University Of Colorado Denver

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

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 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 2024 · 2024-09

There are national movements to improve the quality of primary care for patients while protecting and promoting health worker well-being. The critical barrier to realizing these calls for action is that healthcare systems have struggled to effectively address health worker burnout and turnover, often utilizing low-yield tactics because of the perceived cost of system level changes. Work needs to be done to address the fundamental problem – the healthcare working environment. In this proposal, we aim to address the work environment of federally qualified health centers (FQHC) where critically important care is given to underserved populations who often have multiple chronic conditions. These centers struggle with employee retention, which leads to healthcare access and quality challenges for underserved patients. We propose a multi-method, multi-level investigation of FQHCs to evaluate the safety, health and well-being needs of their workforce to encourage retention. We will partner with the Colorado Community Health Network (CCHN) – all Colorado (CO) FQHCs are members and receive support from them – as well as CO practice-based research networks to recruit FQHCs and their staff to participate. Our project is guided by a vision for a FQHC workforce that is thriving in an environment that fosters their well-being. Aim 1: Determine how FQHCs can utilize leadership practices to design work that increases the employee value proposition for existing and future FQHC staff. Aim 2: Evaluate FQHC primary care workforce well-being using the NIOSH Worker Well-being Questionnaire (WellBQ) and assess its relationship to turnover intentions. We address AHRQ’s call to understand approaches to support, develop, retain, and grow the primary care workforce and further understand and improve their well-being. In the short-term, we will share results and resources with CO FQHCs for the purpose of helping them identify strengths and opportunities in the way they are supporting their workforce’s well-being. Our aim is to use our findings to begin to work towards shifting the current clinical practice of FQHC’s leadership and management of provider and staff well-being towards a systems-based approach, informed by multi-method and multi-level assessment strategies.

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 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 2024 · 2024-08

PROJECT SUMMARY Newly emerging and long-standing infectious challenges, including arboviruses, Ebola virus and pandemic coronaviruses (CoVs), among others, pose serious public health concerns. Additionally, the potential use of biological agents as weapons of mass destruction poses an ongoing threat to humanity. All of these issues have in common the need for development strategies that allow for the rapid design, screening and formulation of potential vaccine candidates. We have developed a “designer nanoparticle” platform based on λ phage-like particles, or nanophages (NPs), that can display multiple antigenic biomolecules alone and in combination in rigorously defined ratios. The NPs can be rapidly modified to screen and evaluate potential vaccine candidates against newly emerging threats. Herein we propose to develop tools and technologies for rapid screening of multivalent vaccine candidates effective for current and emerging SARS-CoVs and pre- emergent SARS-like CoVs. We will engineer “second generation” nanophages (NPs) that display the spike receptor binding domain (RBD) for these pathogens, the primary target of neutralizing antibody (Ab) responses. Physiochemical and structural characterization of the preparations will be employed to ensure that they possess properties that are appropriate for a pharmaceutical preparation. We will also employ a novel atomic layer deposition technology to generate thermostable, timed-release, single-shot vaccine formulations that reduce or eliminate onerous “cold-chain” requirements for their distribution. We further propose to determine the immunogenicity and protective capacity of mosaic NPs engineered to simultaneously display multiple antigens. These studies will identify vaccine candidates that elicit potent, durable, and broad neutralizing Ab and T cell responses and protective immunity against SARS-CoV-2 variants and pre-emergent SARS-like bat CoVs. In addition to developing this powerful platform and implementing novel formulation strategies, these studies will help define mechanisms of immunogenicity and develop a platform for the rapid engineering of vaccine candidates for existing and untoward emerging biological threats. In sum, this application seeks to provide compelling evidence that the  nanophage system provides a platform for facile and rapid generation, and formulation of highly active multi-antigen presenting vaccines.

