This research program will use pedigreed, selectively bred baboons (Papio sp.) to study the interaction of diet and genotype in the etiology and pathogenesis of dyslipoproteinemia and experimental atherosclerosis. Project 1-A will examine the roles of triglyceride-rich postprandial plasma lipoproteins, apoprotein polymorphisms, and blood-pressure related variables in experimental atherosclerosis. Project 1-B will study the mechanism of genetic regulation of plasma low density lipoprotein (LDL) levels by methods of physiology and molecular biology; it will focus initially on the role of the hepatic LDL receptor in mediating genetic control. Project 2 will develop stable lines on oncogene-transformed hepatocytes from the livers of pedigreed baboons with genetic dyslipoproteinemias; and the cultured hepatocytes will be used to study lipoprotein metabolism. Project 3 will examine pedigreed dyslipoproteinemic baboons for variants in apolpoproteins and in the LDL receptor by restriction fragment length polymorphisms, allotypes of apoprotein B, and apolipoprotein distributions among major lipoprotein classes. Project 4 will use complex segregation analysis and related statistical genetic techniques to detect major genes contributing to dyslipoproteinemic phenotypes in pedigreed baboons. Project 5 will use genetic markers and linkage analysis to assign major genes responsible for dyslipoproteinemic phenotypes to specific linkage groups. Project 6 will attempt to identify mechanisms by which breast and formula feeding in infancy differentially affect lipoprotein and cholesterol metabolism in adulthood. Project 7 will examine the mechanisms by which overfeeding baboons in the preweaning period produces obesity in adulthood. A colony of about 120 male and female baboon breeders, the results of about 10 years of selective breeding based on their lipoprotein phenotypes, are mated either to test genetic hypotheses or to produced phenotypically extreme offspring. The research projects are supported by core laboratories for lipid and lipoprotein biochemistry, monoclonal antibodies, molecular biology, biometry, veterinary services, and administration.
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