University Of Colorado Denver

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract: The precision and accuracy of vertebrate movement is mediated by the cerebellum. Cerebellar damage results in a signature motor phenotype called dysmetria, characterized by prominent endpoint errors in movements such as reaches. These endpoint deficits have been attributed to the absence of anticipatory braking signals from the cerebellar interposed nucleus that accurately slow the limb to target. Our previous work in mice has shown a causal role for activity in the interposed nucleus that scales the rate of reach deceleration relative to peak reach velocity, producing stable endpoints despite reach-by-reach kinematic variability. We hypothesize that this activity is learned and under adaptive control from Purkinje neurons and the inferior olive (IO): Reaches that end off target will alter the frequency of teaching signals from the IO, reweight contextual signals to Purkinje cells, and recalibrate interposed deceleration signals such that future reaching attempts land on target. Despite this developing framework, the interposed nucleus houses multiple projection neuron types, including inhibitory neurons that project densely to the IO, termed nucleoolivary neurons (NO). This proposal uses our unique behavioral paradigm of closed-loop circuit manipulations to advance the cerebellar learning hypothesis by asking how the cerebellum tunes its own teaching signals via this inhibitory output pathway and actuates control with these neurons. Together these projections raise the intriguing possibility that the cerebellum teaches its teachers. The outcomes of these studies will advance our long-term goal of understanding the circuit mechanisms of feedforward motor control in mammals, which is critical for precise movement and hypothesized to be impaired in movement disorders that involve the cerebellum.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Hospitals across the United States are increasingly relying on physicians and advanced practice providers who care for hospitalized patients (hospitalists). Hospitalists provide critical services and face a variety of stressors, including unprecedented work conditions, exposures to highly infectious diseases, high patient volumes, and unpredictable work demands. These factors contribute to high levels of job stress, which in turn can lead to occupational burnout and mental health problems among hospitalists. In a recent single center study, 62% of hospitalists reported burnout, with workload being the most commonly cited factor. This is concerning because of the high reliance on hospitalists and the links between burnout and poor mental health and suboptimal patient safety outcomes, and physician turnover. Burnout among US physicians has been estimated to cost the US society $4.6 billion annually and health care organizations $7,600 per employed physician each year. However, existing research on factors contributing to burnout and the consequences of burnout are primarily based on physicians working in outpatient practices, leaving a critical gap in evidence-informed strategies to address burnout among hospitalists and a lack of understanding of the cost of burnout to hospitals. Additionally, there have been even fewer studies focused on hospitalist mental health. There is an urgent need to address the issue burnout and poor mental health among hospitalists, as over one-third have considered leaving their current job, threatening the sustainability of the workforce. Hospitalist turnover not only affects the long-term viability of the field, but also has the potential to incur substantial costs for healthcare organizations; however, the costs are not fully known. Determining the costs associated with hospitalist turnover is a crucial next step as it can inform organizational decisions about work structure and environment and ultimately improve the well-being and resilience of hospitalists. We will utilize a prospective multi-measure design to assess prevalence of burnout and mental health and the relationship to hospitalist turnover using validated survey measures at 10 hospitals (Aim 1). Factors related to work structure and work environment that may contribute to burnout and poor mental health among hospitalists will also be examined. We will gather data on the costs of hospitalist turnover by surveying hospitalist group leaders at the 10 sites to model the probability of turnover, exploring relationships with burnout, mental health status, and other covariates (Aim 2). A cost-consequence analysis will help leaders understand the economic impact of turnover. The results of this study have the potential to inform policies and interventions aimed at improving hospitalist well-being and reducing burnout and turnover in a significant portion of the healthcare workforce. This is important because the results of this study will influence organizational decisions about work structure and work environments that may be driving burnout and worsening mental health among hospitalists and serve as a blueprint for other specialties.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY. Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is a leading cause of intellectual and developmental disability, with an estimated prevalence of 1 in 700 live births. Individuals with DS display increased risk of numerous co-occurring neurological conditions including autism, seizure disorders, and Alzheimer’s disease (AD). Recently, an increasing number of reports have documented individuals with DS displaying a condition known as Down Syndrome Regression Disorder (DSRD), which include symptoms such as catatonia, mutism, depersonalization, loss of ability to perform activities of daily living, hallucinations, delusions, and aggression. The etiology of DSRD is unclear, with affected individuals being subjected to highly heterogenous diagnostic work ups and disparate therapeutic interventions, including psychiatric medications (e.g., Lorazepam), electroconvulsive therapy (ECT), and intravenous immunoglobulin (IVIG). Therefore, additional research into the etiology of DSRD and the relative efficacy of different therapies is clearly needed. We propose here a comprehensive clinical research program that will not only advance our understanding of DSRD etiology, but which would also provide important information about the relative safety and efficacy of three different therapeutic approaches. Importantly, we hypothesize that many DSRD cases are driven by immune dysregulation affecting the central nervous system (CNS) and that these cases will benefit from immune- based therapies. Therefore, we propose to complete a comparative mechanistic investigation of three potential DSRD therapies: the benzodiazepine Lorazepam, IVIG, and the JAK inhibitor Tofacitinib. Our Specific Aims are: 1. To define the relative safety profile of Lorazepam, IVIG, and Tofacitinib in DSRD. We will complete a randomized, open-label, Phase II clinical trial for Lorazepam, IVIG, and Tofacitinib in individuals with DSRD with the primary endpoint being safety. 2. To compare the efficacy of Lorazepam, IVIG, and Tofacitinib in DSRD. Using key metrics for the evaluation of individuals with DSRD, a suite of secondary and tertiary endpoints will assess improvements in overall neurological health, activities of daily living, and quality of life, as well as domain-specific improvements in catatonia, movement and motor function, speech, sleep, and cognition. 3. To investigate potential mechanisms underlying DSRD and its response to therapies. Using biospecimens from individuals affected by DSRD collected during the trial and control samples from a companion active cohort study of individuals with DS, we will define biosignatures associated with DSRD diagnosis and the impact of each treatment modality on these biosignatures. Results from this phase II trial will generate much needed insights into DSRD etiology and treatment, paving the road for future larger trials to fulfill an unmet need in the DS community.

