Utah State Higher Education System--University Of Utah

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Lung cancer is the leading cause of cancer-related mortality in the U.S., accounting for approximately 1 in 5 cancer-related deaths. Approximately 80% of lung cancers are attributable to cigarette smoking. Annual Low- Dose Computed Tomography screening for lung cancer (hereafter referred to as Lung Cancer Screening or LCS) is recommended by the U.S. Preventive Services Task Force (USPSTF). Despite evidence of effectiveness and the USPSTF recommendations, implementation of LCS into clinical practice has been exceedingly limited, with only 6.5% of eligible individuals screened in 2020, and there are major health inequities in LCS related to race/ethnicity and socioeconomic status. The long-term goal of this program of research is to increase the reach of LCS among low resource healthcare settings and populations that have been historically marginalized. The proposed project, LUNG-IS, is a mixed-methods, pre-post quasi-experimental design conducted in three Utah safety-net healthcare system “Free Clinics.” LUNG-IS will establish partnerships with one free clinic per year for first 3 years of the project, and in the first year will collaborate with a nonprofit, no-cost, Free Clinic that provides high-quality, multi-disciplinary healthcare to 3,018 uinsured patients annually, 97% of whom are ≤200% of the Federal Poverty Level (FPL), 65% are ≤100%, 88% are Latino. LUNG-IS leverages existing pathways to care and Centralized Hub infrastructure that enables eligibility assessment, LCS shared decision making (SDM) with clinical decision support, screening referral, and screening logistics assistance to help overcome numerous social determinants of health that impact low resource settings and historically marginalized populations. The Centralized Hub model uses ubiquitous technologies (i.e., text messaging/telehealth) to enable safety-net patients to be assessed for LCS eligibility, engage in SDM if eligible, and be referred for LCS. For patients who decide to complete LCS, they will be provided patient navigation via Community Health Workers designed to address logistical barriers, hesitancy, and financial constraints around completing LCS. The specific aims are to 1) evaluate the impact of implementation strategies on LCS eligibility screening, SDM completion, and LCS completion, 2) characterize multi-level factors that influence implementation and effectiveness outcomes, and 3) identify and classify adaptations to implementation strategies that occur throughout the study.

NIH Research Projects · FY 2025 · 2024-09

SUMMARY The Mountain West Prevention Research Center (MW-PRC) will address the increasing inequities in childhood obesity in lower income rural and micropolitan (<50,000 residents) communities in Idaho, Montana, Nevada, Utah, and Wyoming. These communities experience a confluence of poverty, economic instability, high obesity rates, food insecurity, and a lack of access to healthcare and existing evidence-based interventions. There is a critical research and translational gap in the dissemination and implementation of evidence-based, family healthy weight programs to address obesity in these communities. To date, our team has developed successful strategies to address three key dissemination and implementation barriers to eliminating obesity- related inequities in lower income rural and micropolitan communities. These include the development of the Building Healthy Families (BHF) Online Training Resources and Program Package and Action Learning Collaborative that addressed known barriers related to local implementation capacity, delivery by diverse organizations, and access to relevant program materials. The goal of the MW-PRC is to eliminate income- related inequities in childhood obesity by addressing a fourth key barrier—challenges in identifying, enrolling, and retaining families in evidence-based family healthy weight programs. We will focus on increasing access to and the reach of BHF, the only CDC-recognized family healthy weight program designed in, and by, rural and micropolitan communities, using population health management (PHM) and community-based participatory research methods. Our Center will utilize a Community Advisory Board representing state and local health departments, community health centers, and other community-based organizations and aims to build local academic and community capacity to conduct applied prevention research to resolve income and geographic inequities in childhood obesity. The Core Research Project will include a type 3 hybrid effectiveness implementation study using a sequential, multiple assignment, randomized trial design to determine the impact of integrating PHM via text messaging and direct enrollment in BHF for lower income families with a child (6-12 years) with obesity identified through community health center electronic health record data. Furthermore, we will participate in the PRC Network to share translational resources for disseminating and implementing family healthy weight programs to benefit low-income populations. The MW- PRC will produce generalizable translational tools to move family healthy weight interventions into action in rural and micropolitan communities and eliminate obesity-related inequities.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Osteoarthritis (OA) impacts about 1 in 4 adults in the U.S and is responsible for considering costs and loss of quality of life for impacted individuals. The prevalence and adverse impacts of OA are greater for persons from racial/ethnic minoritized groups, with lower income and/or living in rural communities. Secondary prevention of arthritis-attributable activity limitations is a critical goal for persons with OA. Arthritis-appropriate evidence- based interventions (AAEBIs) are available. A core component of AAEBIs is physical activity, which is often decreased for persons with OA. Available AAEBIs include counseling from a healthcare provider about physical activity, and CDC-endorsed programs to increase physical activity and promote self-management. Despite the potential benefits, uptake of AAEBIs is low, particularly in communities that experience disparities. The Mountain West Arthritis Secondary Prevention Program (MW-ASP) is special interest project situated in the Mountain-West Prevention Research Center (MW-PRC). The MW-PRC seeks to increase the reach of EBIs to persons in communities experiencing disparities and to disseminate, scale and sustain strategies and tools to community, public health and academic audiences. The MW-ASP aligns with these goals and will work with the MW-PRC to connect persons with OA to physical activity counseling and community-based AAEBIs. We will conduct a hybrid type 3 effectiveness-implementation trial using sequential, multiple assignment, randomization to evaluate 1) two text messaging (TM) strategies to reach persons with OA and enroll them in physical activity counseling provided by physical therapists; and 2) two strategies to engage enrolled persons in the Walk with Ease (WWE) AAEBI for sustained self-management. Persons with OA receiving care in clinics partnering with the MW-PRC will be identified via a population health management strategy through the electronic health record and randomized to; 1) TM outreach, or 2) TM outreach + motivational messages to enroll in activity counseling. Enrolled persons are then randomly assigned to activity counseling and information to engage in WWE delivered with one of two formats promoted by the Arthritis Foundation; 1) self-directed; or 2) enhanced self-directed. The trial has 3 Aims; 1) Determine differences in reach between two TM strategies to enroll persons with OA in activity counseling (primary outcome), 2) Determine differences in reach between two strategies to engage enrolled persons in the WWE AAEBI (secondary outcomes), and 3) Examine outcomes across additional RE- AIM domains (effectiveness, adoption, implementation, maintenance). The findings from the MW-ASP will produce generalizable tools to increase the reach of effective interventions for persons with OA.

