GENETIC ALTERATIONS ON LIPOPROTEINS AND ATHEROSCLEROSIS

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This is a renewal of a Program Project Grant whose original goal was to use genetically altered animals to understand significant aspects of lipoprotein metabolism and vascular biology. Our goals remain the same, but our objectives in lipoprotein physiology are now more tightly focused on one of the strengths of the Institute, i.e., the understanding of the physiological functions of apolipoprotein (apo-) E and apo-B. In addition, we now have a major new emphasis in vascular biology and vascular gene therapy. The research focuses on the metabolic and mechanistic consequences of the expression, modification, or deletion of key molecules on lipoprotein metabolism, intracellular metabolism, vascular wall remodeling, and atherosclerosis. The key molecules that will be investigated in lipoprotein transport and metabolism are apo-E and apo-B. In intracellular biosynthesis and catabolism of lipoprotein, these molecules include APOBEC-1 (the enzyme responsible for apo-B mRNA-editing), microsomal triglyceride transfer protein, and the low density lipoprotein receptor-related protein; and in cell and vascular wall metabolism, they are NTA1 (novel target for APOBEC-I) and transforming growth factor (31. While transgenic animals, knockout mice, and somatic gene altered animals are the main model systems, many other intact cell and cell-free model systems will be employed. In addition, a wide variety of techniques will be used, including those from the disciplines of biochemistry, molecular biology, genetics, cell biology, animal physiology, and microscopy. New technologies are shared among the projects and are provided by the Transgenic Animal Core and by the Metabolism and Pathology Core, which are heavily used by all of the projects. The successful completion of this program project will enhance the understanding of fundamental mechanisms of lipoprotein metabolism and vascular wall biology.