The overall goal of this project is to develop a mechanistic understanding of the structural determinants of the function of apolipoproteins in lipid transport and metabolism, so that critical metabolic processes such as lipoprotein secretion and receptor-ligand interactions can be modeled at the molecular level. An important component of this effort is the isolation and characterization of a number of new proteins we are finding in lipoproteins that have been isolated by immunosorption under minimally denaturing conditions. These newly emerging proteins may have important roles in lipoprotein metabolism, which will only become known as their structures are elucidated and their functions explored in model systems. Detailed chemical characterization of the changes wrought in lipoproteins by oxidation, and the identification of the ligands for the scavenger and oxidized LDL receptor(s) can be expected to provide valuable insights into this important process. Furthermore, characterization of lipoproteins eluted from freshly excised human atherosclerotic plaques and from normal subintima will allow the identification of the covalent modifications that actually occur in lipoproteins in the artery wall. Understanding of normal structure-function relationships in lipoprotein metabolism and of pathological changes occurring to lipoproteins in atherosclerotic plaques may be expected to provide new venues for prevention and reversal of atherosclerosis.