NIH Research Projects · FY 2024 · 2024-09

Project Summary: Heart failure with preserved ejection fraction (HFpEF) has emerged as the greatest unmet medical need in cardiovascular medicine, comprising 50% of all HF cases, with a US prevalence of ³3 million. HFpEF is associated with high morbidity and mortality, with a 5-year survival after hospitalization worse than most cancers of ~35% and, unlike the better understood heart failure with reduced ejected fraction (HFrEF), there are no evidence-based therapies for HFpEF. HFpEF represents an entirely new disease threat because of the systemic metabolic and endocrine nature of its pathogenesis. And, while HFpEF is heterogeneous in its clinical presentation, arguably the most prevalent form is cardiometabolic HFpEF (cMet HFpEF), where the main comorbidities are obesity, type 2 diabetes, and hypertension. These same comorbidities are the major drivers of concomitant obesity-related diseases that includes nonalcoholic fatty liver disease (NAFLD), which is prevalent in more than 50% of HFpEF patients and has been demonstrated to be an independent predictor of all-cause mortality in HFpEF. This is of unique concern as the obesity epidemic continues to grow with current estimations that 45% of the world’s population is either overweight or obese. Our preliminary data support the notion that the heart is a primary regulator of global metabolic syndrome through the serine-threonine kinase, serum glucocorticoid kinase 1 (SGK1). Global SGK1 overexpression has been demonstrated to promote increased obesity, dyslipidemia, while liver-specific deletion of SGK1 has been shown to protect against NAFLD. While there is a clear connection between SGK1 and obesity-related metabolic syndrome, neither a role for SGK1 in cMet HFpEF nor the mechanism by which SGK1 regulates cellular metabolism have been investigated. In this proposal, we will focus on cardiac-specific SGK1 in cMet HFpEF with the hypothesis that SGK1 promotes cardiac pathology and subsequent global metabolic dysfunction in cMet HFpEF via regulating mTORC1 activity and cardiac metabolism. We will address this hypothesis using cardiac-specific targeting of SGK1 in a mouse model of cMet HFpEF with a focus on assessments of cardiac function and metabolism, as well as mechanistic studies in primary cardiomyocytes, in the following Specific Aims which are to: (Aim 1) determine the role for cardiac SGK1 in regulating heart function, metabolism, and heart directed inter-organ communication during cMet HFpEF, (Aim 2) determine whether PRAS40 inhibition by SGK1 promotes mTORC1 mediated pathologic cardiac metabolic inflexibility during cMet HFpEF, and (Aim 3) evaluate the therapeutic efficacy of a novel SGK1 inhibitory peptide for preserving cardiac function and systemic metabolism during cMet HFpEF. These studies are significant as the present the opportunity to identify novel secreted factors from the heart that regulate global metabolic health as well as to test new therapeutic targets for both HFpEF and obesity-related diseases.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT The proposed K01 award describes a research training program for Dr. Schola Matovu, an Assistant Professor at the University of Utah College of Nursing. Her overarching goal is to become an independent investigator conducting global health and gerontological research studies to improve the health and quality of life of older adults with caregiving responsibilities, such as grandmother-caregivers (GMCs). This award provides support for Dr. Matovu to achieve the following Career Development Goals to gain expertise in: 1) developing and testing multi-component and culturally appropriate behavioral interventions in low-resourced settings; 2) implementing aging and health disparities research related to aging, and performing geriatric health assessment and coaching of community-dwelling GMCs; 3) behavioral clinical trial methodology; and 4) research leadership and management skills. To achieve these goals, Dr. Matovu has assembled a dedicated team of mentors and advisors with expertise in family caregiving research (Dr. Lee Ellington, US Primary Mentor), design and implementation of psychosocial interventions for Ugandan populations impacted by HIV/AIDS (Dr. Noeline Nakasujja, Uganda Primary Mentor), mixed research methods and behavioral interventions (Dr. Melissa Watt), gerontological nursing, rural care, and nurse-led health coaching (Dr. Heather Young), microfinance and social protection interventions (Dr. Fred Ssewamala), economics and women’s empowerment (Dr. Eve Namisango), and biostatistics (Dr. Xiaoming Sheng). There are an estimated 163 million children worldwide who are under the care of their grandparents or other relatives. In Uganda, social determinants of health (i.e., poverty, wars, and maternal and perinatal conditions) threaten the middle generation (age 15-49) and leave older adults, especially grandmothers (Bajjajja), to become the safety net. Yet, in this region, knowledge about effective interventions that support the health and wellbeing of these GMCs is limited to nonexistent. As such, Dr. Matovu proposes to refine, adapt, and test her BAJJAJJA intervention. This will be achieved through three Specific Aims: 1) Refine and adapt the BAJJAJJA intervention components through a collaborative and iterative feedback process with a diverse community group of 18 members; 2) Test the feasibility, acceptability and preliminary efficacy of the BAJJAJJA intervention in improving economic and health outcomes among 24 Ugandan GMCs; and 3) Explore the barriers and facilitators to (3a) maintenance of the BAJJAJJA individual intervention benefits and (3b) sustainability of the income generating activity at 6 months post-intervention. This innovative study will be the first in Uganda (to our knowledge) to utilize a community-engaged approach that emphasizes the meaningful involvement of community partners to develop an intervention that targets GMCs. Her outcomes will support her future efficacy clinical trial to test a novel multi-component and community-engaged BAJJAJJA intervention to promote the mental, physical, and economic wellbeing of GMCs.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT There is significant potential for patient care enabled by genomics to enable transformational improvements in health. However, the actual uptake of genomic medicine into clinical care has been limited to date. The University of Utah (UU) Genomics Learning in the Utah Ecosystem (GLUE) Center will contribute to a Genomics-Enabled Learning Health Systems (gLHS) Network that will catalyze the wide implementation of genomic medicine. The GLUE Center will offer the gLHS Network unique expertise, collaborations, and resources to address key areas of need, including the UU ReImagine EHR Initiative, which has been a pioneer in leveraging electronic health record (EHR) interoperability standards to improve patient care and the provider experience at scale; Value-Driven Outcomes, an enterprise platform for assessing and improving care value and efficiency; the Genetic Cancer Risk Detector (GARDE), a standards-based platform for population-level genetic screening; the Mendelian Phenotype Search Engine (MPSE), which continuously analyses the EHR to identify patients most likely to benefit from rapid whole genome sequencing (rWGS); and extensive experience working with safety-net clinics to reduce healthcare disparities through scalable informatics interventions. As a gLHS Network site, the GLUE Center will pursue three Aims to contribute our expertise and ensure the success and broad impact of the network. First, we will provide vision, infrastructure and expertise to the gLHS Network and enable Network-wide implementation of interoperable interventions, including for pharmacogenomics (PGx). We will contribute open-source tools and interoperability expertise to enhance the scalability of interventions chosen for Network-wide dissemination, including for providing PGx guidance. Second, we will support Network-wide dissemination of the standards-based GARDE clinical decision support platform for population-based genetic testing. An open-source, standards-based tool that leverages AI and chatbot technologies, GARDE has been successfully used in a multi-site pragmatic clinical trial to identify, reach, educate, and facilitate at-home genetic testing of hereditary cancer syndromes. GARDE can be adapted to facilitate genetic testing for any condition chosen by the Network. Given its public health importance, we propose the Network focuses on genetic testing for familial hypercholesterolemia. Third, we propose the real- time identification of critically ill newborns most likely to benefit from rWGS. At Rady Children’s Hospital- San Diego and the UU Neonatal Intensive Care Unit (NICU), we deployed an automated, open-source pipeline (MPSE) that prioritizes patients for rWGS using Human Phenotype Ontology terms derived directly from the EHR. Here, we propose a pilot deployment of MPSE at NICUs across the network for daily, automatic review of evolving medical records to prioritize newborns for clinically indicated rWGS. Through these efforts, the GLUE Center will contribute critical and unique expertise that will help ensure the Network is successful in its mission to discover and disseminate effective and equitable strategies for enabling genomic medicine at scale.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY: Implantable electronics can provide a direct connection to the endogenous sensorimotor pathways, can offer an exciting opportunity for intuitive and dexterous control of bionic devices. These implantable devices often need to communicate with external equipment for data acquisition and signal generation. A wired connection between the device and external equipment is traditionally used for this type of communication, but this is fraught with surgical complications, infection, wire breakage, and device malfunction. Significant research has been devoted to wireless biotelemetry systems for implantable electronics devices and these have been implemented in many implantable medical devices. An antenna is an essential electronic component of a wireless biotelemetry system. Antennas are typically included in or on the battery pack, thus limiting their physical size. But advanced fabrication techniques, material synthesis, and device design are shrinking the size of next-generation devices, reducing device footprint to minimize foreign body response. Antenna design remains one of the major challenges in the miniaturization of implantable medical devices. The size of the antenna is determined by the frequency of the transmitted signal. Long-term implants use the MedRadio band (402-405MHz), where a half-wavelength antenna is ≈6 cm in the body. Even applying methods to miniaturize these antennas, they are too large for next-generation (mm-scale) implants. Revolutionary antenna design is much needed to enable the next-generation medical implant miniaturization strategy. This proposal will use innovative antenna system design to create a remotely coupled and injectable antenna system. This new class of implantable antenna can be injected into the body, where they transform into a soft, conductive antenna. Once the antenna is injected, it will be able to remotely coupled with a much smaller antenna in the implantable medical device without physical attachment. This approach will enable a new class of wireless biotelemetry antennas and their associated medical applications.

