The research program uses pedigreed baboons to study the interaction of diet and genotype in determining phenotypes related to lipoproteins, oxidative damage, and adiposity 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 an animal model for atherosclerosis. The use of baboons enables controlled genetic and experimental manipulations designed to detect genetic effects and interactions that may be difficult to identify in humans. In addition, the mechanisms of action of these genes and their interactions with dietary components can be established experimentally. The goal is to identify individual genes that contribute to cross-sectional and longitudinal variation in phenotypes related to lipoproteins, oxidative damage, and adiposity, and to define genotype x diet interactions involved in determining these phenotypes. For this purpose, we are conducting a genome search to determine the chromosomal locations of genes that modulate the 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 risk factors of atherosclerosis and that can then be characterized in both species. Project 10 will continue genotyping baboons for a random marker genome search to find chromosomal regions that segregate with specific phenotypic variables, will identify candidate genes that lie within those regions, and will confirm the roles of two of those positional candidate genes by functional assays. Project 9 will focus on detecting and mapping genes that influence measures of lipids and lipoproteins and novel traits related to oxidative stress, as well as, genes that affect longitudinal changes in these phenotypes. Project 11 will detect and localize genes that influence adiposity, endocrine measures related to adiposity, and levels of specific gene expression in adipocytes; it also will determine the pleiotropic 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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