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(高密度脂蛋白)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。识别参与调节高密度脂蛋白的基因可能会揭示一些新的基因，并为未来疗法的发展铺平道路。杰克逊实验室的ENU突变计划已经确定了16只突变小鼠的优秀集合，这些小鼠都是C57BL/6背景下的，具有升高的高密度脂蛋白。这些都是了解高密度脂蛋白调节和发现新基因的极好资源。已经为这16只不同的突变小鼠建立了各自的菌株。我们现在建议鉴定这16个高密度脂蛋白菌株的突变，目标如下：1.将所有16个高密度脂蛋白突变定位到一个粗略的染色体位置；2.确定基因和原因突变；3.测试每个突变体，以确定高密度脂蛋白是否能保护动脉粥样硬化的易感性。数量性状的ENU突变定位是复杂的，因为数量性状基因座(QTL)的存在是由突变菌株和用于定位杂交的菌株之间的感兴趣表型的自然多态引起的。我们设计了在ENU突变定位中避免这一问题的策略，首先与一个关系密切的菌株杂交，该菌株将具有很少的多态，因此与C57BL/6的QTL很少。当突变的染色体位置已知时，通过与染色体替代菌株杂交进行精细定位，该替代菌株将具有相同的C57BL/6背景，并且只在感兴趣的染色体上有所不同。这一策略应该可以让我们成功地定位和识别这些高密度脂蛋白突变体。 与公共健康相关：这些研究中将识别和表征的基因将使我们更好地了解高密度脂蛋白胆固醇水平的调节。通过识别新基因而发现的生物途径应该会导致预防和治疗心脏病的新的治疗目标。

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.