are regulatory RNA structures that control gene expression by binding to a small molecule and changing conformation, allowing organisms to rapidly respond to changes in their metabolic environments. They are prevalent in bacteria, but in over 20 years of study, only one eukaryotic riboswitch has been found. It has long been postulated that there are more, but the lack of high-throughput screening assays and in silico detection algorithms has limited discovery. To address these challenges, the Rutter lab has developed a high-throughput approach combining dimethyl sulfate (DMS) structure probing and MIDAS (mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically) to screen for novel eukaryotic riboswitches. A preliminary screen of HEK293 mRNA resulted in eight novel interactions in the 5’UTR regions of various transcripts. The overarching objective of this proposal is to investigate the regulatory abilities of these interactions and their downstream metabolic consequences in vivo. One of these, COX7B, is a subunit of complex IV (CIV) in the electron transport chain (ETC) and bound to cyclic AMP (cAMP) as a putative ligand. cAMP is known to stimulate respiration, but an obvious regulatory connection between cAMP and COX7B is unknown. Other subunits of CIV are known to regulate respiration through phosphorylation and substrate sensing, but COX7B’s function is yet to be defined. However, recent literature places it at the interface of complex I (CI) and CIV in supercomplex formation. We propose that COX7B’s 5’UTR is a novel riboswitch that impacts respiration through regulating supercomplex formation. Aim 1 will investigate the binding event using isothermal titration calorimetry, DMS structure probing, and reporter assays. Aim 2 will characterize COX7B’s role in CIV, testing for supercomplex formation, respiration, and CI and CIII activity via blue-native PAGE (BN-PAGE), seahorse assays, and enzymatic assays in wild-type, COX7B knock out (KO) and overexpression (OE) cell lines. Aim 3 will then define the metabolic impact of COX7B mRNA interactions with cAMP in vivo. Mutations in the 5’UTR of COX7B will be introduced and supercomplex formation, respiration, and complex activity in response to elevated cAMP levels will be assessed as described. These data will highlight novel regulatory pathways for respiration and introduce a new field of gene regulation to be explored. The Rutter Lab is the first to develop a high-throughput platform for studying novel RNA-metabolite interactions and has a dedicated team devoted to studying novel riboswitches. In addition, the University of Utah hosts a community of renowned scientists studying metabolism and RNA biochemistry such as my sponsor, Dr. Jared Rutter, and co-sponsor, Dr. Ming Hammond. Finally, this project contains a detailed training plan for developing multidisciplinary research and professional skills that will enable me to become a successful, independent academic scientist.

NIH Research Projects · FY 2025 · 2024-07

The overall objective of this study is to optimize, validate, and evaluate the effectiveness of strategies for reporting back environmental sampling results, with a focus on rural Native American populations and the balance between real-time and delayed feedback for both acute and chronic exposure concerns. The bioethical question of interest is: How does the information source (i.e., the messenger, format, and timing of education) impact the effectiveness of report-back strategies in rural tribal populations? This project is innovative because it addresses unanswered questions regarding the role that real-time exposure information plays in report-back strategies, with application to rural Native American populations. Aim 1: Optimization of Real-Time Report-Back Strategies for Rural Native American Research Participants. Previous work has involved environmental sampling data (indoor/outdoor PM2.5 and indoor radon) at households of N. Arapaho tribal members. Half of the participants received immediate exposure information from real-time, direct-reading displays while the other half only received final, delayed feedback with average data. The question remains as to whether the report-back strategies were as effective as desired. The hypothesis is that real-time exposure feedback will be more acceptable for short-term health outcomes whereas delayed feedback will be more acceptable for long-term health outcomes. Listening sessions and questionnaires will be used to evaluate prior approaches for both acute and chronic exposures, with a specific focus on our bioethical question. Aim 2: Validation of Optimized Report- Back Strategies for Rural Native American Research Participants. Based on the results of Aim 1, a series of vignettes will be developed that target the report-back strategies of interest (e.g., real-time exposure data for acute concerns, etc). These will be presented in 4-8 focus groups, with targeted discussions regarding the messenger type, format, and timing of education. The hypothesis is that the report back strategy that will be perceived as the most acceptable for all of the exposure scenarios will be in-person report-back by a tribal member, with education both before and after sampling. Aim 3: Evaluation of the Implementation of Exposure- Reduction Strategies from Report-Back of Environmental Exposures in Tribal Populations. Evaluation of the developed report-back approaches for long term (radon) and short-term (PM2.5) exposure risks will occur in two tribal populations: N. Arapaho and Utah Navajo. Reliability and generalizability will be tested to understand the extent to which individual tribes have unique needs and where techniques are more universal. Effectiveness of the strategies will be evaluated for the level of engagement with exposure-reduction activities, with a goal of building local capacity for management of evaluation activities into the future. The hypothesis is that real-time exposure feedback will result in more engagement with exposure-reduction strategies. The ultimate outputs of this project will be validated guidance on the most effective strategies for reporting back environmental sampling results, with a focus on increasing engagement with exposure-reduction activities in rural tribal populations.

NIH Research Projects · FY 2026 · 2024-06

The overarching goal of this project is to engage middle and high school students in real-world science, with a particular focus on how biomedical research and innovation address challenges that affect their lives. The project is designed to foster early interest in science and health-related careers, and to provide exposure to the broad range of skilled technical workforce and professional positions in these fields. The project aims to advance goals outlined in the NIH-Wide Strategic Plan, including fostering a strong biomedical workforce and promoting science education. To address this goal, the Genetic Science Learning Center (GSLC) at the University of Utah will use its award-winning expertise to develop four innovative curriculum modules. The modules will address topics not yet included in textbooks, emphasize how science is driving real solutions to biological and health challenges, and include videos that enable students to “meet” individuals in a range of work environments. The modules will flexibly integrate with topics teachers already cover, and support student achievement of standards described in A Framework for K-12 Science Education. The project’s goals are to: GOAL 1: Introduce secondary-level students to (a) the science of developing solutions to biological and health challenges, with a focus on genetics, and (b) related careers, via new curriculum modules. Approach: Involve teachers from across the US in drafting the modules, testing them with their students, and providing feedback for refinement. Conduct a quasi-experimental efficacy study of each module’s impact on NGSS-aligned student learning using validated student assessments. GOAL 2: Prepare teachers to implement the four new modules via online professional development courses and conference workshops. Approach: Offer two, free online courses for teachers to prepare them to use the modules, and present free workshops at state and national science teacher conferences, reaching at least 300 teachers across the US. The project will take advantage of the GSLC’s award-winning expertise in developing effective interactive multimedia learning experiences; its published methods for involving teachers in curriculum development; and its extensive experience in teacher professional development. The modules will be broadly disseminated via the GSLC’s Learn.Genetics and Teach.Genetics websites, which are used annually by >16 million visitors worldwide.