Project Summary The purpose of this five-year proposal is to provide a personalized interdisciplinary training program which will facilitate the applicant's successful transition into an independent career in academic cardiovascular disease (CVD) research. The knowledge and skills imparted by this project will be vital for the applicant to pursue his long-term research goal of identifying and characterizing novel genetic determinants of CVD, and ultimately translating these findings from bench to bedside. In this regard, the proposed application will meet key objectives of 1. Acquiring expertise in human genetics, biostatistics, genome-editing and in mouse models of atherosclerosis; 2. Enhancing the applicant's knowledge base, professional development and grant writing skills. Under the guidance of an Advisory Committee composed of internationally recognized experts in genomics, vascular biology, biostatistics and translational research, the applicant will receive the guidance and resources necessary to accomplish these goals and efficiently transition to independence. Nearly 50% of one's lifetime risk of acquiring cardiovascular disease (CVD) is genetic in nature. A recent meta-analytical GWAS study conducted by members of the applicant's Advisory Committee identified a novel genetic variant within the intron of Leiomodin1 (LMOD1), a smooth muscle cell restricted gene which coincidentally was described by the applicant while a graduate student. Although, this new finding suggests that LMOD1 may be responsible for a portion of CVD risk, the mechanism by which this polymorphism leads to CVD remains to be identified. Thus, in this proposal the applicant will elucidate the role of this variant in CVD. During the mentored (K99) phase of this proposal, the applicant will acquire new skills in advanced human genetics and biostatistics to unequivocally confirm that carriers of the risk allele have reduced LMOD1 expression in the diseased vessel. During the independent (R00) phase of this project, the applicant will build on strong preliminary data and employ advanced molecular biology techniques including luciferase reporter, gel shift and chromatin immunoprecipitation assays to determine the molecular mechanism responsible for reduced LMOD1 expression in cells treated with PDGF-BB. Lastly, the applicant will determine how this reduced LMOD1 expression regulates atherogenesis in mouse models of human disease through the implementation of advanced surgical and genome editing techniques. Taken together, this work will enhance the scientific community's understanding of the heritable component of CVD, and moreover provide a foundation of a lifelong career in CVD research for the applicant. The proposed work is relevant to the mission of the NIH as it will lead to the development of new therapies for patients suffering from pathological conditions such as heart attack and stroke.