This research program uses the pedigreed baboon model to investigate the interactions of diet and genotype to determine variation in phenotypes related to macrovascular endothelial cell (EC) function, lipoproteins, oxidative damage, adiposity, and other risk factors for atherosclerosis. The overall goal of this program is to identify genes that contribute to variation in these phenotypes, and to define genotype * diet interactions that influence them. To achieve this goal, we will continue genome-wide scans to localize relevant genes, follow up previously detected linkage signals in order to identify the quantitative trait loci (QTLs) that are responsible for the signals, and determine the effects of a chronic high cholesterol, high fat (HCHF) dietary challenge on the expression of atherosclerotic risk factors and vascular function. Project 1 will isolate and culture ECs from biopsied femoral arteries of pedigreed baboons. These cells will be subjected to in vitro pro-atherogenic challenges. We will assess the genetics of response to these challenges by quantifying EC dysfunction markers measured before and after the cells are challenged. Project 1 also will assess the genetic control of the number of circulating endothelial progenitor cells (CEPCs);and the relationships between EC functional characteristics, number and differentiation capacity of CEPCs, and extent of atherosclerotic lesions after the HCHF challenge. Project 2 will identify and compare networks of genes underlying variation in clinical risk factors and transcriptional profiles in peripheral lymphocytes and ECs from baboons on basal diet with those following the chronic dietary challenge. Project 3 will focus on identifying genes for QTLs influencing phenotypes related to dyslipidemia, oxidative damage and hypertension using chromosomal region specific gene expression profiling, positional cloning, statistical genomic analysis and whole genome expression profiling. Project 4 will detect and localize genes that influence adiposity and adipokine expression, and will evaluate the effects of the HCHF challenge on adipose tissue and muscle and their relationships to risk of atherosclerosis. The research projects are supported by four core units that provide phenotyping, data management and computing, veterinary services, and administrative services. The 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 or impossible to identify in humans. In addition, the mechanisms of action of these genes and their interactions with dietary components can be established experimentally. This research will lead to a better understanding of the genes that control susceptibility to atherosclerosis and how they interact with dietary factors to determine individual susceptibility to this disease.
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