This application is for F30 support of Alexander Bray during his MD/PhD training. The research plan outlined in this proposal will determine the impact of mitochondrial genetics on susceptibility to atherosclerosis. Atherosclerosis is a chronic progressive disorder of the arterial wall characterized by endothelial dysfunction, accumulation of modified lipids, infiltration of inflammatory cells, and formation of atheromatous plaques. These plaques can occlude blood flow and trigger onset of cardiovascular disease, the leading cause of morbidity and mortality in the United States. Attempts to reduce the prevalence of CVD have focused on identifying individuals at risk for atherosclerosis, and employing preventative measures to impede its development. Unfortunately, the success of this healthcare strategy is limited by an inadequate understanding of the genetic determinants of CVD susceptibility. Mitochondria are sources of cellular oxidants, and vascular mitochondrial dysfunction is frequently observed in the setting of atherosclerosis. This mitochondrial dysfunction promotes cellular oxidative stress and impairs normal endothelial function, both of which are postulated as inciting events in atherogenesis. Mitochondria also possess their own genome (the mtDNA) and polymorphisms within the mtDNA (which encodes genes essential for electron transport chain and oxidative phosphorylation) have been shown to impact mitochondrial function and ROS production in mice. This proposal will test the hypothesis that these polymorphisms are also capable of influencing the progression of atherosclerosis. This will be accomplished through a novel combination of two mouse models: i) the apoE-/- mouse, a well-characterized model of hypercholesterolemia and atherogenesis, and ii) the Mitochondrial-Nuclear Exchange (MNX) mouse, developed and reported by our laboratory. MNX mice harbor the nuclear DNA from one inbred strain and the mtDNA of another. These mice will be used to: (i) Determine the impact of C57BL/6J and C3H/HeN mtDNAs on progression of atherosclerosis, (ii) Determine the influence of mtDNA background on susceptibility to hypercholesterolemia- induced vascular mitochondrial dysfunction, and (iii) Examine the impact of mtDNA background on vascular NF-kB activation and adhesion molecule expression in the setting of hypercholesterolemia. This proposal also provides a training plan for Alexander Bray, with the goal of propelling his career as a physician scientist under the mentorship Dr. Scott Ballinger (sponsor) and Dr. Louis Dell'Italia (co-sponsor).