NIH Research Projects · FY 2025 · 2024-08

Project Summary Horizontal gene transfer (HGT) is a driver of rapid evolution and adaptation in microbial communities. HGT spreads genes among and between bacterial species and is relevant to human health as this process disseminates antibiotic resistance genes, genes involved in toxin production, and other virulence traits. Transduction, the transfer of genetic material by bacterial viruses (phages) or virus-like particles (VLPs), is widespread among bacteria and plays an essential role in the evolution of bacterial pathogens. Despite the importance of transduction to human health, our understanding of the taxonomic range, frequency, and mechanisms of transduction between commensal and pathogenic bacteria are limited. Currently, the study of transduction in microbial communities relies on the reconstruction of historical transduction events that shaped extant microbial genomes. These reconstructions do not measure ongoing transduction. To address this challenge, we developed a novel method termed transductomics, which allows us to measure near to “real time” transduction in microbial communities and identifies the DNA sequence transduced to new bacterial recipients. Transductomics uses shotgun metagenomic DNA sequencing to identify and characterize DNA originating from microbial cells that is carried in phages or VLPs. This technique has the power to identify transducing viruses within microbiomes and can be used to determine the spread of virulence and antibiotic resistance traits that contribute to pathogen success. Recent work, including our own, has shown that phages and VLPs are abundant in the intestine. This indicates that phages and/or VLPs capable of transducing DNA to and from bacteria are significant are understudied players in the spread of genetics traits that can promote bacterial pathogenesis. Although our transductomics method readily identifies both active and potential transduction occurring within diverse bacterial communities, it lacks automation, is low throughput, and labor intensive. The main goals of this project are to establish high-throughput methods with refined resolution that allow for the measurement and identification of transduction within bacterial pathogens and microbiomes and to examine how transduction spreads virulence traits within the microbiota. Identifying transducing events within the microbiota and among established pathogens will facilitate the development of precision therapies aimed at curtailing the spread of virulence and antibiotic resistance genes among bacteria, which can limit pathogenesis.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Advancing our understanding of the neural basis of human cognition is limited due to the rarity of intracranial recordings in humans, and the inherent inadequacy of animal models. Additionally, studying something as complex and flexible as executive function will likely require recording from hundreds of neurons simultaneously, a scenario not currently possible in humans with the existing recording technology. Here we propose to use a new probe, the Neuropixels probe, with 960 possible recording electrodes on a single shank, to study human executive function. Placing these Neuropixels probes in the dorsolateral prefrontal cortex during awake deep brain stimulation recordings, we will assess the neural population activity during an executive function task that employs feature selection, conflict processing, and decisions (Aims 1 and 2). Making use of the unique recording structure of the probe, with electrodes placed regularly along the shank, we will evaluate the local topography, expecting cortical layers to stratify neural responses to task-conditions (Aim 1). We will also evaluate the neural population response to task conditions, hypothesizing that the neural dimensions and geometry exhibit features that explain the flexibility so crucial to executive function (Aim 2). This study will establish the neural underpinnings of human executive function.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT: Almost two billion people worldwide become ill with diarrhea annually, and ~700,000 die. Nontyphoidal Salmonella, such as Typhimurium, cause roughly 180 million diarrheal illnesses and 300,000 of all diarrheal disease-associated deaths. Very young and very old people, as well as immunosuppressed individuals coinfected with HIV or plasmodium, are particularly at risk of suffering life-threatening, systemic nontyphoidal Salmonella infections. During infection, phagocytic cells bombard Salmonella with highly toxic reactive oxygen species produced in the respiratory burst of the protein complex NOX2. The metabolic adaptations that promote growth of Salmonella in macrophages are vital yet largely neglected facets in the pathogenesis of this intracellular bacterium. In the current grant period, we made a series of crucial new observations regarding the hitherto poorly understood terminal electron acceptors used by intracellular Salmonella to resist NOX2 killing. (a) Salmonella exploit anaerobic respiration in order to avoid metabolic pathways particularly sensitive to reactive oxygen species synthesized by NOX2. (b) The O2-consuming activity of phagocytic cells activates Salmonella anaerobic programs in mice, macrophages and hypoxic culture conditions that recapitulate microabscesses developing during Salmonella systemic infections. (c) Anaerobic respiration associated with dmsABC gene products is required for survival of Salmonella in phagocytes and mice. (d) We have identified methionine sulfoxide, a byproduct of NOX2 enzymatic activity in mice, as the relevant terminal electron acceptor utilize by dmsABC gene products. (e) Anaerobic respiration on methionine sulfoxide is associated with production of the antioxidant hydrogen sulfide (H2S) in anaerobic Salmonella undergoing oxidative stress. (f) Intracellular Salmonella also respires on the sulfur compound tetrathionate to avoid NOX2 killing in macrophages, while activating the expression of Salmonella virulence programs. Cumulatively, our data support the hypothesis that intracellular Salmonella has coopted the energetics and signaling pathways arising from a sulfur-centric anaerobic metabolism to counteract the damaging activity of NOX2 enzymatic complexes in macrophages. Aim 1 will investigate the contribution of DmsA-dependent anaerobic respiration to the resistance of intracellular Salmonella to NOX2. Aim 2 will evaluate the degree to which hydrogen sulfide aids the defense of intracellular Salmonella against oxidative stress. Aim 3 will identify the mechanisms through which tetrathionate respiration fosters the antioxidant defenses of intracellular Salmonella. The knowledge generated in the course of these investigations will not only illuminate key aspects of Salmonella pathogenesis but will also identify key terminal electron acceptors utilized by intracellular Salmonella to establish a stronghold within professional macrophages.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT The purpose of this K76 career development award is to support Dr. Fullard’s long-term career goal of becoming an independent clinician-scientist focused on improving shared decision-making for older adults with neurologic disease, including those with mild cognitive impairment (MCI). MCI is common in older adults and can present unique challenges to shared decision-making. In this proposal, we will examine decision-making in MCI using Deep Brain Stimulation (DBS) surgery in people with Parkinson’s disease (PD) and MCI as a model. MCI is common in PD and is especially pertinent to decision-making because it affects executive function, verbal memory and processing speed, domains that are associated with the ability to weigh risks and benefits and appreciate the consequences of a decision. In addition, people with MCI exhibit higher decisional conflict and report more decision regret compared to their healthy counterparts, making this an ideal population for a decision support intervention. The overall objective of this proposal is to examine the approach to decision-making for PD patients with MCI and to improve decisional outcomes using a decision aid that addresses cognitive weaknesses. The central hypothesis is that decisional conflict and decision quality will improve after exposure to the decision aid. The specific aims for this proposal are to: 1) adapt and refine a DBS decision aid for PD patients with MCI considering DBS surgery, 2) evaluate the feasibility, acceptability and preliminary effectiveness of the decision aid for PD patients referred for DBS evaluation, and 3) evaluate implementation of the decision aid guided by the RE-AIM framework. To achieve these aims, semi-structured interviews will be performed with 30 dyads of patients with and without MCI and their care partners who have gone through the DBS evaluation process in order to gain an in-depth understanding of the decision-making process and MCI-specific decisional needs. Insights from these interviews will be used to adapt and refine our existing DBS decision aid to address cognitive weaknesses in MCI. A pragmatic, randomized controlled pilot trial will evaluate the feasibility and acceptability of the decision aid for PD patients undergoing DBS evaluation. The research aims are accompanied by a training plan designed to address gaps in the candidate’s knowledge and prepare her to become an independent clinician-scientist and leader in shared decision-making interventions for older adults with neurologic disease. The training aims for this proposal are to: 1) gain expertise in mixed methods, 2) become proficient in pragmatic clinical trial design, and 3) gain experience in implementation science. These aims will be achieved through didactic coursework, workshops, attendance at scientific meetings, practical experience, and direct mentoring. The candidate is mentored by experts in shared decision-making, mixed methods, neuropsychology, pragmatic clinical trial design and implementation science. Completion of these research and training aims will result in an MCI-sensitive intervention designed to improve decisional outcomes that will be tested for effectiveness in a future R01 and will serve as a model for similar interventions for older adults with neurologic disease and MCI.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT: Dr. Singh’s long-term goal is to lead research efforts that enhance delivery of palliative care to improve person-centered outcomes for hospitalized older adults with advanced cancer discharged to skilled nursing facilities (SNFs) and their family caregivers. The current model of SNF care is inadequate to meet the unique needs of these patients who often experience rapid clinical decline due to the juxtaposition of comorbidities and geriatric syndromes which places them at risk for receiving goal- discordant care. Palliative care nursing home interventions have been challenging to implement and have targeted long-stay residents who have different needs than SNF patients. Dr. Singh is a physician in the Division of Hospital Medicine at the University of Colorado. Her proposal tests the ALIGN (Assessing and Listening to Individual Goals and Needs) intervention which utilizes palliative care social workers to deliver a guideline-based manualized intervention for older patients with cancer discharged to SNFs and their family caregivers. In a preliminary study funded by the National Palliative Care Research Center, Dr. Singh demonstrated that virtual ALIGN visits could be conducted in community SNFs and that the intervention was highly acceptable. Patients experienced high morbidity and mortality leading many to change their goals to comfort focused care and necessitating increased family caregiver involvement in surrogate decision making. This K23 proposal aims to address key gaps and strengthen ALIGN for future clinical efficacy testing. The objectives are to: 1) conduct a pilot randomized controlled trial to test feasibility of enrolling participants into a randomized design, outcome collection, preliminary efficacy, and risk for contamination; 2) evaluate implementation outcomes, including intervention fidelity, of ALIGN in community SNFs; 3) determine processes through which ALIGN prepares caregivers for surrogate decision making to iteratively refine the intervention to improve goal concordant care. The proposed training plan is designed to accelerate Dr. Singh’s development into an independent patient-oriented researcher and includes training in clinical trial design and analysis, implementation science, caregiver focused palliative care interventions, and preparation for independence. Dr. Singh has assembled an exceptional mentorship team, led by Dr. Stacy Fischer, with complementary expertise in clinical trials in an oncology population, palliative care social work, nursing home research, implementation science, surrogate and end of life decision making, and caregiving research. The K23 award would enable Dr. Singh to continue developing her research skills while providing her with data to prepare an R01 proposal for a fully powered clinical trial of ALIGN evaluating efficacy. Successful completion of this research will inform the development of a scalable model of palliative care that can be implemented in community SNFs to maximize real-world effectiveness. Further, it will expand our understanding of how to best prepare family caregivers for surrogate decision making to improve delivery of care aligned with patient preferences after discharge to SNF.