NIH Research Projects · FY 2024 · 2024-09

Here we interrogate a novel therapeutic strategy for improving outcomes of acute ischemic stroke (AIS) in older mice. We will test whether amplifying endothelial cell (EC) autophagy, EC glucose transporter 1 (GLUT1), and/or PKC/PKD signaling serve as viable approaches for improving outcomes of this debilitating condition. AIS deprives cerebral artery ECs of nutrients which decreases mechanistic target of rapamycin complex 1 (mTORC1) activity and stimulates autophagic flux to support basal metabolism. We reported that aging represses autophagic flux in ECs from mice and humans. We hypothesize that the age-associated impairment of EC autophagy worsens AIS outcomes for three main reasons. First, if autophagy is stalled, damaged organelles will accumulate and contribute to cellular toxicity. Second, autophagic flux avails the cell of macromolecules generated from protein/organelle recycling that can be used for ATP production, and impairments would lead to more pronounced energy deficiency. Third, EC autophagy elicits an important metabolic reprogramming of cells that is critical for arterial vasodilation, which impacts blood and oxygen delivery. We hypothesize that restoring EC autophagy in older mice improves AIS outcomes. Several pieces of data support this contention. First, we found that mTORC1 inhibition increases whole-body autophagy and improves outcomes of AIS. Conversely, inhibiting autophagy specifically in ECs worsens outcomes of AIS. Underscoring the importance of EC autophagy, mice with EC specific depletion of autophagy were refractory to benefits of whole-body autophagy upregulation. In Aim 1 (i) we will rejuvenate age- associated reductions in EC autophagy via AAV-mediated delivery of ATG3 directly to ECs. We find that EC autophagy compromise lowers glucose transporter 1 (GLUT1) expression. Mechanistically, the aging-associated decline in EC autophagy and EC GLUT1 blunts EC glycolytic flux and ATP production, diminishing subsequent ATP/ADP-mediated purinergic 2Y1 receptor (P2Y1R) activation of endothelial nitric oxide synthase. As such, EC GLUT1 is a tractable site for intervention downstream of defective EC autophagy. In Aim 1 (ii) we predict that loss of EC GLUT1 worsens AIS outcomes in adult mice, whereas AAV-mediated delivery of GLUT1 directly to ECs mitigates AIS outcomes in older mice [Aim 1 (iii)]. We reported that PKC/PKD activation provides the signaling link between the P2Y1R and endothelial nitric oxide synthase. In autophagy and GLUT1 deficient ECs and arteries, function of both tissues can be re- established by PKC/PKD activation using bryostatin-1. In Aim 2 we hypothesize that repurposing this approved drug rejuvenates signaling to endothelial nitric oxide synthase to improve AIS outcomes in older mice. Results from our studies could hasten development of therapeutics targeting EC metabolism to improve cerebrovascular health and combat the debilitating complications of AIS in older persons.

NIH Research Projects · FY 2025 · 2024-09

Modified Project Summary/Abstract Section Nearly 1 in 2 Hispanic adult suicide deaths involves a firearm, the most lethal suicide method. However, there are critical gaps in characterizing firearm suicide deaths and identifying opportunities for preventing firearm suicide. Our objectives are to leverage the power of machine learning (ML) to identify circumstances preceding firearm suicides among Hispanic adults and generate new information on Hispanic adult firearm suicide decedents in America. We propose to achieve these objectives by: (1) Developing a natural language processing (NLP) pipeline to identify and code circumstances preceding firearm suicide deaths among Hispanic adults and (2) Establishing clinical typologies of Hispanic adult firearm suicide decedents with combinations of demographic characteristics and circumstances preceding death. This project will ultimately provide critical information that will be used to inform intervention and evaluation opportunities through a future R01, such as implementing lethal means counseling, advising when the intervention could be provided, and, ideally, improving suicide prevention for all Americans in the future. The proposed research is significant for two reasons. First, this project will fill a critical need for identifying key circumstances preceding highly-lethal firearm suicide deaths among Hispanic adults. Second, this project will generate clinical profiles of Hispanic adult firearm suicide decedents. The proposed research is innovative for several reasons. First, this will be among the first studies to leverage free-text data to generate information on the circumstances preceding Hispanic firearm suicides. Second, this will be the first project to leverage the power of NLP and ML with free-text data to predict common circumstances preceding firearm suicide death among Hispanics quickly and accurately while also creating standalone, annotated NLP tools. Third, this will be the first study funded to establish subgroups of Hispanic firearm suicide decedents.

