The major theme of this Program Project Grant is to investigate the cellular and molecular biology of lipoprotein and cholesterol metabolism and to correlate the structure and function of specific apolipoproteins (and key enzymes in lipoprotein metabolism) with the mechanisms (pathways) involved in controlling lipoprotein levels and the development of atherosclerosis. A focus is to understand the structure and function of apolipoproteins (apo-) E and B, which are the ligands responsible for regulating plasma lipoprotein-receptor interactions. To accomplish these objectives, four projects and four cores have been assembled. The research is multidisciplinary and relies on X-ray crystallography, transgenic animals, homologous recombination, cellular biology, ultrastructural biology, animal physiology, and clinical investigations. Project 1, Structural and Biochemical Analysis of Apolipoprotein E, continues analysis of the three-dimensional structure and physical biochemistry of apoE and apoE variants. Project 2, Apolipoprotein E in Cholesterol Transport and Metabolism, focuses on defining the pathway mediating chylomicron remnant metabolism and on determining how defective apo-E causes type III hyperlipoproteinemia (the genetic disorder associated with premature atherosclerosis). Project 3, Mechanistic Studies of Hypobetalipoproteinemia, explores the molecular mechanisms responsible for causing the formation of truncated apo-B and low LDL levels, using a range of approaches from homologous recombination in mice to clinical studies in affected patients. Project 4, FDB and the Receptor Binding Domain of Apo-B, is designed to elucidate the receptor binding domain of apoB100 and to determine how a single amino acid change results in LDL which is defective in receptor binding, and responsible for the genetic disorder familial Defective ApoB100. The cores: Core A, Tissue Culture: Core B, Lipoprotein and Protein Production; Core C, Molecular Biology; and Core D, Administration; provide common services for accomplishing the goals of each project.
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