Single-cell, multi-omic investigation of epicardial adipose and coronary endothelial dysfunction in type 1 diabetes

Abstract Cardiovascular disease (CVD) is the leading cause of mortality in patients with Type 1 Diabetes (T1D), driven by complex pathophysiological dysfunctions that remain poorly understood at the cellular and molecular level. Epicardial fat accumulation and dysfunction have recently emerged as significant contributors to coronary artery disease (CAD) in T1D, potentially by inducing coronary artery endothelial dysfunction through pro-inflammatory adipocytokine secretion. This project utilizes the CARE-T1D consortium tissue bank to investigate the cellular and molecular dysfunctions in epicardial fat and coronary vasculature in T1D. Specifically, we hypothesize that T1D induces dysfunction in epicardial adipocytes, causing the release of inflammatory adipocytokines that traffic to coronary endothelial cells disrupting their function. We propose to: 1) Comprehensively identify T1D-specific cell states and regulators in epicardial fat and coronary arteries by performing single cell epigenetic and RNA profiling on CARE-T1D flash-frozen samples. 2) Genetically program “induced” T1D adipocytes in vitro to functionally characterize diabetes-specific adipocyte cellular responses and identify dysregulated adipocytokines. 3) Integrate CARE-T1D coronary vascular profiles with functional genomic perturbations in endothelial cells to define molecular mechanisms of T1D-specific endothelial dysfunction and test identified adipocytokines on endothelial functions such as angiogenesis, adhesion and migration. This research promises to elucidate the cellular mechanisms of CVD in T1D, offering insights into novel therapeutic targets and a genomic atlas of single cell resolution data for future investigation.