NIH Research Projects · FY 2026 · 2024-08

Project Summary Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to kidney failure. The only approved treatment to decelerate kidney disease progression in patients with ADPKD is tolvaptan, but its usage is limited due to frequent side effects affecting adherence. Thus, alternative interventions that may slow ADPKD progression hold considerable clinical importance. In line with the general population, body-mass index and insulin resistance have been increasing in patients with ADPKD. We have shown that visceral adiposity associates strongly with accelerated progression of early-stage ADPKD. Our R03-funded pilot study suggested that diet-induced weight loss may slow kidney growth (%? in height-adjusted total kidney volume [htTKV] by magnetic resonance imaging), and we are currently evaluating the efficacy of daily caloric restriction-induced weight loss for slowing ADPKD progression in a phase IIa clinical trial. However, the long-term adherence to lifestyle interventions is challenging, making pharmacological interventions a compelling adjunct or alternative. Moreover, our recently completed R21-funded study demonstrated that adults with ADPKD and preserved kidney function exhibited insulin resistance (via the gold- standard hyperinsulinemic-euglycemic clamps) and impaired kidney oxidative metabolism (via 11C-acetate PET), which were strongly associated with htTKV. These novel data suggest that targeting improvements in insulin sensitivity and kidney oxidative metabolism, in addition to weight loss, may slow ADPKD progression. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) were recently FDA-approved for the treatment of obesity and show promise in substantially reducing adiposity and improving insulin sensitivity. Additionally, evidence indicates that GLP-1RAs may transform CKD management by reducing nephropathy events in patients with and without diabetes, via effects extending beyond glycemic modulation, and in part via attenuated kidney inflammation and oxidative stress. However, GLP-1RAs have not yet been evaluated as a novel therapy for slowing ADPKD progression in patients with overweight/obesity. Thus, we propose a 24- month, phase II, randomized, placebo-controlled, double-blind clinical trial using a GLP-1RA in 126 adults with ADPKD and overweight or obesity to slow kidney growth (primary outcome). As a novel therapeutic in ADPKD, GLP-1RAs could transform the treatment landscape for patients. Specific Aim 1: Determine the effect of 24 months of GLP-1RA vs. placebo on kidney growth in adults with ADPKD and overweight/obesity. Specific Aim 2: Define changes in total body weight, adipose volume and function, insulin resistance, kidney oxidative metabolism, and inflammation after 24 months of GLP-1RA vs. placebo in adults. Specific Aim 3: Establish the safety and tolerability of GLP-1RA in adults with ADPKD and overweight/obesity.