NIH Research Projects · FY 2025 · 2024-09

Project Summary The circumvallate papilla (CVP) and von Ebner's minor salivary glands (VEG) form a complex at the posterior midline of the tongue. The epithelial trenches of the CVP contain hundreds of taste buds (TBs) which each contain taste receptor cells (TRCs) that transduce taste information that is conveyed to the brain. Taste perception is affected by salivation through tastant dissolution and subsequent clearing from the oral epithelium. Serous saliva produced by VEG acinar cells is transported through salivary ducts that connect to the ventral region of the CVP trenches. Cancer patients undergoing therapy often experience dysgeusia or taste dysfunction, and can experience xerostomia due to reduced salivary gland function. Further, clinical data show that dysgeusia is detrimental to patient quality of life, potentially leading to poor survival outcomes. Therefore, understanding the maintenance of the CVP/VEG epithelium will allow the development of therapies to mitigate the effects of cancer treatments on taste and salivary gland function. CVP homeostasis occurs through the proliferation and differentiation of LGR5+ progenitor cells that generate TRCs in TBs as well as cells of the surrounding keratinized non-taste epithelium that supports TB structure. Though CVP epithelial renewal has been well characterized, progenitor cells involved in VEG homeostasis have yet to be identified. However, our lab performed single-cell RNA sequencing (scRNA-seq) on murine CVP/VEG epithelium, revealing that CVP and VEG lineages may arise from a common progenitor population. Differential gene expression analysis reveals SOX9 marks this common progenitor, and pseudotime analysis suggests SOX9+ progenitors give rise to LGR5+ progenitor cells. Preliminary lineage tracing and immunostaining of Sox9CreERT2;TdTomato mice shows that SOX9+ cells contribute to CVP TBs and non-taste epithelium, although this technique did not allow me to assess contributions to VEG. However, organoids generated from single SOX9+ cells express markers of CVP and VEG, supporting a model where SOX9+ cells are multipotent CVP/VEG progenitors. Together, these findings lead to my hypothesis that SOX9 marks a basal multipotent stem population that gives rise to CVP and VEG epithelia. To test this, in Aim 1 I will use genetic barcoding and scRNAseq of SOX9+ progenitors and their progeny to determine lineage relationships across the CVP/VEG complex. In Aim 2, I will generate organoids from LGR5+-only, SOX9+-only, and LGR5+/SOX9+ double positive cells using CVP or VEG organoid protocols to assess if LGR5 vs SOX9 expression restricts CVP and VEG lineage production. Further, I will ablate LGR5+ cells from heterogenous organoid cultures to determine if single SOX9+ cells are truly multipotent or if they coordinate with LGR5+ cells to maintain the CVP/VEG complex. Together, these findings will contribute to our understanding of CVP/VEG homeostasis.