NIH Research Projects · FY 2025 · 2024-09

Neurodevelopmental disorders often have clear genetic components but linking genotype to phenotype remains challenging. Recent advances in genome editing technology have enabled the rapid generation of animal models for cognitive genetic disorders. However, the differing methodologies used across laboratories to phenotype these models confounds efforts to make predictive links between cellular functions of the brain and behavioral outcomes. I propose harnessing Multiplex Intermixed CRISPR droplet (MIC-Drop) technologies to generate knockouts of all 61 transcriptional regulators present in zebrafish larvae that are associated with human cognitive disorders. I will characterize these mutants at the molecular and cellular level with a multiplexed single-cell RNA sequencing technique I have developed, termed MIC-Drop-seq, that allows the simultaneous characterization of many transcriptomes from hundreds of mutant embryos in a single experiment. I will characterize these mutants at the brain morphology and behavioral levels with a battery of high throughput quantitative microscopy assays. I will use these large-scale quantitative datasets to construct new predictive machine learning models that will uncover the links between genetics, molecular features, brain morphology, and behavioral outcomes in brain development. These models may yield new treatment strategies for many human cognitive disorders. To achieve the goals of my proposal, I will embark on an intensive training plan with my mentorship team that will enable me to transition from my previous background in experimental biology to become a leader in the field of functional genomics and data informatics. My mentorship team at the University of Utah are leaders in the fields of single- cell biology, data science, and developmental biology, and will dedicate time to foster my career development as I transition to lead my own independent research group.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Regulation of autophagy and the nutrient-sensing kinases mTOR and AMPK are not only important in cancer, but have garnered much recent attention in neurodegeneration. The Per–Arnt–Sim domain kinase (PASK) function both up- and downstream of mTOR. Our studies in spinocerebellar ataxia type 2 (SCA2) revealed that PASK is overabundant upon ATXN2 mutation. In yeast, Pask directly phosphorylates the ATXN2 homolog Prp1. This was an intriguing connection to our work as we had previously found that mTOR is dysregulated upon ATXN2 mutation. Our preliminary data support a feedforward control mechanism of PASK in SCA2. When ATXN2 is mutated, PASK levels rise further limiting autophagy. In our previous work we showed that STAU1 is also elevated with ATXN2 mutation leading to enhanced translation of mTOR mRNA, which in turn is known to activate PASK. In preliminary data we have shown that targeting PASK by RNAi or with the PASK- specific inhibitor BioE-115 in cultured cells, or genetically in SCA2 mice significantly reduced STAU1 protein levels, improved autophagic flux and levels of Purkinje cell marker proteins, effectively mimicking ASO knockdown of ATXN2. We hypothesize that the kinase activity of PASK regulates activity in the ATXN2 – STAU1 pathway modulating TDP-43 pathology. We further hypothesize that that targeting PASK is an effective way to normalizing TDP-43 proteinopathy, including amyotrophic lateral sclerosis (ALS) / frontotemporal dementia (FTD) and the Alzheimer’s disease-like dementia disorder limbic age related TDP-43 encephalopathy (LATE). The overall objective of our study is to understand PASK in neurodegeneration and to generate proof- of-concept for targeting PASK for treating SCA2 and TDP-43 proteinopathies to support future therapeutic development. Three specific aims are proposed: In Aim 1 we will use a proteomic approach to identify phosphorylated peptides of the ATXN2 protein. We will also investigate isogenic SCA2 and TDP43 mutant patient iPSC cortical neurons to produce transcriptome and proteomic analysis to identify differentially regulated genes, proteins and pathways dependent on BioE-1115. In Aim 2 we perform two genetic interaction studies to demonstrate modification of motor and molecular autopagy phenotypes in SCA2 (ATXN2-Q127) and Prp-TDP43-Q331K transgenic mice haploinsufficient for Pask. In Aim 3 we will demonstrate modification of molecular phenotypes of Prp-TDP43-Q331K mice treated with BioE-1115, and also conduct a proof-of-concept study showing effectiveness of an ASO targeting Pask in modification of both motor and molecular phenotypes of Prp-TDP43-Q331K mice. Our expectation is to demonstrate that ATXN2 is phosphorylated, that its phosphorylation is modulated by BioE-1115, and to demonstrate PASK as a therapeutic target for SCA2, ALS, FTD and possibly other AD/ADRDs.

NIH Research Projects · FY 2025 · 2024-09

Modified Project Summary/Abstract Section The proposed 5-year K23 award describes a research training program for Kristina Suorsa-Johnson, PhD, a licensed pediatric psychologist who specializes in differences of sex development (DSD). Her overarching career goal is to become an independently funded investigator focused on improving the psychosocial and health outcomes of pediatric patients with DSD by creating tools to facilitate patient engagement in medical decision making through shared decision making (SDM). This award provides support for Dr. Suorsa-Johnson to achieve the following Career Development Aims: Aim 1: Obtain expertise in SDM, including the development of decision aids (DAs) for adolescents and young adults (AYAs); Aim 2: Gain sexual health education training, particularly as it relates to the creation of educational materials to enhance surgical SDM; Aim 3: Develop expertise in evaluating and implementing DAs; and Aim 4: Expand and strengthen research leadership and management skills. To achieve these goals, Dr. Suorsa-Johnson has assembled a dedicated team of mentors and advisors with expertise in SDM (Angela Fagerlin, PhD), SDM in AYAs (Ellen Lipstein, MD), sexual health education (Jordan Rullo, PhD), dissemination and implementation science (Jennie Hill, PhD), qualitative design and clinical trials (Melissa Watt, PhD and Angela Fagerlin, PhD), multi-site trial design (Gregory Stoddard, MBA, MPH), urogenital/gonadal surgeries in AYAs (Kathleen van Leeuwen, PhD), and DSD education (David Sandberg, PhD and Erica Weidler, MEd, MS). A person with lived experience, Noi Liang, MBA, MCPA, is consulting to ensure all aspects of the project align with the needs of those with DSD. DSD are congenital conditions where chromosomal, gonadal, or anatomical sex development is atypical. AYAs with DSD make critical and potentially irreversible, lifealtering urogenital/gonadal surgical decisions. However, we know little about how AYAs approach surgical decision making and no standardized SDM resources exist. As such, Dr. Suorsa-Johnson proposes to create and pilot a set of surgical DAs for AYAs with DSD. This will be achieved through three Specific Aims: Aim 1: Identify informational needs and values influencing surgical decision making for AYAs with DSD; Aim 2: Develop a set of evidence-based DAs for surgical decisions to facilitate SDM for AYAs and their caregivers; and Aim 3: Pilot test and refine DA content, delivery, and feasibility. This project will result in a set of surgical decision aids ready to be tested in a multi-site trial. This project is significant because it will change how we provide care and improve engagement in surgical decision making for this underserved population. This innovative project is the first to explore the needs of AYAs with DSD making surgical decisions from a SDM framework and create associated decision support tools.