NIH Research Projects · FY 2025 · 2024-08

Project Summary/Abstract The goal of this Mentored Career Development Award is to facilitate the primary investigator's transition to independence as a physician-scientist studying the molecular mechanisms underlying brain injury that occurs after a cardiac arrest. The candidate is a MD/PhD critical care physician and anesthesiologist with a background in neurodegenerative and brain injury research. The award will help the candidate gain research experience in the analysis of neuronal cell death pathways and brain inflammation, measurement of synaptic function, and assessment of cognition in mouse models of cardiac arrest. The environment in which the proposed research will be conducted is outstanding, and includes structured mentorship from neuroscientists and physician-scientists with diverse backgrounds. The candidates mentor and co-mentor, Dr. Nidia Quillinan and Dr. Elizabeth J. Kovacs, are well-respected experts in the fields of cardiac arrest, global cerebral ischemia, aging research, and inflammation. The proposed research will investigate the role of inflammasome pathways as molecular mediators of age-related differences in brain injury after global cerebral ischemia induced by a cardiac arrest. The incidence of cardiac arrest dramatically increases with age, with older survivors having a worse neurologic prognosis and poor response to post-arrest care. A potential cause of worsening brain dysfunction after a cardiac arrest in older individuals is age-associated inflammation (inflammaging). Activation of the inflammasome multi-protein complex is a primary driver of inflammaging and has been shown to mediate cognitive deficits in both brain injury and disease. The goal of this project is to test the hypothesis that global cerebral ischemia results in a more robust and sustained inflammasome activation with advanced age that results in increased cell death and synaptic deficits in survivors. In order to test this hypothesis, the primary investigator will use a murine model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR) to (Aim 1) assess for age-related differences in inflammasome-mediated inflammation after global cerebral ischemia and (Aim 2) evaluate the extent to which inflammasome activity contributes to CA/CPR induced neuronal cell loss, acute deficits in synaptic function, and cognitive impairment in young and advanced age mice. The proposed experiments are designed to elucidate a novel aging-relevant molecular mechanism involved in the brain's response to global cerebral ischemia. This career development award will provide the primary investigator with valuable research training relevant to the realms of ischemia, aging biology, and inflammation that will complement his clinical management of cardiac arrest survivors in the intensive care unit, and ultimately provide a skill set for the translation of basic science discoveries into novel therapeutic strategies for patients that suffer a cardiac arrest.

NIH Research Projects · FY 2025 · 2024-08

Cannabis use among pregnant people is on the rise. This trend is likely to be continue, especially among people who are younger or those live in states where cannabis is legal. Yet, pregnant people may not be aware of the potential risks. Prenatal exposure to cannabis has been consistently linked to low birth weight. Our pilot data further suggests that prenatal exposure to cannabis is associated with rapid growth in the first three years of life followed by increased adiposity and glucose at age 5 years. However, important gaps in knowledge remain. It is unclear whether a particular cannabinoid may be driving this association, as epidemiologic studies have examined the independent or joint effects of delta 9-tetrahydrocannabinol (Δ9- THC) and cannabidiol (CBD). Additionally, there is a need to identify protective factors that mitigate risk, given that this exposure may have occurred in the past. Furthermore, it is unknown whether there are developmental windows in which the offspring may be more susceptible to these cannabinoids. In response to NOT-DA-22- 003, our overarching goal is to determine when and how prenatal exposure to cannabis impacts childhood adiposity and cardiometabolic health. These specific health traits are relevant to adult health as they track across the lifespan and have been previously collected in our rich Colorado-based cohort (Healthy Start; R01DK076648). Pregnant people were recruited between 2010 and 2014, amid state-wide legalization of cannabis for recreational use but prior to widespread health messaging about the potential harm to the fetus. We propose to measure Δ9-THC and CBD in maternal serum (collected at ~17 and ~27 weeks gestation) and in umbilical cord blood. Our central hypothesis is that prenatal exposure to cannabis will be associated with increased adiposity and altered cardiometabolic traits at age 5 years. In Aim 1, we will test the hypothesis that the associations between Δ9-THC/CBD and child health will be stronger among those with co-exposure to tobacco and mitigated by a longer duration of breastfeeding and higher intakes of key nutrients. In Aim 2, we will examine windows of susceptibility in which prenatal exposure to Δ9-THC and/or CBD influences growth and cardiometabolic health among the 5-year-old offspring. we will identify windows of heightened susceptibility. This exploratory study includes a well-characterized, observational cohort with a relatively high prevalence of exposure (13% at mid-gestation) and a novel on cardiometabolic outcomes, making it uniquely positioned to advance our understanding of when and how prenatal exposure to cannabis influences child health. Results may inform future targeted interventions to limit the effects of exposure during pregnancy.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY Medication nonadherence leads to increased morbidity, mortality, and costs the US healthcare system hundreds of billions of dollars annually. While there have been decades of research regarding nonadherence, newer research shows that interventions that focus on behavior change, and specifically, habit-building, have the most potential to result in improvement. Given their higher rates of nonadherence and decreased self- management skills, adolescents with chronic conditions will benefit most from medication adherence interventions. Our prior work shows that adolescents with eosinophilic esophagitis (EoE) – a chronic immune- mediated inflammatory disease of the esophagus with a rapidly rising incidence – have low medication adherence rates secondary to lack of planning and forgetfulness. Thus, we created a prototype of a clinical tool (a habit-based medication “Action Plan”) and iteratively modified it using stakeholder engagement. The specific aims of this proposal are to: 1) establish an optimal version of this tool - the “Medication Habit Action Plan (MHAP)” – through usability testing (end-user testing with patients and nurses), 2) conduct a pilot randomized controlled trial of the MHAP to determine feasibility and inform a larger multicenter future hybrid effectiveness- implementation trial, and 3) measure the effect of dupilumab on adherence and EoE clinical outcomes in nonadherent adolescents using a prospective cohort study design. This career development award is designed to support the transition of Pooja Mehta, MD, MSCS, an Assistant Professor of Pediatrics at the University of Colorado, into an independent clinician-scientist and to achieve her long-term career goal of improving outcomes in children with chronic gastrointestinal diseases. Guidance from a multidisciplinary mentorship team (Dr. Glenn T. Furuta- renowned EoE clinical researcher, Dr. Bethany Kwan- dissemination and implementation scientist, and Dr. Sheana Bull- user-centered design and technology expert) will be coupled with training in 1) clinical trial design and conduct, 2) dissemination and implementation science, and 3) healthcare data integration across multiple institutions. Together, these will provide Dr. Mehta with the foundation needed to successfully create and test adherence-related interventions in large-scale multi-center pragmatic trials. The University of Colorado provides a unique environment to conduct pragmatic research and is supported by collaborative partnerships between The Adult and Child Consortium for Health Outcomes Research and Delivery Science, The University of Colorado Mobile Health Impact Laboratory, Children's Hospital Colorado Gastrointestinal Eosinophilic Diseases Program, and Denver Health (Denver's safety net hospital). EoE serves as an ideal disease model to study habit-based medication adherence interventions and will have widespread applicability to a broad range of chronic pediatric gastrointestinal diseases. Ultimately, completion of this research proposal and career development plan will help Dr. Mehta achieve her overall career goal of addressing treatment nonadherence in children with chronic diseases to improve child health outcomes.