NIH Research Projects · FY 2024 · 2024-09

ABSTRACT The proposed project is a resubmission by two promising Early-Stage Investigators as multiple principal investigators (PAR-22-189). The overall goal of this multi-phase proposal is to prepare for (R61) and execute (R33) a randomized clinical trial testing the effectiveness of Rehabbing with Peloton for improving physical activity among patients receiving transcatheter aortic valve replacement (TAVR) and evaluating the implementation of the intervention for future scalability. Despite ample evidence of the benefits of cardiac rehabilitation, only a small fraction of TAVR patients participate, which is thought to be a combination of missed referral opportunities coupled with patient-borne challenges including transportation, scheduling, and physical access to facilities. Participation in cardiac rehabilitation is particularly low among women and racial and ethnic minorities, as well as those with lower socioeconomic status, and/or living in rural areas, contributing to disproportionate morbidity and mortality burden in these patients. Overseeing cardiac rehabilitation content on commercially available fitness platforms (such as the Peloton mobile app) may be an excellent format for ensuring rehabilitation-appropriate modules while reaching TAVR patients currently under-referred and underusing cardiac rehabilitation. In our preliminary work, we engaged TAVR patients and cardiologists to develop the Rehabbing with Peloton intervention. RWP is an 8-week intervention in which TAVR patients engage with the Peloton app (not the fitness bike) to promote physical activity. RWP is a clinically reviewed, pre-set user account controlled by the research team that includes specific modules focusing on walking, strength exercises, yoga breathwork, and stretching, areas of exercise training previously used in home-based cardiac rehabilitation. Building on our previous multidisciplinary research, this proposal describes an innovative type II effectiveness-implementation hybrid randomized control trial of TAVR patients comparing RWP to attention control, controlling for technology. We will dedicate the R61 phase of the project to milestone-driven startup of the trial to successfully start recruitment by month 9 of the project. During the R33 phase, we will randomize N=200 individuals receiving TAVR from the University of Colorado Hospital Heart and Vascular Center to RWP or attention control. At baseline, post-intervention (8 weeks), and follow-up (12 months), we will assess participants’ physical activity (smartwatch accelerometer measured daily steps) and secondary outcomes of interest including functional capacity (Duke Activity Status Index; VO2max), quality of life (Kansas City Cardiomyopathy Questionnaire), and cardiovascular health status (Life Essential 8). The aims of the study are to test the efficacy of RWP on physical activity at 8 weeks (Aim 1) and secondary outcomes (Aim 2). We will use mixed methodologies to evaluate the implementation of RWP using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) Framework (Aim 3). Overall, this research will provide insight into the use of commercial mHealth to deliver CR to a population disproportionately excluded from CR.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Approximately 50% of patients with ovarian cancer harbor deficiencies in DNA damage repair with either a germline/somatic mutation in BRCA1/2 or homologous recombination deficiency (HRD), and benefit from maintenance therapy with a poly (ADP-ribose) polymerase inhibitor (PARPi) following adjuvant platinum- based chemotherapy. Unfortunately, most of these patients will have a disease recurrence and develop resistance to PARP therapy for an ultimately non-curable disease. However, innovative combination strategies can be utilized to overcome resistance as well as provide therapeutic benefit, improving the lives of our patients. We have identified a novel first in class agent, cirtuvivint, that demonstrates single agent activity in ovarian cancer, potentiates a unique mechanism to overcome PARP resistance, and synergizes with PARP therapy in PARP resistant ovarian cancer models. Cirtuvivint is a CDC-like kinase (CLK) and dual specificity tyrosine kinase (DYRK) inhibitor with suspected multiple anti-tumor mechanisms of action. Our preclinical work has demonstrated three distinct mechanisms of activity of cirtuvivint by 1) increasing alternative splicing events, 2) inhibiting Wnt transcriptional activity, and 3) increasing R-Loop formation. Alternative splicing is a normal physiologic function that allows cells to change isoform-specific protein production in response to extracellular and intracellular stimuli. Alterations are implicated in tumorigenesis and metastasis. Cirtuvivint alters alternative splicing in the Wnt genes. Our work established that PARP resistant high grade serous ovarian cancer cells display hyperactivation of Wnt signaling and increased TCF transcriptional activity, leading to PARP resistance. We therefore established rationale for combination Wnt inhibition with PARP therapy to overcome Wnt driven resistance. Additionally, we demonstrate that cirtuvivint induces DNA damage and R-Loop formation in ovarian cancer cell lines. R-Loops are the DNA-RNA hybrids created in DNA damage repair. Increased formation of R-Loops lends to susceptibility to PARP independent DNA damage. Finally, a synergy with PARP inhibition and cirtuvivint was demonstrated in a panel of PARP resistant ovarian cancer cell lines. Based on this rationale Aim 1 will evaluate a Phase I clinical trial of combination cirtuvivint and olaparib (PARP inhibitor) in platinum resistant ovarian cancer patients with a germline or somatic BRCA/HRD deficiency who have previously been treated with a PARPi. We will evaluate the safety and tolerability of this combination with the goal of establishing a recommended phase 2 dosing. Aim 2 will be focused on the evaluation of CLK/DYRK inhibition induction of R-Loop DNA damage and the subsequent susceptibility to PARP inhibition. We strive to elucidate the mechanism for synergy of these two drugs and introduce them as a viable therapeutic strategy for a significant portion of ovarian cancer patients.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Type 2 diabetes (T2D) is one of the fastest growing chronic diseases worldwide and is a leading contributor to comorbidities and early mortality. Current prevention and treatment strategies are not optimal for all individuals due to heterogeneity in the etiology and pathophysiology of T2D. Indeed, substantial variation exists across individuals in the relative contribution of insulin resistance vs. beta cell function to T2D development and progression, as reflected by differences in glucose regulation among persons with comparable glycemia at diagnosis. Recent research has applied clustering algorithms to identify subgroups of diabetic individuals with varying clinical profiles, risk of diabetes complications, and responsiveness to treatment therapies based on clinical variables measured at diagnosis (e.g., body mass index, age, fasting glucose and insulin, hemoglobin A1c, diabetes autoantibodies). Most of these studies leveraged large registry-based European cohorts, which boast large sample sizes but lack diversity and/or data on social determinants of health that are known to drive chronic disease risk in the U.S. Moreover, most subtyping methods that have been applied require subjects to be placed in fixed categories which may not reflect the racial/ethnic and sociodemographic diversity of U.S. populations and may not be ideally suited to accommodate mixed data types (e.g., clinical, omics, behavioral, environmental, social). Such multimodal data provide an untapped opportunity for subtyping based on realistic multi-level drivers of heterogeneity in the clinical course of T2D, from prediabetes to complications and comorbidities. In response to RFA-DK-23-020, we seek to establish the Subtyping Core for Research on the Etiology of Type 2 Diabetes (SCORE-T2D) at the University of Colorado Anschutz Medical Campus. Partnering with the Consortium, SCORE-T2D will lead innovative analytic activities and provide crucial resources for the Consortium Cohort Sites through methodological expertise in subtyping algorithms, data harmonization across large datasets, single and multi-omics analyses, lifecourse epidemiology, and integration of social factors; content expertise in T2D etiology and pathophysiology; and programmatic experience in multi-site study coordination and analyses. Our overarching objective is to work with the Cohort Sites and NIDDK to employ multi-level, multi-dimensional approaches to characterizing heterogeneity in T2D in the Consortium. We will accomplish this through 1) developing and implementing consensus protocols for data sharing, management, harmonization, and analysis; 2) characterizing subtypes of T2D and identify underlying social and physiologic drivers of the etiology and clinical course for each subtype; and 3) coordinating Consortium logistics on results sharing, outreach, and dissemination. SCORE-T2D at the University of Colorado Anschutz Medical Campus will bring a fresh perspective on multi-site coordination and biostatistical expertise by spearheading efforts to quantify and understand heterogeneity in the risk factors, pathophysiological mechanisms, manifestations, and consequences of T2D.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The purpose of the Bold New Bioengineering Research for Heart, Lung, Blood and Sleep Disorder and Diseases is to support early phases of groundbreaking bioengineering projects that have the potential to revolutionize diagnostics and treatment. In response to NOSI (NOT-HL-21-024), we propose a bioengineering research idea that challenges the status quo in platelet function testing, which has been hampered by low throughput, high variance, and unreliable methods that fail to capture the full complexity of platelet physiology. The long-term goal of this line of research is to engineer technologies that can diagnose the spectrum of bleeding disorders at increased specificity, sensitivity, and throughput than is currently available. The overall objective of this application is to design elastic hydrogel microparticles as a platform to measure platelet adhesion, activation, aggregation, and contraction. The rationale for this project focuses on inherited platelet disorders that are challenging to detect using conventional clinical assays, or lack a specific diagnosis as in the case of many acquired bleeding disorders associated with acute or chronic inflammation. We will meet our overall objective with two specific aims: 1) Immobilized particle assay to measure platelet function kinetics; and 2) Suspended particle assay to measure platelet function equilibrium. We will synthesize peptide-functionalized polyethylene glycol (PEG) particles that present ligands in a combinatorial manner using microfluidic single and double emulsion approaches. In Aim 1, the kinetics or speed of platelet adhesion, activation, aggregation, and contraction will be measured by optical microscopy on immobilized beads in a channel. The equilibrium or strength of these same platelet subfunctions will be measured in suspension in a well-defined shear flow using a rotational rheometer. This approach simulates force-dependent platelet function that is regulated by blood flow in vivo, but with the throughput of a flow cytometer. By creating a platform where each particle serves as an individual test site and each assay includes thousands of test sites, we aim to improve the reliability and reproducibility of platelet function testing, as well as identify new patterns of underlying bleeding disorders. The proposed research is innovative, in our opinion, because it represents the creation of a diagnostic approach that incorporates four key elements of platelet function—adhesion, aggregation, activation, and contraction—within a high throughput format via a lab-on-a-particle platform. This contribution will be significant because it has the potential to improve the lives of people with bleeding disorders by standardizing diagnostic criteria which is currently undefined.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Our primary objectives for the Total Worker Health® education planning workshop (workshop) and the 4th International Symposium to Advance Total Worker Health® (Symposium) are to convene stakeholders across academia, industry, labor, and government to explore research and case studies in TWH, to establish partnerships and collaborations that advance TWH, and to build capacity by providing the necessary knowledge and skills to professionals, employers, workers, educators, policymakers, and students. The Workshop aims to convene a diverse group of participants to set the agenda for the 2025 Symposium as well as broader action steps for TWH educational offerings. The three-and-a-half-day hybrid Symposium will include a mix of sessions and preparatory workshops emphasizing the latest TWH science and practice. Our goal is to support prior and current NIOSH TWH initiatives, as well as national and global demands to protect and enhance the health of all workers. We have three main goals: 1. Identify and share the most compelling research, education, and interventions that advance worker safety, health, and well-being, 2. Build collaborations between different stakeholders (e.g., researchers, educators, employers, government agencies, business professionals, public health professionals, and others), and 3. Disseminate findings to advance TWH research, education and practice that address existing and emerging issues facing workplaces and workers globally. The overall aim of the Symposium is to enhance both the work environment as well as prevention efforts that advance worker well-being through research, education, and practice. These events will significantly contribute to advancing national goals set by NIOSH to reduce injuries and illnesses through enhancing training and professional development in TWH. It will do this by better understanding workplace interventions, research methodologies, and applied TWH practices. The planning committee will address diversity and inclusion as priority areas for submissions, keynote speakers, and the overall program. We will include strong research to practice (r2p) emphasis, as well as the advancement of a TWH research agenda, that aligns with the NIOSH National Occupational Research Agenda (NORA) goals, in particular those cross-sector goals relevant to the NIOSH FY2019-2026 strategic plan. Short term outcomes will include general satisfaction with the Symposium, including the quality and relevance of sessions and perceived changes in knowledge and abilities as a result of attendance. Intermediate outcomes will include increased engagement and new collaborations that develop because of attending the conference. The key long-term outcome is to increase the capacity and collaboration of researchers and practitioners focused on TWH studies and interventions to improve the effectiveness and sustainability of TWH implementation.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Cardiovascular disease (CVD) is the leading cause of death for people with type 1 diabetes (T1D), and abnormalities preceding overt CVD (left ventricular hypertrophy, diastolic dysfunction) are more prevalent in T1D as early as childhood. Disparities in CVD and its risk factors within T1D according to the social construct of race/ethnicity are concerning, especially given rising incidence of T1D specifically in non-Hispanic Black (NHB) and Hispanic youth. Such youth are more likely to have elevated weight, blood pressure, lipids, and glycemia than non-Hispanic White (NHW) youth from T1D diagnosis onward, and NHB individuals experience twice the CVD mortality and 8 times the CVD event rate as NHW peers. Prior studies of CVD within T1D focused on NHW participants with ≥25 years T1D duration treated in an earlier clinical environment, and therefore do not reflect today’s increasingly diverse T1D population with ostensible access to modern diabetes technologies and subspecialty care networks. We and others have reported that social determinants of health (SDOH), including socio-economic factors (low income, limited parental education, food insecurity), inadequate health behaviors (unhealthy diet, physical activity and sleep patterns, smoking), and healthcare access barriers (lack of, or limited, health insurance, high out-of-pocket costs), are associated with lower quality of T1D care and worse T1D outcomes. The impact of SDOH on CVD risk factors and subclinical abnormalities within diverse T1D populations is not known, yet critical for informing multi-level CVD prevention strategies for T1D. We propose to investigate whether SDOH-related barriers may account for racial/ethnic disparities in CVD risk factor trajectories from diagnosis onward and subclinical abnormalities in early adulthood. We will enroll 1000 participants from the SEARCH for Diabetes in Youth Study, including 300 Hispanic or NHB young adults. We will rigorously investigate racial/ethnic differences in prevalence of subclinical CVD in early adulthood (mean age 25 years, T1D duration 16 years) via new assessments of structural and functional abnormalities of the heart and vascular system (with echocardiography, carotid ultrasonography, vascular tonometry). Longitudinal modeling of CVD risk factor trajectories (weight, lipids, blood pressure, A1c, albuminuria, autonomic function), SDOH factors (as defined by Health People 2030) collected from diagnosis onward will enable us to understand how and which SDOH barriers account for racial/ethnic differences in CVD outcomes within T1D. Our aims are 1) To quantify racial/ethnic disparities in trajectories of CVD risk factors, and in subclinical cardiac and vascular outcomes during early adulthood among SEARCH participants with youth-onset T1D.; 2) To understand which SDOH-related barriers are associated with CVD risk factor trajectories and subclinical cardiac and vascular outcomes, using mixed methods; and 3) To determine if specific SDOH-related domains (identified in Aim 2) explain racial/ethnic inequities in CVD risk factors and subclinical cardiac and vascular outcomes.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Indigenous populations in the United States (American Indian, Alaska Native, and Native Hawaiian) face significant substance use disorder inequities. The National Institutes of Health (NIH) has increased efforts to address these inequities through investing in research to understand the root causes and studies focused on prevention and intervention in these populations. These efforts have included the launch of the Intervention Research to Improve Native American Health (IRINAH) Initiative in 2012, the establishment of the NIH Tribal Health Research Office (THRO) in 2015, and the Native Collective Research Effort to Enhance Wellness (N CREW) in 2023. The advances resulting from these efforts are significant, but they are also incremental, slowed by many complexities encountered in research with diverse Indigenous populations. One particular challenge is the continued underrepresentation of Indigenous Principal Investigators (PIs), leaders who have unique potential to fully integrate scientific and cultural knowledge throughout study design, measurement, analysis, interpretation and dissemination. The NCRE Scholars Program works to address this gap by fostering the development of early career Indigenous substance use and disorder researchers, particularly those whose work focuses on the impacts and developmental course of problematic substance use in childhood and adolescence. NCRE Scholars began in 2012 on the foundation of the Native Children’s Research Exchange (NCRE) network of researchers partnering with communities to understand Indigenous children’s development (prenatal through early adulthood). The NCRE network and biennial conferences provide a platform for connecting graduate students, postdoctoral fellows, and junior faculty to senior research mentors who provide substantive mentoring and career development support. The NCRE Scholars Program leverages this network to support the development of the next generation of Indigenous substance use and disorder scientists by: (1) providing supplemental opportunities for developing (1) substantive expertise, (2) methodological expertise, (3) technical expertise, and (3) connections with peers, mentors, and communities. NCRE Scholars V will support 20 graduate students and early career researchers in five new cohorts of four Scholars each, providing tailored mentoring and training opportunities, coursework, writing support, and opportunities for connection and collaboration.