NIH Research Projects · FY 2024 · 2024-09

Research confirms that patient outcomes improve when healthcare providers practice in an evidence-based manner. Evidence-based practice (EBP) involves a problem-solving approach to clinical care that incorporates the conscientious use of current best practices from well-designed studies, a clinician's expertise, and patient values and preferences. EBP has been shown to increase patient safety, improve clinical outcomes, reduce healthcare costs, and decrease variation in patient outcomes. The importance of EBP is substantiated; however, significant barriers to widespread use of current evidence to inform decision-making remain, including the lack of access to published research. Publisher paywalls limit access to approximately 75% of the published biomedical literature. That represents a massive amount of information being withheld from physicians who lack subscriptions to the content. This notable disparity in health information access presents an opportunity to democratize information access by providing all physicians in the state with the means to acquire the evidence necessary to support clinical decision-making. This ideal aligns with NLM’s strategic goal to reach more people in more ways through enhanced dissemination and engagement. In pursuit of that objective, the Eccles Health Sciences Library (EHSL) at the University of Utah has devised a pathway that enables licensed physicians across the state to retrieve full-text articles from PubMed without encountering a publisher paywall. By removing one of the obstacles to information access that disproportionally affects physicians (and their patients) in rural and under-served areas in the state, EHSL seeks to minimize disparities in health information access by healthcare providers in Utah. This project will eliminate the barrier of publisher paywalls as an impediment to EBP and be guided by the following aims: Aim 1: To increase access to usable health information for Utah physicians, particularly those in rural areas with high health disparity populations. Aim 2: To solicit feedback regarding the impact of expanded health information access on physicians’ ability to provide evidence-based care. Aim 3: To evaluate the suitability and sustainability of a subsidized article delivery service in PubMed as a means of alleviating the unequal access to information experienced by Utah physicians. This proposal’s significance and opportunity for change is exemplified by the fact that most Utah physicians have limited access to the published biomedical literature. If proven effective, our approach can be replicated or adapted in other locations where physician health information access disparities need to be addressed.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Sunlight, while essential for life on earth, also produces harmful ultraviolet radiation (UVR) that penetrates the ozone layer. UVR, particularly UVB, is known to damage organelles and DNA. A variety of UVR-protective mechanisms have arisen during metazoan evolution. Until recently, melanin was believed to be the only vertebrate sunscreen. Recently, our lab discovered a novel vertebrate sunscreen named gadusol. Gadusol is maternally deposited from the ovary to the egg to protect against UV damage during the earliest stages of development, prior to the production of melanin. We do not yet know the function of zygotically produced gadusol, after maternally provided gadusol is depleted and fish have developed other UV protective mechanisms including melanin, skin, and scales. Here, I will investigate both the zygotic function and evolutionary origins of gadusol. First, I will determine if zygotically produced gadusol acts as a spatially organized sunscreen and characterize the response to UVR exposure in mutants lacking gadusol and wildtype controls with single cell RNA sequencing. Second, I will determine if UVR exposure upregulates gadusol production as a form of protection against future exposures and the mechanism by which this occurs. Third, I will investigate the evolutionary origins of gadusol, identifying the source and conservation of the gadusol producing enzymes, eevs and MT-Ox, from algal to metazoan species and identify extant species in which eevs and MT-Ox are co-expressed with the melanophore master regulator mitf. This project will provide insights into how this novel vertebrate sunscreen, gadusol, is synthesized and used in vertebrates. My research project will leverage the strong community of zebrafish researchers, developmental biologists, and evolutionary geneticists at the University of Utah to learn techniques and develop skills I will take with me to my own independent research lab.

NIH Research Projects · FY 2025 · 2024-09

Family caregivers provide much of the support to people with Alzheimer’s disease (AD) and AD-related dementias (ADRD) living in the community. As a result, caregivers for people with AD/ADRD may experience measurable declines in financial well-being due to the costs of care, such as medical treatments and home modifications, or because of changes to their employment status and income. These financial burdens are a particular concern for National Institute on Aging (NIA) priority populations, including people who are Hispanic/Latino, Black/African American, or living in a rural area, who experience racial and geographic disparities in economic well-being. However, no comprehensive measure of the financial impacts of AD/ADRD care exists. Furthermore, few existing measures consider the caregiver’s broader social network, even though they may impact the caregiver’s financial situation or experience indirect financial effects of care. Therefore, the full extent of the financial impacts of AD/ADRD care on family caregivers and their social network remains unknown. To address this gap, this study aims to: (1) Engage diverse family caregivers of people living with AD/ADRD and their social network to identify areas of financial impact, (2) Develop and pilot a comprehensive quantitative measure of the financial impact of caring for a person living with AD/ADRD, and (3) Validate a revised measure of financial impact to accurately capture the experiences of caregivers of people living with AD/ADRD and their networks. We will use a mixed methods approach incorporating interviews and surveys guided by the NIA Health Disparities Framework and a family caregiving framework to identify both existing and novel areas of care-related financial impacts. We will over-sample caregivers from three NIA priority populations: Hispanic/Latino, Black/African American, and people living in rural areas. Drawing from best practices in survey design, we will engage with key stakeholders including people with lived experience of AD/ADRD, clinicians, and researchers to develop candidate measures. In partnership with an experienced survey research center, we will field an initial survey of 100 caregivers of people with AD/ADRD, using both telephone and Internet surveys conducted in English and Spanish. We will use exploratory factor analysis to evaluate the structure of the new measure and Rasch analysis to assess item redundancy and adequacy of response options. Based on our quantitative results and additional feedback from stakeholders, we will revise the measure and validate the instrument in an independent sample of 300 caregivers of people with AD/ADRD using the same partnership and methods as the initial survey. The validation process will use confirmatory factor analysis, Rasch analysis and other psychometric methods to assess the measure’s properties overall and within each of our three priority populations. Our approach will result in a novel, validated measure of the unique financial impacts experienced by caregivers of people with AD/ADRD. Our aims are designed to assure the measure is valid and reliable in the general population and among Latino/Hispanic, Black/African American, and rural caregivers. Ultimately, this measure can be used to better understand caregiving networks in AD/ADRD and will inform the development of interventions and policies that will better support caregivers and families of people living with AD/ADRD.