NIH Research Projects · FY 2025 · 2024-08

SUMMARY The goal of this project is to develop strategies for the eradication of leukemia-initiating cells (LICs) in AML patients who have received initial therapy with venetoclax and azacitidine (ven/aza). As demonstrated previously, almost all AML patients treated with ven/aza will eventually relapse. Thus, providing improved therapeutic regimens is an urgent unmet need. Our previous studies have demonstrated that more than one subtype of LIC can exist simultaneously in the same patient. Importantly, different LIC subtypes can demonstrate highly variable responses to therapy, including resistance to ven/aza. Thus, LIC heterogeneity may be a prevalent feature of AML biology, and as such poses a significant challenge in designing optimal therapies that effectively eradicate them. Consequently, a major goal of this project is to characterize and target ven/aza resistant LICs. Our preliminary data indicate that reliance on uptake of calcium into mitochondria is a distinct feature and vulnerability of ven/aza resistant AML cells. Thus, we have investigated the role of the calcium uniporter, MCU, as a potential therapeutic target. Our findings show that both genetic and pharmacological inhibition of MCU is highly cytotoxic to ven/aza resistant LICs. Importantly, normal hematopoietic stem/progenitor cells do not share this extensive reliance upon MCU for mitochondrial metabolism and survival. Thus, this axis appears to represent a unique feature of ven/aza-resistant LIC and in turn, an attractive opportunity for therapeutic intervention. To translate this strategy to clinical practice, we have leveraged a recent finding that shows the well characterized chemotherapy agent, mitoxantrone (mitox), is a strong inhibitor of MCU. Intriguingly, we demonstrate that mitox is effective in suppressing mitochondrial calcium uptake and downstream metabolism at doses 10-100 fold lower than used for conventional chemotherapy purposes. Indeed, at doses as low as 10nM, we observe potent eradication of ven/aza resistant LICs, with no evidence of DNA damage, and no discernable effect on the growth of normal hematopoietic stem/progenitor cells. Based on these findings, our goals are to: 1) perform preclinical modeling studies as a prelude to clinical investigation and to better understand the mitox mechanism of action, 2) conduct a clinical trial using lower-dose mitox in combination with ven/aza as a strategy to target drug-resistant LICs and thereby increase remission duration, and 3) to perform a detailed in vivo analysis of LIC subtypes in patients undergoing ven/aza/mitox therapy to better define the role of mitochondrial calcium uptake and any other molecular events that contribute to therapy resistance in the heterogenous LIC compartment. Taken together, the proposed studies will provide a comprehensive evaluation of mitox as a clinical strategy to augment ven/aza therapy and will determine the prevalence and role of calcium uptake in the biology of drug resistant LICs.

NIH Research Projects · FY 2025 · 2024-08

Project Summary: Breastfeeding has been shown to protect mothers and their children from metabolic disease later in life. However, maternal obesity and diabetes independently predict poor lactation outcomes, even after adjustments for breastfeeding support and socioeconomic factors. The physiological reasons for this relationship remain unclear. This proposal aims to identify the molecular mechanisms linking lactation to metabolism with a long-term goal of developing interventions to improve lactation outcomes in women with obesity and/or diabetes. Investigations of human lactation are challenging due to ethical and practical barriers related to accessing mammary tissue in the lactating state. Single cell RNA sequencing of human milk-derived cells has shown that these cells are remarkably similar to mammary epithelial cells (MECs) resident in the lactating gland. Additional cell sorting efforts have established milk-derived MECs as “liquid breast biopsies” which may be used to answer many outstanding questions regarding lactation biology. Furthermore, a delicate balance of insulin signaling is required for MEC differentiation and maintenance. Mammary specific knockout of the insulin receptor (mam-IRKO) blocks MEC secretory differentiation, and therefore impedes lactation. Conversely, mammary-specific expression of an active form of insulin’s downstream mediator, AKT, also drives lactation failure. In order to identify appropriate interventional approaches to improve lactation performance, it is critical to understand if MECs are responsive or resistant to insulin in the context of hyperinsulinemia. Studies of non-lactating mammary glands in women with obesity and diet-induced obese mice suggest that premature insulin signaling may be responsible for these effects, by driving dysregulated glandular development. The aims of this project are to 1. establish the effect of maternal gestational diabetes (GDM) on MEC progenitor insulin signaling and milk-derived MEC profiles and 2. define the effects of insulin and other metabolic hormones on MEC secretory differentiation and function. Milk-derived MECs of women with and without severe GDM, matching for BMI, will be utilized to determine if MEC progenitors from women with GDM are sufficiently responsive or resistant to insulin, and differences between MEC populations which may explain impaired lactation outcomes in these women will be assessed. In vivo and in vitro models of MEC development will be used to identify the mechanism underlying insulin’s effect on lactogenic prolactin signaling, which is downregulated in mam-IRKO mice. Effects of adipokines leptin and adiponectin on MEC development and function will also be investigated. This proposal will inform future efforts to investigate additional links between obesity and/or diabetes and human lactation dysfunction. The proposed approach has the potential to break a vicious intergenerational cycle of metabolic disease. A collaborative team of experts in mammary physiology and diabetes in pregnancy will support the applicant to ensure success of this innovative project.