NIH Research Projects · FY 2025 · 2024-09

Project Summary An intact epithelial barrier is key for maintaining intestinal homeostasis and preventing inflammation. Barrier dysfunction has been associated with inflammatory bowel disease and increased susceptibility to enteric infection. Previous work from the Kuhn lab has demonstrated that IL-6 produced by TCRαβ+ CD4+ colon intraepithelial lymphocytes (cIELs) are required to maintain epithelial barrier integrity and thus intestinal homeostasis. In contrast with phenotypically distinct small intestine IELs, which have been widely characterized, very little is known about cIEL function and development beyond the importance of IL-6 production. This project aims to define the mechanism that recruits cIELs to and retains them in the epithelium. Preliminary data indicate that upon exposure to luminal bacteria, myeloid cells produce sphingosine-1-phosphate (S1P) in a MyD88- dependent fashion. Conditional knockout of MyD88 in myeloid cells and S1P signaling blockade significantly reduce the number of TCRαβ+ CD4+ cIELs in the epithelium. However, further experiments are required to confirm this mechanism and understand the characteristics of recruited cIELs. Intestinal epithelial cells (IECs) express MHC class II (MHCII) and act as non-professional antigen presenting cells capable of influencing T cell function independent of local dendritic cells, and conditional knockout of MHCII on IECs changes cIEL effector- memory ratios. This proposal hypothesizes that intestinal bacteria are recognized by myeloid cells to recruit commensal reactive cIELs through S1P signaling to the epithelium, where interactions with epithelial MHCII lead to tolerance. Aim 1 seeks to demonstrate the mechanism by which myeloid cells recruit commensal reactive cIELs to the colon epithelium. The requirement for cIEL S1P signaling and myeloid cells will be shown by inhibiting each variable using the S1P receptor 1 inhibitor W146 and CD11c-DTR mice, respectively. cIELs will be stained for markers of differentiation, antigen experience, and activation. Commensal-reactive cIELs will also be identified by staining with MHCII-restricted tetramers containing the commensal antigenic peptide Cbir1, and their TCR Vβ chains will be identified using a flow screening panel. Aim 2 will investigate the mechanism by which cIELs are recruited to the colon epithelium by utilizing a conditional knockout mouse line in which IECs are deficient in MHCII (MHCIIΔIEC). Single cell assay for transposase-accessible chromatin (ATAC) sequencing and bulk T cell receptor (TCR) sequencing will be performed on cIELs from MHCIIΔIEC and MHCIIWT mice. These experiments will identify how epithelial MHCII influences cIEL gene regulation and TCR repertoire diversity, respectively. Lastly, MHCIIΔIEC and MHCIIWT mice will be infected with the murine enteric pathogen Citrobacter rodentium. This experiment will demonstrate the importance of epithelial MHCII in influencing cIELs in the immune response.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Over 30 million Americans have type 1 diabetes (T1D) or type 2 diabetes (T2D), a disease with significant effects on morbidity and mortality1 that disproportionately affects non-White adults and low-income populations.2,3 For diabetes patients, tight glycemic control can reduce the risk of micro- and macrovascular complications, ultimately reducing lifetime health care costs and improving longevity and quality of life.4 To achieve tight glycemic control, patients rely on various medications and different formulations of insulin.5 List prices for insulin more than tripled from 2007 to 2018.6 The list price is often used to determine cost sharing amounts for patients. In 2017, an estimated one-quarter of insulin-using individuals with diabetes reported insulin-underuse due to out-of-pocket costs.7,8 Furthermore, insulin-underuse is more common among Black and Hispanic populations,9 a fact that raises equity concerns regarding health care access and outcomes. State policymakers have responded to insulin affordability issues by capping insulin out-of-pocket costs. Colorado was the first state to do so on January 1, 2020.10 Following Colorado, an additional 24 states plus Washington, DC have passed such caps.11 These caps standardize the price patients pay for insulin and may enable T1D and T2D patients to switch to clinically preferred products that were previously unaffordable. Yet, capping out-of-pocket costs for insulin and not other medications to manage T2D may induce patients with T2D to use insulin rather than more expensive medications with better cardiorenal protective effects. We explore the market effects of insulin out-of-pocket caps through 3 aims: • Aim 1. Measure the effect of state-level caps on insulin out-of-pocket costs on changes in the use of clinically preferred insulin products to treat diabetes. • Aim 2. Measure the effect of state-level caps on insulin out-of-pocket costs on changes in the use of clinically preferred non-insulin products to treat type 2 diabetes. • Aim 3. Identify key patient considerations regarding choice of treatments for managing T2D given a state- level cap on insulin out-of-pocket costs. We will accomplish Aims 1 and 2 with difference-in-differences analyses using a 25% sample of claims and enrollment data from IQVIA PharMetrics Plus for the time period of 2018-2022. We will accomplish Aim 3 using qualitative focus groups. Aim 3 will inform interpretation of the findings from Aim 2 by, for example, providing preliminary evidence for whether patient preferences for T2D treatment diverge from clinical recommendations due to affordability considerations. In addition to providing specific findings in the context of an insulin out-of- pocket cap and diabetes care, the output from this grant will provide a methodology we can apply to measure the effects of other price ceiling policies, such as Medicare's annual out-of-pocket cap for Part D drugs.