NIH Research Projects · FY 2025 · 2024-09

Risk for major depressive disorder (MDD) risk increases with aging. Later-life depression affects 12-40% of people over 65yrs old, with biological risk factors including female sex, systemic inflammation and cognitive deficits. Women exhibit 5-10 fold higher risk for later-life depression vs. men. Environmental factors can contrib- ute notably to mental health status in aging. Rates of MDD rise significantly with living at altitude. Chronic hypo- baric hypoxia (CH-hypoxia) exposure occurs at altitude. We established a novel sex-based translational model to study impact of CH-hypoxia on vulnerability to depression. After 2-3wks in CH-hypoxia (4,500ft,or 18% partial pressure of oxygen or ppO2) vs normal oxygen levels (sea level or 21%ppO2), young adult rats (2.5m old) exhibit symptoms of depression, anxiety, anhedonia and cognitive dysfunction. Females are particularly susceptible. Rats in CH-hypoxia exhibit poor brain bioenergetics and systemic inflammation (elevated serum interleukin 6 or IL6, an inflammatory cytokine). Rats in CH-hypoxia do not respond to most selective serotonin reuptake inhibitors (SSRIs), but show antidepressant-like response to bioenergetic compounds such as cyclocreatine. Systemic inflammation and brain hypometabolism are hallmarks of aging, implying that CH-hypoxia may act as a signifi- cant risk factor for later-life MDD, especially in women. Systemic inflammation is linked to SSRI inefficacy and treatment-resistant depression. In older MDD patients, elevated serum IL6 is linked to impaired cognitive func- tion. The means by which inflammatory mediators may promote a depressive phenotype is as yet unclear, but may involve impact on neurotrophic factors and hippocampal neurogenesis. We now propose studies utilizing this model to evaluate age and sex as biological variables for impact of CH-hypoxia on vulnerability to depres- sion. Impact on behavioral and molecular biomarkers of depression will be addressed, including impact on in- flammatory and bioenergetic pathways, cognitive deficits linked to MDD, and efficacy of therapeutics. Our cen- tral hypothesis is that aging will intensify the impact of CH-hypoxia on inflammatory and brain bioenergetic processes, to worsen depressive and cognitive symptoms, and reduce treatment efficacy, with females more susceptible. Rats at the age of young adults (2.5m), older adults (4m, 8m) or aging adults (18m) will be tested after housing in CH-hypoxia (4,500ft) vs. normal oxygen levels (sea level). In Aim 1, rats will be tested for de- pression-like and anxiety-like behaviors. In Aim 2, rats will be tested for cognitive function, including learning and memory, and cognitive bias. Rats will be sacrificed and brain/serum tested for bioenergetic compounds (creatine, ATP), inflammatory mediators (IL6, IL-1β, TNFα, CRP), BDNF and hippocampal neurogenesis. In Aim 3, young adults (2.5m) and aging adults (18m) in CH-hypoxia or sea level, will be tested for antidepressant-like effects of the SSRI fluoxetine and the bioenergetic compound cyclocreatine. These studies will lay the foundation for future research on the role of age and sex in CH-hypoxia-induced vulnerability to depression, and will allow us to explore novel therapeutics for later-life MDD based on the role of inflammatory and bioenergetic pathways.

NIH Research Projects · FY 2025 · 2024-09

PROJECT ABSTRACT While the microbiota has emerged as an important aspect of mammalian health, the vast majority of current studies have focused on the bacterial component of the microbiota, despite the presence of fungi, archaea and viruses. The virome has recently just begun to become characterized and while there are eukaryotic viruses present within a healthy individual, the overwhelming majority of the viruses on the human body are bacteria infecting viruses called bacteriophages (phages). Changes in these phage communities have been reported in animal and humans during a variety of diseases including inflammatory bowel disease and obesity, however we known very little about these populations during the healthy state. Our recent work has demonstrated that bacteriophages, despite being unable to actively infect mammalian cells, are capable of inducing immune system development. These data suggest that bacteriophages represent an unappreciated microbe that is capable of shaping immune system responses. Recent studies on the bacterial component of the microbiota, have revealed that identifying what bacteria the immune system reacts to, can provide insight into specific bacteria that influence disease, novel biomarkers and unique antigens that can influence natural immune system development. However, this has yet to be performed with the virome. Antibodies, including IgA and IgG, and are highly abundant at mucosal surfaces and sera, respectively and are known to have high reactivity to commensal bacteria. We present data within this application that both sera and mucosal antibodies have high reactivity to commensal bacteriophages in both humans and mice. Based on this, we propose to characterize and identify the commensal viruses that are targeted by IgA and IgG. We will propose three distinct aims. Aim 1 will catalog the mucosal IgA/IgG reactivity against commensal viruses from stool samples obtained from healthy humans. To do this, we have optimized a strategy to purify and sort viral particles allowing us to capture IgA bound DNA and RNA viral particles. As sera antibody reactivity can often reveal unique commensal organisms of interest, Aim 2, will characterize the sera reactivity against the gut resident viral communities using paired sera and stool samples from humans. Finally, to understand how antibodies can influence these human associated viral communities, Aim 3 will utilize gnotobiotic mice that lack adaptive immunity and IgA and colonized with healthy human microbiota to understand how viral communities are controlled by mammalian immunity. These studies will be the first to catalog how the human immune system reacts to commensal viruses of healthy human intestine and will provide a rich resource of data that has the potential to identify novel viruses of interest and establish paradigms how the immune system establishes homeostasis with the resident viral community.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Alzheimer's Disease (AD) stands as a formidable neurodegenerative affliction impacting millions globally. While substantial headway has been made in deciphering the genetic and molecular underpinnings of AD, critical questions persist regarding transcriptomic responses to hippocampal sclerosis (HS) and TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy, two established features of the disease. Aberrant gene expression has been linked to both HS and TDP-43 proteinopathy. Different TDP-43 species have been found to have distinct binding abilities to specific RNA regions and thus selectively influence its RNA-regulatory network. HS is accompanied by the disruption of the gene regulatory network involved in neuronal apoptosis. However, the transcriptomic impact of their interplay remains unexplored. Recently, we have characterized a unique phosphorylation-independent anti-TDP-43 monoclonal antibody specific for a new TDP-43 species in frontotemporal lobar degeneration (FTLD)-TDP type A and type B. The goal of this proposal is to investigate the regional and transcriptomic bases of the contribution of the new TDP-43 species and HS to AD. Our central hypothesis is that the interplay between TDP-43 proteinopathy and HS influences hippocampal transcriptomic abnormalities. In this study, we propose to combine the strengths of the unique anti-TDP-43 antibody and the state-of-the-art spatial sequencing developed to investigate the transcriptomic aspects of how novel TDP-43 species contribute to HS in AD. Aim 1 will quantitatively analyze the distributions of TDP-43 proteinopathy (new TDP-43 species) and neuronal loss in the hippocampi of AD brains. Aim 2 will determine hippocampal gene expression profiles associated with the new TDP-43 species using spatial sequencing technologies. The successful execution of this project will significantly advance our understanding of TDP-43 research, particularly in terms of our limited knowledge concerning pathologic TDP-43 species and its intricate association with HS in AD.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT The goal of this research program is to optimize population oral health through strengthening the scientific basis for innovations in population approaches to improving dental care access, utilization, and quality for all Americans. Mounting evidence suggests that oral and dental conditions in the US are largely attributed to population-specific differences in access to, utilization of, and the quality of oral health care services. These differences arise from system-wide interactions between biological, psychological, social, environmental, economic, policy, and other factors. While there is increasing awareness of these complexities, meaningful scientific progress and translation is stymied by the preponderance of investigations that maintain a focus on individual, single-level factors in isolation. This research program incorporates a framework that integrates multi-level perspectives and approaches (e.g., patient, provider, and population) to optimize oral and dental health, facilitated by the PI’s expertise as an epidemiologist and complex systems scientist. Specifically, the research program will generate novel data on US populations and employ methodologies to conduct innovative investigations situated at the intersections of dental care access, utilization, and quality. Findings will be leveraged to develop comprehensive, cost-effective policies and strategies to provide high-quality dental care and optimize oral health for all Americans.

