Genetic and Genomic Analysis of apoAV

描述（由申请人提供）：基于人/小鼠比较序列分析，我们已经确定了11号染色体载脂蛋白（apoAI, apoCIII, apoAIV）基因簇的第四个成员，我们将其命名为载脂蛋白AV （apoAV）。我们最近对人类和小鼠的研究表明，apoAV是血浆甘油三酯水平的重要决定因素。在小鼠实验中，人类apoAV转基因基因的过度表达导致血浆甘油三酯浓度降低，而小鼠apoAV基因的失活导致甘油三酯水平升高。与这些小鼠研究结果相辅相成的是，三项独立的人类研究一致表明，两种次要的载脂蛋白单倍型与甘油三酯升高密切相关。这些初步研究表明，新发现的载脂蛋白基因apoAV是哺乳动物血浆甘油三酯水平的重要调节剂。因此，该授权侧重于破译apoAV的几个基本特性，包括：1)利用apoAV转基因和敲除小鼠确定apoAV影响血浆甘油三酯及其致动脉粥样硬化后果的机制，2)研究参与apoAV表达调控的因素和DNA序列，以及3)结合人类单倍型研究和小鼠基因组的定义操作来鉴定直接参与决定人类甘油三酯水平的apoAV单核苷酸多态性（snp）。

DESCRIPTION (provided by applicant): Based on human/mouse comparative sequence analysis we have identified a fourth member of the chromosome 11 apolipoprotein (apoAI, apoCIII, apoAIV) gene cluster which we have named apolipoprotein AV (apoAV). Our recent studies in humans and mice indicate that apoAV is an important determinant of plasma triglyceride levels. In mice, the overexpression of a human apoAV transgene resulted in decreased plasma triglyceride concentrations, while inactivation of the mouse apoAV gene led to increased triglyceride levels. Complementing these mouse findings, three independent human studies consistently showed that two minor apoAV haplotypes are strongly associated with increased triglycerides. These initial investigations indicate that the newly discovered apolipoprotein gene, apoAV, is an important modulator of plasma triglyceride levels in mammals. Accordingly, this grant focuses on deciphering several fundamental properties of apoAV that include: 1) determining the mechanism by which apoAV affects plasma triglycerides and its atherogenic consequences using apoAV transgenic and knockout mice, 2) investigating the factors and DNA sequences involved in the regulation of apoAV expression and 3) using a combination of human haplotype studies and defined manipulations of the mouse genome to identify apoAV single nucleotide polymorphisms (SNPs) that directly participate in determining triglyceride levels in humans.