NIH Research Projects · FY 2024 · 2024-09

Project Summary Colorectal cancer (CRC) patients with a high body-mas index (BMI) have poor efficacy to chemotherapy, creating an urgent need to design targeted therapy for this group of cancer patients. During obesity, the excess visceral adipose tissue (AT) deposited around major organs in the abdomen triggers systemic metabolic dysregulation and creates an environment conducive to cancer development, particularly colorectal cancer (CRC). Obese AT secretes more extracellular vesicles (EVs) compared to non-obese AT, which can be taken up by distant tissues. EVs are lipid-membraned vesicles that carry cargo from the parent cell and are important for inter-organ communication. Unbiased proteomic analysis revealed that obese EVs (OB-EVs) and non-obese (N-OB) EVs are distinctly different in terms of their cargo, with an enrichment of the glycolytic enzyme triose phosphate isomerase 1 (TPI1) in OB-EVs. Consequently, OB-EV treatment of CRC cells resulted in higher TPI1 levels compared to N-OB EV treatment. Functionally, OB-EVs increased basal glycolysis of human and mouse CRC cells and enhanced the ability of CRC cells to form 3D tumoroids and spheroids. CRC cells can aberrantly increase glycolysis to support tumor growth and aggressive, however, it is not known whether these pro- tumorigenic effects can get enhanced during obesity. In the F99 portion of this grant, I will determine if the cargo from AT-derived EVs is utilized by CRC cells to change their metabolism and promote a pro-tumorigenic phenotype, and whether it is enhanced during obesity. I will use a novel mouse model of intestinal tumorigenesis lacking EV secretion from adipocytes that will be challenged with obesity to elucidate the role of OB-EV cargo in CRC development. The goals of this project are to 1) confirm whether OB-EVs transfer TPI1 to CRC cells and its regulation on glycolysis and 2) determine the oncogenic role of OB-EV and TPI1 in CRC development in vivo. The results from this study will help advance the field of EV biology in cancer during obesity and identify potential targets for cancer therapeutics in obese CRC patients. In the K00 portion of this grant, I will expand on elucidating the impact of AT-derived EVs on the immune population of CRC TME. Obese CRC TME is known to be immunosuppressive with increased infiltration of M2- like macrophages. However, there is a lack of studies enumerating the underlying molecular players mediating the observed phenotype. Therefore, I propose to determine whether OB-EVs reprogram macrophages in the obese TME to an immunosuppressive M2-like phenotype to promote tumor progression. I will seek K00 labs with comprehensive expertise on tumor immunology and associated signaling pathway to provide me with the training I require to complete my project and characterize the impact of obesity in CRC TME.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Alcohol use accounts for 1 in 5 deaths of individuals aged 20 to 49 years old, and Alcohol Use Disorder (AUD) is associated with deficits in brain structure and function, but it remains unclear which of these brain abnormalities can recover when alcohol use stops. Understanding brain changes associated with early abstinence occurring through evidence-based residential treatment may offer insights into the biological basis of AUD and potential therapeutic targets. This proposal aims to fill a gap in understanding how the neural mechanisms associated with cognitive reappraisal (e.g., prefrontal cortex [PFC]) and alcohol cue reactivity (e.g., striatum) change during early abstinence, and whether changes in these mechanisms can predict the individuals most likely to return to heavy alcohol use. We and others have shown that, relative to healthy adults, individuals with AUD have greater difficulties with emotion regulation and greater craving and alcohol cue reactivity. Yet, it remains unclear how abstinence affects brain function during reappraisal and cue reactivity, and how this relates to risk for future alcohol use. Here, we propose to study patients with AUD (N = 150) engaged in ecologically-valid residential treatment to determine the neural mechanisms that change during early abstinence and if they indicate risk for return to heavy drinking. We will assess these individuals using fMRI within 4 days of admission to treatment and again within 2 days before discharge. We will also follow participants for 6 months to assess frequency of heavy drinking. We will use cutting-edge analytic techniques to maximize our ability to observe differences. Specifically, we will use multivariate pattern analysis to quantify neural signatures of reappraisal and cue reactivity. We and others have developed models can accurately identify brain activation associated with a) cognitive reappraisal and b) cue reactivity to drug stimuli. These processes likely reflect circuit-driven neural underpinnings, thus in addition to neural signatures we will examine connectivity between PFC and subcortical regions linked to craving and emotional reactivity. We can then use machine learning algorithms to identify relationships between neural signatures, connectivity, and variables associated with relapse risk, such as craving and poor emotional coping skills. We will use these models to test our central hypothesis that neural function associated with reappraisal and alcohol cue reactivity will change across abstinence and indicate likelihood of treatment success. Specific Aims are to 1) determine how neural mechanisms related to reappraisal and alcohol cue-reactivity change across early abstinence during treatment, 2) determine how circuit strength between the PFC and subcortical regions change across early abstinence, and 3) identify neuroimaging variables that prospectively predict return to heavy drinking. The proposal will improve understanding of the neural mechanisms that may recover with reduced drinking levels and whether neural function indicates long-term success.

