During the last 5 years, remarkable progress has been made in understanding the molecular machinery of lipid metabolism in health and disease. This progress provides the tools to now identify genetic factors which influence the development of atherosclerosis and the molecular mechanisms by which this influence is exerted. Using a multidisciplinary approach, we will not focus on a wide variety of candidate genes which play roles in lipid transport, including structural genes coding for the apo lipoproteins and the enzymes, and the regulatory genes which determine plasma lipid levels and response to dietary challenge. Fundamental information essential for understanding molecular mechanisms will be provided by a detailed molecular, genetic and physiologic characterization of tow enzymes which play key roles in lipid transport catabolism, lipoprotein lipase and hepatic lipase. Both enzymes were successfully cloned during the previous grant period. Also we will continue efforts to understand at a fundamental level how apo lipoprotein B is related to the packaging of triglycerides to form the VLDL and chylomicrons. Project I will focus on the genetic polymorphism of human apo B, attempting to classify the various human allotypes, to examine how these affect lipid metabolism, and to construct a comprehensive model. Projects II and VI will explore the structure, function and regulation of lipoprotein lipase and hepatic lipase. Project III will employ the mouse model to identify genes regulating plasma lipid levels and their response to dietary challenge, while Project IV will attempt to identify the corresponding human genes, and their actual involvement in human atherosclerosis. Project IV will focus on molecular mechanisms, especially those involving apo B, utilized in the formation of the triglyceride-rich lipoproteins. The researchers involved in this program provide the necessary expertise in molecular biology, human and mouse genetics, molecular genetics, immunochemistry, biochemistry, biophysics, enzymology, molecular physiology and medicine.