The objective of this research is to identify the genes that regulate high-density lipoprotein cholesterol (HDL-C) concentrations. Specifically, this research proposes to identify genes responsible for the variation of HDL-C levels in mice, establish the relationship between the expression of these genes and atherosclerosis, and find the human homologue genes via comparative genomics. Atherosclerosis is a multigenic disease that is also strongly affected by environmental factors. Of all the genetic and environmental factors affecting atherosclerosis, those controlling lipoprotein production and metabolism are especially important, and HDL may protect against atherosclerosis in multiple ways. Thus finding novel genes that regulate HDL concentrations may provide new therapeutic targets in preventing atherosclerosis, the number 1 killer in industrialized nations. As recent studies show, the pace of finding genes from quantitative trait loci (QTL) has been accelerated, and more importantly, identifying QTL genes in animal models helps identify disease-responsible genes in humans, which might be especially true for this study because previous studies show that mouse QTL for HDL-C levels are highly predictive of the human ones. This study proposes to clone the genes from the mouse QTL controlling HDL-C concentrations by means of overlapping congenics; test the candidate genes in the narrowed QTL regions for their rnRNA and protein expression differences; and sequence differences between the two parental strains. The genes will be proved with the techniques of gene targeting and transgenics. Human homologue genes will be identified by comparative genomics. ? ?
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