NIH Research Projects · FY 2025 · 2024-09

PROJECT ABSTRACT Diagnostic errors affect 12 million patients in the U.S. and contribute to 80,000 deaths per year. The main causes for diagnostic errors include cognitive biases introduced by healthcare providers, miscommunication between healthcare teams, lack of access to key data, and not recognizing time-sensitive data in the electronic health record (EHR). The cognitive burden from information overload in the EHR cause clinicians to take decisional shortcuts with biased heuristics and miss critical data in the EHR, leading to missed opportunities for timely and accurate diagnoses. Artificial Intelligence (AI) and clinical Natural Language Processing (cNLP) provide opportunity to help understand medical text and can automate EHR analysis, pointing to the promising direction of invoking medical knowledge and clinical experience as humans do. However, the majority of the cNLP tasks are not designed for bedside application to generate diagnoses and augment bedside decision-making. We have have gathered preliminary data and designed cNLP benchmark tasks for clinical diagnostic reasoning. Our tasks address key cognitive processes to build models in this proposal that can synthesize EHR data to generate diagnoses that align with evidence-based medicine and medical knowledge representation. The proposal aims to develop novel cNLP models that understand and integrate multi-modal EHR data, and conduct reasoning over a large-scale medical knowledge base to build a model that provides higher accuracy than current neural network models. I will first develop a multi-modal generative model that reads in both structured and unstructured EHR data to output diagnoses using a two-stage training process (Aim 1). In a separate aim, I will construct a knowledge base using a neural symbolic approach from medical concepts and relations sourced from the National Library of Medicine's Unified Medical Language System (UMLS). The knowledge base will be part of the model to generate diagnoses given the information from a daily care note collected in the EHR (Aim 2). The third aim will design and pilot a clinical diagnostic decision support system using human-centered design principles. The best models from Aims 1 and 2 will be evaluated for diagnostic accuracy by clinicians in the system using previously validated instruments for patient safety and diagnostic error (Aim 3). Completion of the aims will inform future clinical studies on developing NLP-driven clinical decision support tools for reducing diagnostic error. I will complete this project under the direct supervision of my co-mentors and advisors who have expertise in developing clinical neural language models, implementation of AI-driven tools in health systems, and clinical decision support systems with augmented intelligence. Together, this multidisciplinary team brings nationally renowned expertise in clinical informatics with a track record of successful mentorship. My 4-year proposal with intensive mentorship, clinical research training, formal coursework in health systems engineering and informatics, and computing resources at the University of Wisconsin-Madison will ensure my success as I grow into an independent scientist.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Cardiovascular disease (CVD) is the leading global cause of death, claiming approximately 17.9 million lives annually. Women face a significantly higher risk of heart failure or mortality following a heart attack than men, yet the molecular mechanisms behind this disparity remain poorly explored. This research aims to determine the role of thyroid hormones (TH), an underexplored sexually dimorphic risk factor for female heart failure development, with a primary focus on its tissue-level regulation. TH significantly influences the cardiovascular system, and the higher prevalence of thyroid disease in women highlights its potential impact on female heart health. Specifically, the study will concentrate on type 3 deiodinase (DIO3), which regulates TH levels within tissues. Recent findings from my lab show a sexual dimorphism in Dio3 expression in the heart. We have also demonstrated that female mice with Dio3 deficiency exhibited compromised cardiac function, including a reduced ejection fraction, altered mitochondrial substrate utilization, and impaired recovery from myocardial infarction. These results underscore the protective role of Dio3 in the female heart and the importance of Dio3- dependent tissue-level TH regulation. This proposal aims to determine the role of Dio3 in cardiovascular health outcomes in females. The overarching hypothesis is that cardiac Dio3 expression is regulated in a sex-specific manner, playing a pivotal role in driving sex-specific outcomes in cardiovascular health. In Aim 1, we will investigate whether Dio3 expression post-MI differs between sexes, potentially contributing to higher heart failure susceptibility in females. In Aim 2, we will determine the interplay between estrogen and Dio3 in influencing cardiovascular function in female mice. This aim hypothesizes that low estrogen levels reduce Dio3 activity in female mouse hearts, impairing myocardial function. The study also investigates Dio3's role in mediating estrogen's cardioprotective effects on cardiovascular function. Together, these aims will address crucial knowledge gaps regarding thyroid dysfunction and the sexually dimorphic onset of heart failure, aligning with priorities identified by the NHLBI Working Group. Beyond enhancing our understanding of sex-specific factors in cardiovascular health, this work will provide vital scientific and technical training to support Dr. Teixeira's independent program. Ultimately, it will improve women's cardiovascular health, reduce disparities, and advance cardiovascular science.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Dysphagia and aspiration are significant health problems associated with aging. By 2030, the United States elderly population is anticipated to exceed 72 million, with over 12 million of these individuals experiencing swallowing dysfunction. In the over 1,000,000 acute respiratory failure (ARF) patients each year who require mechanical ventilation, one common cause of prolonged swallowing dysfunction is injury from the endotracheal tube. Occurring in as many as 44% of these ARF survivors, post-extubation aspiration is associated with deleterious consequences including pneumonia, percutaneous feeding tube placement, long term care facility admission, and increased hospital mortality. These complications of aspiration must be weighed against delaying the resumption of oral feeding that is associated with prolonged enteral tube feeding, increased caregiver burden, patient dissatisfaction, and increased health-related costs. As our population ages, elderly ARF survivors are growing in number, and are at increased risk for post-extubation dysphagia and aspiration. The only current treatment options are to modify the dietary texture and/or place enteral feeding tubes while waiting weeks to months for the dysphagia to resolve. In our previous R21 cohort of 213 ARF survivors, we identified that at the time of extubation, laryngeal edema was present in 56% of ARF survivors and associated with a 3-fold risk of aspiration. Corticosteroids may reduce this inflammatory laryngeal edema. Clinical trials and meta-analyses have demonstrated that peri-extubation intravenous corticosteroids reduce the need for reintubation, raising the possibility that corticosteroids work through reducing the laryngeal edema. We hypothesize that a similar dosing regimen of a short course of intravenous corticosteroids could restore normal laryngeal swallowing function, improve post-extubation dysphagia, and reduce susceptibility of aspiration. This proposal will continue to utilize our established multi-center research group at Colorado, Boston University, Stanford, and Yale. We have worked together as a collaborative research group for nearly ten years. With our current R01 infrastructure, we will conduct a multi-center randomized trial of corticosteroids for ARF survivors with documented post-extubation laryngeal edema. The patients with laryngeal edema on their post extubation FEES examination (performed as part of the R01 protocol) will be randomized to 24 hours of intravenous corticosteroids or an equivalent placebo, and then undergo a repeat FEES examination within 48 hours of the last study dose. Our primary mechanistic outcome will be improvement in laryngeal edema using the revised Patterson edema scale, with secondary in hospital outcomes of improved swallowing function and reduction in aspiration. We will also follow participants after hospital discharge to determine whether corticosteroids improve quality life including enhanced swallowing function and return to their pre-hospitalization diet. The results of this R21 proposal will help develop the first personalized therapy for post-extubation dysphagia, a common disorder in our aging population.