NIH Research Projects · FY 2025 · 2024-09

Abstract Diarrheal diseases are the among the leading cause of death in children worldwide, most of which occur in low- and middle-income countries (LMICs). The cornerstone for management of diarrhea is rehydration, though antimicrobials are beneficial in some instances. Unfortunately, given that treatment is frequently empiric, based mostly on clinical suspicion for bacterial causes, antimicrobials are overused in management of diarrheal illness worldwide. Thus, there is a need for clinical decision support tools to inform clinical management and promote antimicrobial stewardship. In particular, frontline healthcare providers in rural areas, such as village doctors in Bangladesh, often have inadequate knowledge for the basis of antimicrobial use, and may benefit greatly from guidance. We have recently developed a mobile phone based electronic clinical decision-support tool (eCDST), and shown the impact of etiological prediction on physician antibiotic prescription practices for pediatric diarrhea in two LMICs. In this proposal, our overarching goal is to customize our eCDST into a comprehensive mHealth application (Accessible Diarrhea Etiology Prediction Tool, ADEPT) to support rural health care providers in the management of pediatric diarrhea (R21 phase), and to measure its impact through the performance of a pilot before-after feasibility study (R33 phase). Our work will contribute to an evidence base for mHealth-enabled antimicrobial stewardship, with potential to extend beyond diarrheal illness, and into other syndromes, including respiratory illness and febrile illness.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Social context is tied to health outcomes, driving the rapid adoption of screening for tangible social needs (e.g. for housing, utilities, food) by healthcare systems. Our preliminary studies (R21HS026505, R01NR019944) underscore the potential for narrowing health disparities by linking social needs screenings in clinical settings – particularly in emergency department (ED) settings where 50% of patients endorse one or more need – to United Way 211's (211) Service Navigators (SNs) through clinically-integrated and adaptable software solutions. However, 34% of those with social needs seen in EDs provided either another person’s phone number or only an email address for outreach, a factor we have linked to a decreased likelihood of connecting to services; higher instances of housing, utilities, and transportation needs; and greater frequency of ED visits compared to those who provide their own telephone number. Moreover, 24% lacked home internet and faced considerable difficulties in establishing service connections, particularly with navigating online forms. These findings highlight the role that Information and Communication Technology (ICT), specifically stable telephone access, internet, and digital navigation, may play in meeting patients' social needs and the ability of community services to improve health outcomes. In this NIH stage 3 real-world efficacy study, we will utilize a community- engaged process and rapid cycle testing with partnering community, governmental, and clinical service representatives to develop, refine, and launch an ICT screening and access program (stable cellphones and digital navigation) in three ED settings across the state of Utah. Then, in a randomized controlled trial of 600 ED patients with social needs and ICT access barriers, we will leverage existing screening and referral protocols to determine whether providing stable cellphones, 211 service outreach, and digital navigation assistance to patients with social needs and ICT access barriers result in improved health outcomes over 6 months compared to patients who are offered cellphones and 211 service outreach alone. Our proposal meets the goals of the National Institute of Nursing Research (NINR) as it emphasizes the essential role of technology access in fostering public health equity. By embedding advanced digital tools in social needs screenings and referrals, we aim to close the gap between recognizing social needs and connecting individuals to vital services using a scalable, sustainable approach.

NIH Research Projects · FY 2024 · 2024-09

There is an urgent need for tools that can monitor the influences of the exposome on human health across large populations. Due to the heterogeneity and complexity of biological responses in the body, the capacity to obtain organ-level insights from a simple blood draw is much desired. Extracellular vesicles (EVs) are bilayer membrane structures of diameters 30 – 1000 nm, and they are released into the bloodstream by cells throughout the body, at concentrations on the order of 1010 per ml. Their molecular content of proteins, dsDNA oligomers, microRNAs, mRNAs, and other analytes, may play multiple functional roles via EV trafficking, and may also provide a diagnostic report back on the tissue of origin. As such, EVs provide a unique opportunity to study the health impact of environmental exposures through blood analyses. The long-term goal of this proposed program is to conduct population-level exposomic monitoring through the development of a minimally invasive method that can provide a systems view of health status. The method will be capable of monitoring tissue-specific signatures across individual organs and organ systems through measurements of circulating EVs. The overall objective of this project is to develop, validate, and apply the analytical infrastructures (technologies, software, and resources) that powers the method, focusing on investigating the environmental impact on the human lungs as a proof-of-concept. To establish the technological foundation of this project, we will integrate an exciting technology trio collectively termed the Extracellular Vesicle Tricorder. The first technology, VET-seq (Vesicle Epitope Transcript Sequencing), is a droplet-based sequencing method that resolves the organ source of circulating EVs by detecting EV proteins and RNA cargoes simultaneously at single-vesicle resolution. The second technology, OrganView, aims to sort and assemble scrappy information carried by EVs into meaningful biological messages with organ specificity. The third technology, VPU (Vesicle Processing Unit), integrates a sensitive nanoparticle method, digital microfluidics, and on-chip immunoassay, to facilitate population-level analysis of EVs. Towards these challenging goals, I have assembled a research team with complementary technical expertise in micro-nanotechnologies, molecular epidemiology, EV biology, bioinformatics and statistical modeling, lung cancer, and infectious diseases. The proposed research is highly innovative because it harnesses an emerging class of analytes (EV omics) to develop an unconventional systems approach for monitoring the influence of environmental exposures on human health. Overall, the new concepts, technologies, and resources derived from this work will augment current methods for exposome research, with the potential to deepen our understanding of human exposome and reveal unknown health threats in our environment.