NIH Research Projects · FY 2025 · 2024-08

Project Summary Children with type 1 diabetes (T1D) suffer from subtle cognitive impairments and structural alterations in the brain. These impairments progress with age and may eventually lead to increased difficulty managing the disease, resulting in worsening glycemic control, potentially life-threatening complications, and reductions in quality of life. Causes of cognitive decline in T1D are not well understood. Episodes of hypoglycemia, chronic hyperglycemia, glycemic variability and diabetic ketoacidosis (DKA) have all been suggested to play roles. Our team at the University of Colorado proposes to join a multicenter NIH consortium to investigate the impact of T1D on neurocognitive and psychosocial functioning in pre-pubertal children. We propose collaborative development of the study protocol, enrollment of a representative study population, and prospective follow-up to collect exposure and outcomes data for hypothesis testing. This study will further elucidate the role of DKA, chronic hyperglycemia, severe hypoglycemia and established or emerging treatment modalities on neurocognitive and psychosocial functioning of pre-pubertal children followed for up to three years after T1D diagnosis. We propose to test the following hypotheses: H1: DKA at diagnosis of T1D has a detrimental long-term effect on neurocognitive and psychosocial functioning (including full scale IQ), independent of sex, race/ethnicity, and socioeconomic status. H2: Chronic hyperglycemia exposure, assessed by repeatedly measured HbA1c or CGM time above range (TAR >250), has a detrimental long-term effect on neurocognitive and psychosocial functioning, independently of sex, race/ethnicity, and socioeconomic status of the child. H3: Recurrent severe hypoglycemia or excessive time below range (TBR <70 mg/dl) has a detrimental long-term effect on neurocognitive and psychosocial functioning, independently of sex, race/ethnicity, socioeconomic status, and glycemic control assessed by HbA1c or time in range (TIR 70-180). H4: Routine vs occasional use of CGM has a protective long-term effect on neurocognitive and psychosocial functioning, independently of sex, race/ethnicity, and socioeconomic status of the child and average HbA1c. The proposed studies will help to further understand the impact of DKA, hyperglycemia, hypoglycemia, and current diabetes management modalities on the developing brain, including neurocognitive and psychosocial functioning.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT Pediatric treatment-induced high-grade glioma (HGG), also known as radiation-induced glioma (RIG), is an incurable secondary cancerous brain tumor that affects children who have previously received cranial radiotherapy (RT), most commonly for leukemia or a separate, primary brain tumor (the two most common childhood cancers). They affect up to 4% of children who have received cranial RT and account for up to 10% of pediatric brain tumor deaths. They have no known effective treatment, and research on these uniformly fatal tumors has been unacceptably limited. We recently broadly characterized these tumors’ molecular features in a large patient sample cohort. We found that while RIG and primary pediatric HGG share histological similarities, their genetic alterations and gene expression profiles are different. RNA-seq analysis of treatment- induced HGG shows they form two expression subgroups (A and B) of approximately equal incidence. Findings in both groups suggest the presence of germline DNA repair defects that may place some patients at increased risk of developing these tumors after receiving RT. We have characterized these tumors’ cells of origin through single-cell RNA-Seq. We have also developed a world-first set of patient-derived cell culture and orthotopic xenograft (PDX) models of these tumors. We found that RIG is vulnerable to many clinically relevant therapies, including DNA disruptors and MEK inhibitors. For this proposal, we hypothesize that germline susceptibility to DNA disruption from RT contributes to oncogenesis of these tumors, but this origin in DNA disruption in turn renders them susceptible to DNA disrupting treatment like RT and specific chemotherapies, so that combining DNA disrupting treatment with targeting of tumor-specific molecular dependencies will improve outcomes. Our first aim is to discover and validate germline risk factors for RIG through DNA sequencing of the germlines of patients and controls and then testing putative genetic variants conferring risk through an in vitro stem cell model. Second, we will inhibit predicted pathways of tumor growth in three types of RIG cells of origin to establish pathways key to tumor growth and treatment resistance. We will supplement the predicted pathways with screens based on orthogonal functional genomic techniques in vitro and in vivo. Lastly, we will use our patient-derived models of these tumors to test combinations of effective chemotherapies and RT in cell culture and take the most successful treatment plans for validation in our PDX models. We will also conduct orthogonal assessment of treatment efficacy through our newly opened RIG patient registry. Through these aims, we will lead research on these tumors from current limited biological understanding to advanced understanding of tumor origins with a pathway to prevention, with implications for other secondary cancers as well. Critically, we will also understand rational, combination treatment susceptibilities. We will be able to translate this knowledge to a RIG-specific clinical trial to finally improve outcomes for these tragic patients currently dying of brain tumors caused by treatment that helped cure their primary cancer.

