Identifying Genes Regulating HDL Cholesterol Levels

描述（由申请人提供）：本研究的目的是鉴定调节高密度脂蛋白胆固醇（HDL-C）浓度的基因。具体而言，本研究拟通过比较基因组学的方法鉴定小鼠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之间的关系，并寻找人类同源基因。 动脉粥样硬化是一种多基因疾病，也受到环境因素的强烈影响。在影响动脉粥样硬化的所有遗传和环境因素中，那些控制脂蛋白产生和代谢的因素尤为重要，HDL可能以多种方式保护动脉粥样硬化。因此，发现调节HDL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，从数量性状基因座（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的疾病相关基因，这可能对本研究尤其如此，因为先前的研究表明，小鼠HDL-C水平的QTL对人类具有高度预测性。本研究拟通过重叠同源系的方法从控制HDL-C浓度的小鼠QTL中克隆基因;检测缩小的QTL区域中的候选基因的mRNA和蛋白质表达差异;以及两个亲本品系之间的序列差异。这些基因将通过基因打靶和转基因技术得到验证。人类同源基因将通过比较基因组学鉴定。

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.