NIH Research Projects · FY 2025 · 2024-09

Project We Summary/Abstract have identified that semaphorin 7a (SEMA7A)—a signaling molecule that activates integrin-β1 signaling in cancer—is upregulated in postpartum breast cancer (PPBC) and is associated with increased lymphatic vessel density (LVD), tumor-associated macrophages (TAMs), and metastasis. Additionally, SEMA7A+ tumors recapitulate the accelerated tumor progression observed in PPBC and high SEMA7A expression correlates with decreased survival. As such, PPBCs likely only represent a subset of SEMA7A+ cancers; there are currently no therapies targeting SEMA7A. cell are SEMA7A+BC, SEMA7A+ breast cancers exemplify four key hallmarks of cancer: 1) resistance to death, 2) angiogenesis and lymphangiogenesis, 3) immune evasion, and 4) invasion and metastasis; TAMs implicated n each and in creating a pro-tumor microenvironment (TME). As TAMs and LVD are amplified in it is probable that they contribute to the worse prognosis of PPBC. the F99 portion of this grant, my goals i In are to: 1) investigate SEMA7A-mediated alterations immune cells of the TME in relation to mechanisms of antitumor immunity, 2) dissect SEMA7A-induced mechanisms that govern tumor cell migration, and 3) determine if monoclonal antibody-induced inhibition of SEMA7A impedes tumor growth and immune suppression. I will define the mechanisms of SEMA7A-induced effects on immune cells of the TME that promote immunoevasion. I will also establish whether monoclonal antibody-induced inhibition of SEMA7A impedes tumor growth and immune suppression. The results of these studies will identify how SEMA7A promotes tumor progression, immunosuppression, and lymphatic-meditated metastasis, as well as offer insight for future therapies to target SEMA7A+ breast cancers and provide insight to mechanisms of immunoevasion in similar cancers, such as (PDAC) and advanced stage renal cell carcinomas (RCC). RCC, to endure immunotherapy expertise immune progress the K00 portion of this grant, will expand my interest in mechanisms of immunoevasion to PDAC and which are highly aggressive cancers with elevated tumor heterogeneity, therapy resistance, and resistance antitumor immune responses. The mechanisms by which PDAC and RCC evade the immune system and immunotherapy remain to be discovered. I propose to identify novel mechanisms of immunoevasion and resistance in PDAC and RCC, with an initial focus on SEMA7A. I will seek K00 laboratories with in tumor immunology, immunotherapy, ex vivo models, and knowledge of dysregulated signaling within cells. These studies will provide crucial insight into how highly aggressive tumors like PDAC and RCC resulting in dismal prognoses and identify potential cells and mechanisms for future immunotherapies. In I

NIH Research Projects · FY 2025 · 2024-09

PROJECT ABSTRACT Cancer-related fatigue (CRF) is one of the most common and functionally limiting symptoms reported by cancer survivors. While no standard of care exists for CRF management, clinically supervised exercise is one of the best-known interventions for CRF. Exercise prescription (ExRx) for survivors, however, is currently guideline- driven, lacking personalization and limiting overall efficacy. Rural cancer survivors experience poor health outcomes, including increased risk of CRF, have limited access to clinical exercise programs, and stand to benefit from improved ExRx personalization. The long-term goal of this investigation is to develop an effective telehealth exercise program for rural cancer survivors with CRF. While many investigations of interventions for rural survivors focus on the implementation of established services, this proposal utilizes innovative accessible methodology to integrate assessments of exercise-associated mechanisms of CRF remediation into a clinical efficacy trial. The purpose of these assessments is to provide the foundation for future innovations in improved ExRx personalization, optimizing individual survivor outcomes, and to do so first in an underserved population that stands to benefit from the outcomes. This investigation will be accomplished by pursuing three specific aims. Aim 1 investigates the efficacy of a novel telehealth exercise program for rural cancer survivors with CRF (the BfitBwell Telehealth Program [BfitBwell-TP]) in a randomized control trial. Rural breast and prostate cancer survivors within five years of completing curative treatment and experiencing CRF (N=134) will be recruited into the intervention or wait-list control group. A pilot investigation of BfitBwell-TP demonstrated feasibility, acceptability, and similar reductions in CRF compared to the clinically supervised program upon which it is based. BfitBwell-TP utilizes existing telehealth methodologies to deliver a combination of synchronous and asynchronous exercise sessions paired with CRF monitoring and symptom-triggered ExRx personalization to support CRF improvement. Aim 2 examines the effects of impaired objective physical function and fatty acid oxidation on reduced CRF response to exercise during the intervention with integrated within-program (every two weeks) remote assessments. Both have been associated with fatigue and both can be specifically targeted by ExRx personalization. Recent advances have allowed the remote assessment of objective physical function and the use of remotely collected, stable dried blood spot (DBS) samples in metabolomic analyses of impaired fatty acid oxidation. Finally, Aim 3 explores additional biomarkers of exercise-associated CRF remediation through the investigation of dynamic exercise metabolic profiles established during controlled, laboratory-based exercise sessions. This Aim performs necessary work to provide the foundation for the development of remotely assessed dynamic exercise metabolic profiles. This proposal is significant because it utilizes an accessible intervention to reduce CRF in underserved rural cancer survivors and integrates innovative methodology to drive continued improvement in this intervention, ultimately reducing the burden of cancer for rural survivors.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT Social determinants of health are known to have a significant impact on patient outcomes. However, controversies exist on how to best capture this information in routine care. Most SDH information is captured in the form of a survey or unstructured free text or narrative and not regularly captured or screened for variety of factors (e.g., time constraints, clinician experience/comfort in asking, patient fears of sharing potentially stigmatizing information. This is a particularly rich and robust source of information, especially when trying to identify patients' goals of care, preferences, or behavioral/social challenges that may exist. In this proposal, we use natural language processing and generative AI models to capture SDH information from patients. We will then process this information into discrete data elements that can then be passed into the EHR and acted upon by clinical decision support system. We will pilot this intervention in a large academic medical center that provides care to an at-risk patient population and community.