NIH Research Projects · FY 2024 · 2024-09

Project Summary: Transesophageal echocardiography (TEE) is an essential diagnostic tool in cardiology. There are over one million TEEs performed annually in the United States. A major advantage of TEE over transthoracic echo (TTE) is superior resolution of posterior structures such as the mitral valve and the left atrial appendage (LAA). TEE also substantially reduces ultrasound scatter from the lungs, which provides better images than transthoracic imaging, making TEE an essential imaging modality in critically ill patients. Examples of the clinical usefulness of TEE include diagnosing and managing infectious endocarditis (infection of the valves of the heart), diagnosing acute cardiovascular events in critically ill patients, trauma patients, and patients before and after cardiovascular surgery. TEE requires the use of sedation (anesthesia). Sedation requires specialized procedural space and skilled providers, which increases procedural cost, burdens the workflow, increases the risk to the patient, and overall limits the availability of TEE. Sedation accounts for the majority of the harm associated with TEE including cardiovascular (hypotension, arrythmia) and respiratory compromise. The serious risks of anesthesia are amplified by the high prevalence of co-morbidities in patients undergoing TEE. Alternative TEE methods that do not require anesthesia, will reduce cost, enhance workflow, expand availability, reduce risk, and in some cases will provide more accurate information compared to conventional TEE in such cases as non-sedated exercise mitral valve assessment, and assessment of cardiac causes of cryptogenic stroke. The nasal orifice is an alternative to the oral approach, and nasal-TEE can eliminate the need for sedation. Hence, nasal-TEE represents a unique opportunity to reduce cost, improve workflow, expand availability, and improve safety. However, prior attempts utilizing nasal-TEE systems have considerable gaps to making nasal- TEE an effective tool over traditional TEE. Prior attempts at nasal-TEE resulted in poor image quality, unacceptable rates of nasal bleeding, and thermal burns to the esophageal wall from overheated ultrasound probes. Therefore, innovative strategies are needed to overcome previous limitations of nasal-TEE. We are proposing to develop a novel, innovative nasal-TEE system to acquire high quality cardiac imaging without the need for anesthesia. The overall objective of this project is to develop an innovative nasal-TEE prototype with the potential to revolutionize cardiovascular diagnostic imaging. The proposed nasal-TEE platform will be faster, less expensive, expand availability, safer, and in some cases provide more accurate information compared to conventional TEE.

NIH Research Projects · FY 2025 · 2024-09

Project Summary: Transesophageal echocardiography (TEE) is an essential diagnostic tool in cardiology. There are over one million TEEs performed annually in the United States. A major advantage of TEE over transthoracic echo (TTE) is superior resolution of posterior structures such as the mitral valve and the left atrial appendage (LAA). TEE also substantially reduces ultrasound scatter from the lungs, which provides better images than transthoracic imaging, making TEE an essential imaging modality in critically ill patients. Examples of the clinical usefulness of TEE include diagnosing and managing infectious endocarditis (infection of the valves of the heart), diagnosing acute cardiovascular events in critically ill patients, trauma patients, and patients before and after cardiovascular surgery. TEE requires the use of sedation (anesthesia). Sedation requires specialized procedural space and skilled providers, which increases procedural cost, burdens the workflow, increases the risk to the patient, and overall limits the availability of TEE. Sedation accounts for the majority of the harm associated with TEE including cardiovascular (hypotension, arrythmia) and respiratory compromise. The serious risks of anesthesia are amplified by the high prevalence of co-morbidities in patients undergoing TEE. Alternative TEE methods that do not require anesthesia, will reduce cost, enhance workflow, expand availability, reduce risk, and in some cases will provide more accurate information compared to conventional TEE in such cases as non-sedated exercise mitral valve assessment, and assessment of cardiac causes of cryptogenic stroke. The nasal orifice is an alternative to the oral approach, and nasal-TEE can eliminate the need for sedation. Hence, nasal-TEE represents a unique opportunity to reduce cost, improve workflow, expand availability, and improve safety. However, prior attempts utilizing nasal-TEE systems have considerable gaps to making nasal- TEE an effective tool over traditional TEE. Prior attempts at nasal-TEE resulted in poor image quality, unacceptable rates of nasal bleeding, and thermal burns to the esophageal wall from overheated ultrasound probes. Therefore, innovative strategies are needed to overcome previous limitations of nasal-TEE. We are proposing to develop a novel, innovative nasal-TEE system to acquire high quality cardiac imaging without the need for anesthesia. The overall objective of this project is to develop an innovative nasal-TEE prototype with the potential to revolutionize cardiovascular diagnostic imaging. The proposed nasal-TEE platform will be faster, less expensive, expand availability, safer, and in some cases provide more accurate information compared to conventional TEE.

NIH Research Projects · FY 2025 · 2024-09

Project summary Viruses and the organisms they infect impose strong reciprocal selective pressure on each other. This is particularly pronounced at protein-protein interfaces between viruses and their hosts, such as in the case of antiviral proteins and the virus-encoded proteins that they target. Studying the biology of infection therefore provides insight into infectious disease as well as into the underlying mechanisms of protein evolution. Host- virus interactions have been extensively studied in mammals and to a lesser extent other vertebrates, yet protein-based immunity has been studied less in other metazoans. Studying protein-based immunity in divergent species will provide an important comparative point to better understand how antiviral proteins evolve. It additionally presents an opportunity to characterize unique ways by which other species combat viral infection, with potential implications for our own struggles with viral diseases. This Pathway to Independence proposal will support the development of a research program focused on the use of structural homology as a means of uncovering and studying independently evolved effector proteins, both in understudied, biodiverse species and in the viruses that infect them. Throughout the proposal, structural modeling is used to close the gap in our understanding of the structural and functional diversity present in the proteomes of model organisms and viruses and those that have been less studied. In Aim 1, I will perform extensive structural homology searches for viruses and diverse animals. The goals of these searches will be to 1) define patterns of gene capture in diverse viruses, with focus on unique domain organizations, and 2) define structural homologs of antiviral proteins in diverse metazoans. Aim 2 investigates the apparent independent evolution of an antiviral zinc finger-containing protein in mollusks and vertebrates. This aim will provide insight into how domains adapt to serve unique functions. It integrates virological and biochemical approaches to understand the relationship between RNA binding properties and antiviral potential of proteins that include this domain. Aim 3 involves the use of yeast as a heterologous system to study the functional plasticity of antiviral EIF2a kinases and virus-encoded proteins that inhibit them. This aim will provide insight into the rules of pathogen sensing by kinases and expand the study of translational shutoff during viral infection beyond vertebrates and model organisms. Aims 2 and 3 of this proposal will establish a foundation for the future study of other independently evolved effector proteins, such as those found in the searches proposed in Aim 1. This proposal will provide me with extensive training to attain my career goals. I already have robust experience in molecular biology and virology techniques, as well as a developing skillset in computational biology. By completing the Aims of this proposal, I will learn new techniques in computational biology, biochemistry, and yeast genetics from my outstanding mentor and advisory committee that will supplement my skillset and diversify the research paradigms in my future independent career.