Reverse translational multi-omics to identify treatment targets for atrial myopathy - Project Summary/Abstract Atrial fibrillation is the most common sustained arrhythmia and its prevalence is increasing. Accumulating evidence suggests that upstream to atrial fibrillation, structural, mechanical, or electrophysiological changes in the atria—collectively known as atrial myopathy—may be a primary mediator of heart failure, ischemic stroke, and mortality in patients with atrial fibrillation. However, the pathophysiology of atrial myopathy is incompletely understood, there are currently no targeted therapies, and treatment targets suggested by human population studies remain unvalidated experimentally. Therefore, treatment target validation and understanding the pathophysiologic mechanisms that contribute to atrial myopathy are unmet needs. This project aims to fill this gap by identifying novel treatment targets through large-scale human data analysis and by investigating the protective role of the protein DLK1 in atrial myopathy. The primary aim leverages human cohort data to identify candidate treatment targets by discovering circulating proteins and metabolites linked to both left atrial function and atrial myopathy. By combining traditional multivariable linear regression analyses with advanced genomics-based causal inference methods, we aim to prioritize promising targets for further preclinical investigation, ultimately paving the way for novel atrial myopathy therapies and improved clinical atrial fibrillation management. Because prior studies suggest DLK1 protects against fibrosis and inflammation and our preliminary data found that higher levels are associated with better left atrial function. The secondary aim of this project will investigate DLK1's role in mouse models of atrial myopathy, testing if increasing atrial DLK1 expression improves left atrial function and if decreasing atrial DLK1 expression impairs left atrial function. Aiming to become an independent physician-scientist in atrial fibrillation and atrial myopathy research and to bridge population and basic science, the applicant seeks K08 funding for protected time to solidify his skillset in characterization of cardiac fibrosis, interrogation of atrial pathophysiology, and Mendelian randomization for causal inference. This protected research time will give the applicant an opportunity to build his research program, gather preliminary data, and ultimately secure R01 funding to establish himself as an independent investigator in the cardiovascular field. The applicant has also assembled an accomplished and well-funded multidisciplinary mentoring team, comprised of internationally known experts in the fields of atrial fibrillation and atrial myopathy epidemiology, cardiomyocyte biology, cardiac fibrosis and diastolic dysfunction, and Mendelian randomization. With their support and guidance, and the research infrastructure available at University of Minnesota, the applicant is well-positioned to achieve his proposed research aims and accomplish his stated career development goals. The applicant’s clinical expertise in multi-modality cardiovascular imaging aligns perfectly with his research goals, enabling him to investigate novel biomarkers and translate research findings to improve patient care.
