Mapping Gene Mutations That Alter HDL Cholesterol Levels in Mice

描述（由申请人提供）：血浆高密度脂蛋白胆固醇（HDL）水平升高可预防心血管疾病，心血管疾病是美国死亡的主要原因。确定参与HDL调节的基因可能会揭示一些新的基因，并为未来治疗的发展铺平道路。Jackson实验室的ENU诱变项目已经确定了16只具有C57BL/6背景的突变小鼠，它们的HDL水平升高。这些是了解HDL调节和发现新基因的重要资源。已经为这16种不同的突变小鼠建立了菌株。我们现在建议确定这16株HDL升高菌株的突变，并有以下目的：将所有16个HDL突变映射到粗染色体位置，2。2 .确定基因和致病突变；检测每个突变体以确定升高的HDL是否对动脉粥样硬化易感性有保护作用。数量性状的ENU突变定位是复杂的，因为在突变菌株和用于定位杂交的菌株之间存在由感兴趣表型的自然多态性引起的数量性状位点（QTL）。为了避免这一问题，我们设计了一些策略，首先将其杂交到一个与C57BL/6密切相关的菌株，该菌株将具有很少的多态性，因此与C57BL/6的QTL很少。当突变体的染色体位置已知时，通过与染色体替代菌株的杂交进行精细定位，该菌株将具有相同的C57BL/6背景，仅在感兴趣的染色体上有所不同。这种策略应该使我们能够成功地绘制和识别这些HDL突变体。

DESCRIPTION (provided by applicant): Elevated levels of plasma high-density lipoprotein cholesterol (HDL) protect against cardiovascular disease, which is the leading cause of death in the United States. Identifying the genes involved in the regulation of HDL may reveal some novel genes and pave the way for the development of future therapies. The Jackson Laboratory's ENU mutagenesis program has identified an excellent collection of 16 mutant mice, all in the C57BL/6 background, that have elevated HDL. These are a great resource for understanding HDL regulation and for discovering novel genes. Strains have already been established for each of these 16 different mutant mice. We now propose to identify the mutations underlying these 16 strains with elevated HDL and have the following aims: 1. Map all 16 HDL mutations to a coarse chromosomal position, 2. Identify the gene and the causal mutation, and 3. Test each mutant to determine whether the elevated HDL protects against atherosclerosis susceptibility. Mapping ENU mutations for quantitative traits is complicated because of the presence of quantitative trait loci (QTL) caused by natural polymorphisms for the phenotype of interest between the mutated strain and the strain used for the mapping crosses. We have designed strategies to avoid this problem in ENU mutant mapping by first crossing to a closely related strain, which will have few polymorphisms and thus few QTL with C57BL/6. When the chromosomal location of a mutant is known, fine mapping is carried out with a cross to a chromosomal substitution strain, which will have the same C57BL/6 background and differ only in the chromosome of interest. This strategy should allow us to successfully map and identify these HDL mutants. PUBLIC HEALTH RELEVANCE: The genes that will be identified and characterized in these studies will give us a better understanding of the regulation of HDL cholesterol levels. The biological pathways that will be uncovered by identifying novel genes should lead to new therapeutic targets for preventing and treating heart disease.