Identifying Genes Regulating HDL Cholesterol Levels

描述（由申请人提供）：本研究的目的是确定调节高密度脂蛋白胆固醇（HDL-C）浓度的基因。具体而言，本研究拟鉴定小鼠HDL-C水平变化的相关基因，建立这些基因的表达与动脉粥样硬化的关系，并通过比较基因组学寻找人类的同源基因。动脉粥样硬化是一种多基因疾病，也受环境因素的强烈影响。在所有影响动脉粥样硬化的遗传和环境因素中，那些控制脂蛋白产生和代谢的因素尤为重要，HDL可能从多个方面保护动脉粥样硬化。因此，发现调节高密度脂蛋白浓度的新基因可能为预防动脉粥样硬化提供新的治疗靶点，动脉粥样硬化是工业化国家的头号杀手。最近的研究表明，从定量性状位点（QTL）中寻找基因的步伐已经加快，更重要的是，在动物模型中识别QTL基因有助于识别人类疾病相关基因，这可能对这项研究尤其正确，因为先前的研究表明，小鼠HDL-C水平的QTL可以高度预测人类的水平。本研究拟采用重叠同源的方法克隆控制HDL-C浓度的小鼠QTL基因；检测窄化QTL区域候选基因的rnRNA和蛋白表达差异；两亲本株的序列差异。利用基因靶向和转基因技术对这些基因进行验证。人类同源基因将被比较基因组学鉴定。

DESCRIPTION (provided by applicant): 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.