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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074086-04
Application #
7221999
Study Section
Metabolism Study Section (MET)
Program Officer
Srinivas, Pothur R
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$240,364
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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Su, Zhiguang; Ishimori, Naoki; Chen, Yaoyu et al. (2009) Four additional mouse crosses improve the lipid QTL landscape and identify Lipg as a QTL gene. J Lipid Res 50:2083-94
Su, Zhiguang; Cox, Allison; Shen, Yuan et al. (2009) Farp2 and Stk25 are candidate genes for the HDL cholesterol locus on mouse chromosome 1. Arterioscler Thromb Vasc Biol 29:107-13
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Su, Zhiguang; Tsaih, Shirng-wern; Szatkiewicz, Jin et al. (2008) Candidate genes for plasma triglyceride, FFA, and glucose revealed from an intercross between inbred mouse strains NZB/B1NJ and NZW/LacJ. J Lipid Res 49:1500-10
Su, Z; Korstanje, R; Tsaih, S-W et al. (2008) Candidate genes for obesity revealed from a C57BL/6J x 129S1/SvImJ intercross. Int J Obes (Lond) 32:1180-9
Chen, Yaoyu; Rollins, Jarod; Paigen, Beverly et al. (2007) Genetic and genomic insights into the molecular basis of atherosclerosis. Cell Metab 6:164-79
Rollins, Jarod; Chen, Yaoyu; Paigen, Beverly et al. (2006) In search of new targets for plasma high-density lipoprotein cholesterol levels: promise of human-mouse comparative genomics. Trends Cardiovasc Med 16:220-34

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