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，心血管疾病是美国的主要死亡原因。确定参与HDL调控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。杰克逊实验室的ENU诱变程序已经鉴定了16只突变小鼠的优秀集合，它们都在C57 BL/6背景中，具有升高的HDL。这些是了解HDL调节和发现新基因的重要资源。已经为这16种不同的突变小鼠中的每一种建立了品系。我们现在提出鉴定这16种HDL升高菌株的突变，并具有以下目标：1.将所有16个HDL突变映射到粗略的染色体位置，2.识别基因和致病突变，3。测试每一个突变体，以确定是否高密度脂蛋白对动脉粥样硬化的易感性保护。数量性状的ENU突变作图是复杂的，因为在突变菌株和用于作图杂交的菌株之间存在由感兴趣的表型的天然多态性引起的数量性状基因座（QTL）。我们已经设计了策略，以避免这个问题，ENU突变体作图的第一个交叉密切相关的菌株，这将有很少的多态性，因此很少QTL与C57 BL/6。当突变体的染色体位置已知时，用与染色体置换菌株的杂交进行精细作图，所述染色体置换菌株将具有相同的C57 BL/6背景并且仅在感兴趣的染色体上不同。这种策略应该使我们能够成功地映射和识别这些HDL突变体。 公共卫生相关性：在这些研究中确定和表征的基因将使我们更好地了解HDL胆固醇水平的调节。通过识别新基因发现的生物学途径应该会导致预防和治疗心脏病的新治疗靶点。

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.