This program uses pedigreed baboons to study the interaction of diet and genotype in determining lipoprotein and adiposity-related phenotype as risk factors for atherosclerosis. The high degree of physiological similarity and the close phylogenetic relationship between baboons and humans make the baboon well suited as a animal model for atherosclerosis. The high degree of physiological similarity and the close phylogenetic relationships between baboons and humans makes the baboon well suited as an animal model for atherosclerosis. The baboon model enables controlled genetic and experimental manipulations designed to detect genetic effects and interactions that may be difficult to identify in humans. The mechanisms of action of genes identified in the baboon model can be established experimentally. The overall goal is to conduct a genome search to identify individual genes that contribute to variation in lipoprotein and adiposity-related phenotypes and to define genotype-diet interactions involved in determining lipoprotein and adiposity-related phenotypes and to define genotype-diet interactions involved in determining lipoprotein and adiposity-related phenotypes. Initially, we will determine the chromosomal locations of genes the modulate the cholesterolemic responses to dietary cholesterol and/or dietary saturated fatty acids and of genes that modulate adiposity-related phenotypes. Because most baboon and human genes are arranged in the same linear order, the localization of a gene in baboons may implicate one or more defined human genes as candidates. When observed effects cannot be attributed to known candidate genes in humans, results from baboons will lead to identification of new genes that affect phenotypes related to atherosclerosis and that can then be characterized in baboons as well as humans. During the proposed project period, all matings will be arranged to produce inbred progeny so that lipoprotein and adiposity-related phenotypes can be analyzed with respect to chromosomal regions that are identical by descent. Phenotypic and genetic marker data from these inbred families, as well as data currently being collected from non-inbred families will be subjected to statistical genetic analyses. Dr. Hixson's project will conduct a random marker genome search, continue seeking linkages of candidate genes with specific phenotypic variables, and continue molecular analyses of apo(a) as a paradigm for gene structure and function analyses. The next project will focus on localizing the major genes already detected for lipoprotein phenotypes, detecting and localizing new genes that affect lipoprotein phenotypes, and identifying pleitropic effects. The last project will detect and localize loci that influence adiposity, endocrine measures related to adiposity, and levels of specific gene expression in adipocytes; it also will determine the pleitropic effects of those genes on lipoprotein phenotypes. The research projects are supported by core units comprising a lipid and lipoprotein biochemistry laboratory, data management and computing, veterinary services, and administration.
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