NIH Research Projects · FY 2026 · 2024-08

Proposal Summary Inflammatory bowel disease (IBD), comprised of ulcerative colitis and Crohn's disease, contributes to significant morbidity and mortality in the United States. The inflammation in IBD is initiated by a breakdown in the mucous layer and intestinal epithelial cells that act as a barrier in the gastrointestinal tract. Current therapeutics are inadequate in that they largely target systemic immunosuppression which have been associated with increased infection and malignancy risk as well as being efficacious in a minority of patients. These problems result in many IBD patients having active and debilitating disease. We have previously identified a key role for creatine, an energetic regulator, in intestinal epithelial cell barrier function and wound healing. This is significant in that IBD patients have decreased expression of the creatine transporter (CRT) which brings creatine into cells. More recently we have identified dysregulation of intestinal epithelial cell differentiation in cells that are deficient for CRT. Loss of creatine results in decreased goblet cell marker expression in CRT deficient organoids and decreased mucous containing goblet cells in the colon of CrtFloxVillinCre mice. This deficiency decreases mucous layer formation, which is expected as goblet cells are the major producers of the protective mucous layer which serves to protect the intestinal mucosa. In the follow proposal we aim to evaluate the hypothesis that the creatine pathway is integral to goblet cell function and dysregulation identified in CRT deficient epithelial cells will impact the microbiome and metabolism of the colonic lumen as well as contribute to increased colitis susceptibility. In Specific Aim 1, we propose to evaluate the contribution of glycolysis on goblet cell differentiation and activity in CRT deficient intestinal epithelial cells. We will also determine the cause of the dysregulation by evaluating key goblet cell signaling pathways. This aim is vital in that identifying the mechanism of goblet cell loss may provide options for therapeutic intervention. In Specific Aim 2 we will identify changes in microbiome that could be impacted by the decrease in mucous and other goblet cell produced factors as well as changes to the creatine content in the lumen. We will determine if these changes may contribute to a stressed metabolic colonic lumen environment. We believe that alteration to the microbiome may contribute to the inflammatory mucosal environment. Specific Aim 3 will assess for colitis disease susceptibility due to epithelial CRT loss in CrtFloxVillinCre mice. We will conduct salmonella colitis and TNBS colitis experiments which cause ulcerative colitis like inflammation in CrtFloxVillinCre mice and compare disease susceptibility. We will make use of findings in the prior aims to determine if there are interventions to prevent increased susceptibility in CrtFloxVillinCre mice including stimulation of differentiation pathways and alteration of the metabolic or microbial environment. The findings from this proposal will clarify the contribution of CRT loss in goblet cell activity and contribution to colitis which will provide potential mucosal specific IBD therapeutic targets.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Aging is the primary risk factor for cardiovascular diseases (CVD) and Alzheimer's disease and its related dementias (ADRD),1, 2 due in part to adverse changes in peripheral vascular endothelial3 and cerebral vascular function,4 respectively (i.e., vascular aging). Regular aerobic exercise (AE) protects against vascular aging by favorably targeting several pillars of aging (i.e. inflammation, mitochondrial dysfunction, cell senescence, impaired nutrient sensing and proteostasis) and reducing oxidative stress. However, there is considerable heterogeneity in the endothelial and cerebral vascular benefits to AE in middle-age and older (MA/O) adults, including sex differences. The reason(s) for AE response variation are poorly understood but could be related to age/sex differences in the biological changes underlying vascular aging and/or the molecular transducers (i.e., circulating exerkines including endothelial microvesicles [EMVs]) that communicate and coordinate the effects of AE on the vasculature in the periphery and brain. Here, we propose a randomized controlled 12- week intervention of AE (3 d/week, 60-80% heart rate reserve, ~1 h duration) or non-exercise control in groups of young (18-39 years), middle-aged (40-59 years) and older (≥60 years) adults, balanced by sex. Outcomes to be assessed before and after the intervention include: 1) peripheral endothelial function (brachial artery flow- mediated dilation -- primary outcome), 2) cerebrovascular function (cerebrovascular reactivity to a hypercapnic stimulus -- primary outcome), and 3) biospecimens: blood and/or vascular endothelial cells assayed for transcriptomic, proteomic, metabolomic and EMVs and their cargo (e.g., micro RNA) obtained (a) before, (b) during (blood only) and (c) after acute treadmill AE (40 minutes; 60-80% VO2max) or control period. Aim 1 will determine if pre- and post-intervention molecular signatures associated with the pillars of aging are associated with age and sex differences in vascular adaptations to chronic AE training. Aim 2 will determine the influence of age and sex on the dynamic circulating molecular responses to acute and chronic AE, and their association with changes in vascular function with chronic AE. Aim 3 will determine if circulating exerkines (e.g., EMVs) are linked to changes in peripheral and cerebral vascular endothelial cell function with chronic AE, as well as the corresponding influences of age and sex, by assessing peripheral (aortic) and cerebral endothelial cell culture nitric oxide, endothelial nitric oxide synthase, and reactive oxygen species production pre-post AE or non-exercise control after serum or EMV exposure. The proposed research will advance our understanding of the molecular signals and pathways underlying the systemic and local effects of AE on endothelial and cerebral vascular function that may explain the heterogeneity in AE responses with age and sex. This knowledge will allow for the development of personalized age- and sex-specific AE recommendations, and/or provide insights into molecular targets that can be manipulated to enhance and/or mimic exercise in non- responders or in persons unable to exercise.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY / ABSTRACT Total Knee Arthroplasty (TKA) reduces pain and disability caused by knee osteoarthritis, but the surgery results in substantial trauma to the knee. This acute trauma exacerbates underlying weakness— especially in the quadriceps. Quadriceps strength decreases by 80% just days after surgery and remains 60% impaired 1 month after surgery, which leads to a decrease in patient functional performance of up to 90%. This acute strength leads to muscle atrophy, which likely contributes to the long-term weakness and disability patients with TKA experience relative to their healthy peers. Therefore, attenuating quadriceps strength loss should be a primary target for improving rehabilitation outcomes after TKA. Neuromuscular electrical stimulation (NMES) is recommended in recent TKA clinical practice guidelines to attenuate quadriceps strength loss. In controlled settings, NMES has established efficacy and attenuates quadriceps strength loss by 40% in the first month after surgery by overriding muscle activation deficits and reducing muscle atrophy. However, the effectiveness of NMES after TKA has not been adequately studied in real-world clinical settings, and our preliminary data suggests that less than 4% of rehabilitation clinicians are using NMES as recommended by current TKA practice guidelines. Therefore, we propose to conduct a cluster randomized trial in two healthcare systems (Intermountain Health and UCHealth) and their associated outpatient physical therapy clinics (n=30) to evaluate the effectiveness and implementation of NMES to address musculoskeletal deficits after TKA. We will compare outcomes between patients who receive contemporary rehabilitation supported by a comprehensive NMES implementation strategy (NMES) to patients who receive contemporary musculoskeletal rehabilitation alone (Usual Care). We will gather information on NMES implementation to promote its uptake and translation to clinical practice. This study will fundamentally change rehabilitation practice to improve function, strength, and quality of life for millions of Americans who undergo TKA each year. This investigation seeks to provide large-scale, foundational evidence that NMES is effective and can be systematically implemented into TKA rehabilitation practice. It will also evaluate and identify effective implementation tools and strategies that healthcare organizations can readily adopt and deploy to promote widescale NMES usage after TKA.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY: The leading cause of health inequities and premature death in the United States (US) is smoking. Creating equitable access to smoking cessation aids and supporting quit attempts by smokers from diverse racial and ethnic groups are top health priorities. Advancements to personalizing smoking cessation treatment based on the genetic profiles of individuals is promising but requires further scientific knowledge and research, especially in historically marginalized groups such as American Indian and Alaska Native (AIAN) peoples. Important conversations with AIAN community stakeholders about genomics and innovative community-based participatory research (CBPR) approaches have set the stage for more Indigenous-centered approaches to science. Merging these advancements to develop an Indigenous pharmacogenomics approach to smoking cessation is lacking in the field and holds promise to support innovative smoking cessation efforts through personalized treatment and culturally appropriate interventions. This project aims to leverage the promise of genome-wide and epigenome-wide association studies, which have successfully mapped thousands of loci associated with complex traits, as methods to reveal altered mechanism in nicotine metabolism and will result in a better understanding of the relationship between nicotine metabolism, smoking cessation, and corresponding tobacco-related disease and death in AI communities. Working closely with the Strong Heart Study (SHS) cohort, the longest running study of cardiovascular diseases (CVD) and its risk factors among AI communities, we will evaluate associations between genomic and epigenomic variation with nicotine metabolism, predict risk factors for smoking behavior and health outcomes, and use a CBPR approach to have conversations and develop a culturally appropriate intervention for smoking and tobacco use in AI communities. The SHS prioritizes research from American Indian investigators and the topic of nicotine metabolism and its relation to genomic/epigenomic variation and smoking cessation research is a significant area of interest. A three phased approach will be used to promote health equity and smoking cessation efficacy. The phases of this proposal are 1) to identify genetic and epigenetic influences on nicotine metabolism in AI smokers using a genome-wide and candidate resequencing approach, 2) develop genetic risk scores to examine associations with behavioral traits and comorbidities, and 3) develop a personalized approach to incorporating precision medicine as well as traditional and cultural knowledge to improve smoking cessation efficacy. Importantly, phase 3 community engagement will be continuous throughout the research proposal, with the diverse AI communities involved in the SHS contributing to study outcomes and future directions guided by these interactions. This study will provide a framework for tailoring precision medicine with cultural considerations in diverse AI communities and across other racial and ethnic minority groups to advance health equity and reduce substance use.

