ABSTRACT Coronary artery disease (CAD) remains the leading cause of death in the U.S. and worldwide. Identifying genetic risk factors and uncovering the underlying biological processes will lead to the development of much needed new avenues for therapies. Decades of genetics research, especially genome wide association studies (GWAS), have led to the discovery of numerous genetic loci associated with an increased risk for CAD. However, the majority of these loci lie in non-protein-coding regions. Efforts are needed to identify causal genes associated with these loci and the underlying cellular processes and signaling pathways. Recent advances in epigenomic and transcriptomic profiling at unprecedented depth and resolution, along with targeted genome/epigenome editing provide new opportunities to identify specific genes and cellular mechanisms in CAD. This K08 career development award is designed to launch the principal investigator’s career as an independent physician scientist that utilizes complementary computational and molecular approaches to discover the mechanisms that underlies human genetic risk to cardiovascular disease and translates these findings into treatment. The principal investigator ‘s Mentor (Thomas Quertermous) is a world leader in mechanistic studies of genetic risk of atherosclerosis. The proposed training is further supplemented by an advisory committee of leaders in computational biology, genetics, and single-cell multi-omic analysis, including Michael Snyder, Erik Ingelsson, William Greenleef, and Siddhartha Jaiswal, along with formal didactic courses at Stanford University and Cold Spring Harbor. Funded by an F32, the principle investigator used a combination of in vitro and in vivo models of atherosclerosis and linked the non-coding CAD risk loci at 2q22 to ZEB2, a transcriptional repressor with a critical role in cell-state transitions. ZEB2 appears to be specifically up-regulated in phenotypically modulated smooth muscle cells (SMC) in atherosclerotic lesions, and modulates their cell-fate decisions. The proposed study will: (1) identify the causal regulatory element(s) responsible for the CAD-Risk-associated region at 2q22; (2) reveal the molecular mechanisms by which ZEB2 affects phenotypic modulation of SMC; (3) determine the cellular mechanism by which perturbation of smooth muscle cell Zeb2 expression modulates atherosclerotic lesions in vivo. The result of this study will elucidate new regulatory mechanisms that modulate atherosclerosis biology. Additionally, the principle investigator will gain the training needed to transition into an independent physician scientist focusing on translating genetic findings of human cardiovascular disease into specific mechanisms and novel therapies.