ABSTRACT Among patients with diabetes, cardiovascular diseases (CVDs) are the primary cause of their mortality. Reducing CVD risk is a critical clinical goal for treating diabetic patients. Diabetes exacerbates atherosclerosis development and progression, which is the major cause of many CVD, including heart attacks, strokes, and peripheral vascular disease. Vascular smooth muscle cell (VSMC) dysfunction contributes to the pathogenesis of atherosclerosis throughout all the stages. The genetic relationship between diabetes and CVD provides the promise for the prevention and treatment of both disorders. Recent genetic studies have demonstrated that the specific variants at the coiled-coil domain containing 92 (CCDC92) locus are associated with both type 2 diabetes (T2D) and coronary heart disease (CHD). The biological function and detailed mechanisms by which CCDC92 regulates these diseases, a necessary step towards the ultimate goal of targeting CCDC92, remain unclear. Our preliminary data demonstrated that Ccdc92 knockout inhibits high-fat diet-induced insulin resistance and atherosclerosis in mice. We further present extensive preliminary studies showing that CCDC92 induces proatherogenic phenotypes, contributing to atherosclerosis pathogenesis. Here we hypothesize that VSMC CCDC92 promotes atherosclerosis development and progression by regulating the lysosomal pathway. By taking advantage of our unique animal models combined with molecular, cellular, histological approaches, we will define the role of CCDC92 in proatherogenic phenotypes in VSMCs in vitro (Aim 1); Determine the role of CCDC92 in atherosclerosis under diabetic and euglycemic conditions in vivo (Aim 2). Successful completion of the proposed study would provide a deep understanding of how CCDC92 elicits atherosclerosis and will likely set a profound foundation to define CCDC92 as a novel therapeutic target to treat atherosclerosis and diabetes-associated CVD.