NIH Research Projects · FY 2026 · 2024-08

Project Summary Medicare beneficiaries with Alzheimer's Disease and Related Dementias (ADRD) typically require significant amounts of formal and informal healthcare. These treatments often lack coordination, conflict with patient and family preferences, and are costly to patients, families, and public payers. While most research has focused those in Traditional Medicare (TM), nearly half of Medicare beneficiaries are now enrolled in Medicare Advantage (MA), the managed care alternative to TM. MA plans receive flat, per-enrollee payments to incentivize efficient care and have flexibility in benefit design that enables them to offer expanded home care, concurrent palliative and curative care, and other services that may benefit complex ADRD patients. However, MA plans increasingly rely on predictive software and non-clinical care managers to make decisions about patient care, limiting plans' spending on patient care including use of these tools to deny many services that would be covered in TM. MA coverage denials may result in large bills for patients who must pay for necessary care out of pocket and/or greater reliance on help from family and friends, demands that can harm financial, physical, and mental well-being of informal caregivers. Additional spending or informal care use has the potential to further exacerbate socioeconomic disparities; out-of-pocket ADRD spending in the last 5 years of life represented 84% of wealth in Black households and 47% for those with less than a high school education. Thus, treatment decisions in MA can create intergenerational spillovers to the health and finances of patients' family members. In this grant, we study healthcare utilization and intergenerational transfers among patients who eventually develop ADRD using administrative and survey data. We ask 4 related questions to understand the impact of Medicare coverage choice on ADRD patients and their families: 1- Do ADRD patients experience more potentially preventable hospitalizations, burdensome transfers, and discharges without home care in MA vs. TM?; 2- Does MA mitigate or contribute to disparities in access to post-discharge care by race, ethnicity, or income among ADRD patients?; 3- Do intergenerational time and money transfers differ in ADRD families when the patient has MA vs. TM?; 4- Do posthumous family transfers differ in ADRD families with MA vs. TM? Wealth and housing are key social determinants of health. We may see widening disparities in subsequent generations If ADRD patients disproportionately need to rely on transfers from children in MA or TM or leave fewer resources to their children and grandchildren. With growing enrollment in MA, it is critical to understand the impacts on ADRD patients and families. Research on the value of MA has not yet considered whether MA shifts the burden of care to families, potentially imposing large and unappreciated social costs. Our team will consider these questions while working with the U54 coordinating center to meet research milestones, share code and preliminary results, and translate findings to policymakers, patients, and other stakeholders.