The overall goal of this grant proposal entitled Biogenesis of HDL Through Cholesterol Efflux and ApoA-I Structural Reorganization is to define a novel role for Procollagen C Proteinase Enhancer 2 (PCPE2) in the formation and function of HDL as it relates to the progression of atherosclerosis. By 2025, worldwide death due to atherosclerosis and associated complications is projected to surpass that of every major disease, including cancer, infection and trauma. The total cost of atherosclerosis-related diseases in the U.S. alone is estimated to be $286 billion annually. After statins, there is no break-through strategy in the pipeline to combat this deadly global disease. Our laboratory has studied the role of HDL apoA-I in atherosclerosis for the last 25 years and have shown, as others have, that apoA-I is an important modulator of atherosclerosis. Despite this clarity, all attempts to reduce atherosclerosis in humans by pharmacologically raising HDL levels have failed. Many believe this is a result of increasing plasma HDL concentrations without increasing or raising its functionality. Therefore, we expect to show that PCPE2 enhances HDL functionality at both the level of cholesterol efflux, as well as, its role in HDL turnover and catabolism. To do this we have crafted three specific aims. Specific Aim 1: To investigate molecular transitions of specific apoA-I helical domains responsible for promoting the biogenesis of nascent HDL (nHDL). Specific Aim 2: Delineate the role of the accessory protein, PCPE2 in nHDL assembly by examining interactions between these two proteins and to determine how this interaction affects the opening of lipid-free apoA-I. Specific Aim 3. Examine the role PCPE2 plays in mediating HDL metabolism and in the development of atherosclerosis in a newly created LDLr- /-, PCPE2-/- mouse model. At the end of the project, we expect that PCPE2 will be found to be a novel molecule mechanistically involved in increasing HDL functionality in humans providing a new strategy for combating atherosclerosis.