PROJECT SUMMARY Atherosclerotic cardiovascular disease, including coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide. Although existing lipid-lowering therapies can now reduce low-density lipoprotein cholesterol to very low levels, there is a significant burden of residual risk, highlighting a need for novel non-lipid therapeutic targets. Genome-wide association studies (GWAS) hold great potential for identifying novel therapeutic targets but have largely failed to deliver on this promise in part because the causal genes underlying GWAS loci are unknown. Through a large-scale genetic association study of protein-altering variation we discovered a variant in the extracellular matrix gene SVEP1 that positively associated with coronary artery disease without any effect on plasma lipids. We have now found with Mendelian Randomization that SVEP1 protein levels are causally associated with CAD in humans. To conclusively demonstrate that SVEP1 is the causal gene in this risk locus, we generated complementary mouse models of Svep1 deficiency. Our preliminary data show that SVEP1 is made by vascular smooth muscle cells (VSMCs) in the atherosclerotic plaque and that depleting SVEP1 in the arterial wall decreases the development of atherosclerosis. Based on our preliminary data, we hypothesize that VSMC-derived SVEP1 promotes atherosclerosis by activating integrin and Notch signaling to influence the behavior and fate of VSMCs in a cell- autonomous manner. In this proposal, we propose the following series of experiments to test this hypothesis: in Aim 1, we will define the cellular effects of depleting SVEP1 in the development of atherosclerosis; in Aim 2, we will define the molecular mechanisms by which SVEP1 influences VSMC phenotypes; and in Aim 3, we will determine if the pro-atherogenic and cellular effects of SVEP1 on VSMCs are dependent on binding to its partner integrin α9β1. Our investigative team has developed substantial preliminary data to support all proposed studies which are poised to reveal the mechanisms by which SVEP1 promotes atherosclerosis while providing new insights into the pathogenesis of CAD with the potential to reveal novel therapeutic approaches.