NIH Research Projects · FY 2026 · 2024-09

Homelessness increased by 45% from 2020 to 2021, largely from economic hardship caused by the COVID-19 pandemic and has reached all-time highs across the US. More than 1.25 million people experience homelessness in the US at some point in a year, with some groups being affected more heavily. Denver and San Francisco are two cities in which homelessness is at crisis levels. Homelessness increased by more than 30% since 2022 in Denver and San Francisco has the highest prevalence of homelessness in the US. Homelessness can lead to and is associated with profound health effects. People who experience homelessness die on average 30 years earlier than other Americans and have increased risk of substance use disorders and incident HIV than people who are stably housed. It is critical that we develop feasible, effective, and cost-effective tailored approaches to improve health among all people in the US, specifically with regard to life expectancy, overdose, and HIV. Yet, while effective, evidence-based solutions that improve health outcomes exist, they are far from ubiquitously implemented. Homelessness and the health issues among people experiencing it are heterogeneous, driven by locale-specific factors. Thus, locale-specific solutions are needed urgently. Simulation models can quickly fill knowledge gaps by serving as laboratories for testing hypotheses in real-time. Models that simulate the housing continuum can be important in augmenting randomized trials that provide evidence on system innovations, projecting the impact on health and costs. Our goal is to provide an evidence base for the prioritization and optimization of strategies to improve health outcomes of people experiencing homelessness including decreasing HIV incidence, reducing fatal and nonfatal overdose, and increasing life expectancy. In Aim 1, we will employ a Group Model Building (GMB) approach to engage stakeholders in the scientific process and inform the development of agent-based models that simulate health outcomes along the housing and homelessness continuum of care. In Aim 2, we will develop agent-based models simulating the dynamic processes contributing to overdoses, HIV, and life expectancy among people along the housing continuum of care in Denver and San Francisco. In Aim 3, we will simulate and compare HIV and substance use service delivery programs implemented along the housing continuum versus housing-centered programs. We will assess changes in HIV and overdose rates among the general population experiencing homelessness. We will also examine the potential of these programs for specific population health outcomes as well. Through this proposal, we will develop a national resource that generates the scientific knowledge needed to improve health among people experiencing homelessness, decrease overdose, and end the HIV epidemic.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT The proposed project is a resubmission by two promising Early-Stage Investigators as multiple principal investigators (PAR-22-189). The overall goal of this multi-phase proposal is to prepare for (R61) and execute (R33) a randomized clinical trial testing the effectiveness of Rehabbing with Peloton for improving physical activity among patients receiving transcatheter aortic valve replacement (TAVR) and evaluating the implementation of the intervention for future scalability. Despite ample evidence of the benefits of cardiac rehabilitation, only a small fraction of TAVR patients participate, which is thought to be a combination of missed referral opportunities coupled with patient-borne challenges including transportation, scheduling, and physical access to facilities. Participation in cardiac rehabilitation is particularly low among women and racial and ethnic minorities, as well as those with lower socioeconomic status, and/or living in rural areas, contributing to disproportionate morbidity and mortality burden in these patients. Overseeing cardiac rehabilitation content on commercially available fitness platforms (such as the Peloton mobile app) may be an excellent format for ensuring rehabilitation-appropriate modules while reaching TAVR patients currently under-referred and underusing cardiac rehabilitation. In our preliminary work, we engaged TAVR patients and cardiologists to develop the Rehabbing with Peloton intervention. RWP is an 8-week intervention in which TAVR patients engage with the Peloton app (not the fitness bike) to promote physical activity. RWP is a clinically reviewed, pre-set user account controlled by the research team that includes specific modules focusing on walking, strength exercises, yoga breathwork, and stretching, areas of exercise training previously used in home-based cardiac rehabilitation. Building on our previous multidisciplinary research, this proposal describes an innovative type II effectiveness-implementation hybrid randomized control trial of TAVR patients comparing RWP to attention control, controlling for technology. We will dedicate the R61 phase of the project to milestone-driven startup of the trial to successfully start recruitment by month 9 of the project. During the R33 phase, we will randomize N=200 individuals receiving TAVR from the University of Colorado Hospital Heart and Vascular Center to RWP or attention control. At baseline, post-intervention (8 weeks), and follow-up (12 months), we will assess participants’ physical activity (smartwatch accelerometer measured daily steps) and secondary outcomes of interest including functional capacity (Duke Activity Status Index; VO2max), quality of life (Kansas City Cardiomyopathy Questionnaire), and cardiovascular health status (Life Essential 8). The aims of the study are to test the efficacy of RWP on physical activity at 8 weeks (Aim 1) and secondary outcomes (Aim 2). We will use mixed methodologies to evaluate the implementation of RWP using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) Framework (Aim 3). Overall, this research will provide insight into the use of commercial mHealth to deliver CR to a population disproportionately excluded from CR.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Approximately 25% of children with congenital heart disease (CHD) require intervention in the first year of life. Although surgical mortality has decreased, the incidence of acute and chronic postoperative morbidities remains high. Morbidities are primary drivers of hospitalization, long-term outcomes, and cost, and are most common in children requiring neonatal surgery and those undergoing staged palliation for single ventricle heart disease (SVHD). While our patients struggle with these morbidities daily, our understanding of the mechanisms and molecular phenotypes of organ injury/recovery remain limited. Our preliminary data suggest that targeting a limited number of biomarkers/pathways is insufficient to address the complicated reality of CHD. Instead, diagnostic approaches allowing simultaneous measurement of hundreds of molecules (“omics”) paired with high dimension data analysis techniques could represent a better strategy. Our team has been highly productive in detailing the acute metabolomic and proteomic response to CHD surgery. We also found that the robust datasets generated through this work provide an excellent environment for training junior researchers in data science methods. Under this K24 proposal, we will use our two established cohorts (neonatal surgery and longitudinal SVHD palliation) to expand beyond the acute postoperative period, exploring the systems biology of subacute and chronic morbidity in our CHD patients. We will also leverage these high dimension datasets to train the next generation of researchers interested in using data science techniques to improve the lives of children with CHD. Overall Hypothesis: Postoperative injury and abnormal development following CHD surgery result in disruption of the circulating proteome and metabolome during initial injury, repair, and longitudinal growth. Serial measurements of the proteomic and metabolomic signature will validate novel candidate biomarkers of key chronic morbidities and identify previously unexplored interactions among diverse molecular pathways in a systems biology approach to understanding this complex pathophysiology. Specific Aim 1 (New Science under the K24): Utilize proximity extension assay technology to perform longitudinal measurement of the circulating proteome in the convalescent period after neonatal CHD surgery and determine the proteomic phenotype/changes in targeted protein biomarkers preceding two critical postoperative morbidities: subacute intestinal injury and chronic neurodevelopmental delay. Specific Aim 2 (Career Development): Expand my skills in the analysis of omics and deep clinical data through a combination of experiential and didactic training, with an emphasis on learning novel strategies to integrate and analyze multiple streams of high dimensional data. Specific Aim 3 (Mentoring): Using our established cohorts as a training platform, develop a pipeline of new patient-oriented physician-scientists interested in learning and applying data science methods towards mechanistic, diagnostic, and therapeutic discovery in children with CHD.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT This K99/R00 application aims to provide support for Dr. Felix Poppelaars, a talented postdoctoral fellow in the laboratory of Dr. Joshua Thurman, to conduct further research and training that will allow him to successfully transition into an independent investigator in the field of kidney immunology. As part of the K99 training plan, he will expand his knowledge and skills in molecular imaging of complement activation needed to establish himself as a leader in translational research of complement biology in nephrology. Furthermore, he will enhance his intellectual and professional skills, gain valuable mentorship, and participate in various career development activities, that will fast-track him to reach scientific independence. Guided by strong preliminary data, his proposed research project aims to develop an innovative medical tool for the visualization and quantification of complement deposition in the kidney, using antibody-based positron emission tomography (Immuno-PET) imaging. Activation of the complement system results in the deposition of smaller fragments on tissue. Complement deposition is often present in the renal biopsy of patients with kidney disease, making it an attractive target-of-interest for molecular imaging. Dr. Poppelaars will first (Aim 1A) uncover the molecular footprint associated with complement deposition in kidney disease using a multi-omics approach in mice. With training from leading experts, he will then (Aim 2A) examine the application of PET imaging of complement deposition in mice with kidney disease for disease staging and prognostication. After transitioning to a faculty position, Dr. Poppelaars will (Aim 1B) characterize the in vivo kinetics of complement deposition during kidney disease, followed by (Aim 2B) longitudinal studies of PET imaging of complement deposition in mice with kidney disease to monitor treatment responses. Finally, he will (Aim 3) translate his findings to humans by establishing the feasibility of ex-vivo PET imaging of complement deposition in discarded donor kidneys. Overall, the proposed research has the potential to improve the care and outcomes of patients with kidney disease, by 1.) enabling longitudinal noninvasive evaluation, 2.) tailoring treatment plans, and 3.) advancing our mechanistic understanding of the pathophysiology of kidney disease. In addition, the proposed research will open exciting avenues for future fundable research in the field of kidney transplantation. The primary mentor, Dr. Thurman, and co-mentor, Dr. Michael Holers, are internationally recognized and NIH-funded scientists with a strong history of successful mentoring in translational immunological research. With their guidance and the support of the advisory team members Dr. Jason Lewis, Dr. Laura Barisoni, and Carl Atkinson, as well as collaborators, Dr. Poppelaars will be able to successfully complete the proposed research and training plan and transition to an independent, extramurally funded tenure-track position at a top-tier research institution.