The Role of Mia2 in Lipoprotein Biogenesis

描述（由申请人提供）：血浆胆固醇和甘油三酯与动脉粥样硬化有因果关系，动脉粥样硬化是心脏病的前兆，是工业化世界的主要杀手。因此，全面了解胆固醇和甘油三酯代谢以及血液中携带它们的脂蛋白对于对抗这种疾病和实现NIH和NHLBI的使命至关重要。一项前向基因筛查发现了一个胆固醇水平非常低（约为正常水平的25%）的小鼠家族。对突变小鼠的大小分离血浆的分析显示，两种主要小鼠脂蛋白（HDL和VLDL）的胆固醇和甘油三酯含量降低。导致这种低胆固醇表型的基因已被确定为Mia2。它是脂蛋白代谢中的一个新角色，显然

DESCRIPTION (provided by applicant): Plasma cholesterol and triglyceride are causally related to atherosclerosis, a precursor to heart disease, which is the leading killer in the industrialized world. A complete understanding of cholesterol and triglyceride metabolism and the lipoproteins that carry them in the blood is therefore essential to combat this disease and fulfill the mission of the NIH and NHLBI. A forward genetic screen has identified a family of mice with very low (~25% of normal) cholesterol levels. Analysis of size- fractionated plasma from mutant mice revealed a reduction in the cholesterol and triglyceride content of the two major mouse lipoproteins (HDL and VLDL). The gene responsible for this low cholesterol phenotype has been identified as Mia2. It is a novel player in the metabolism of lipoproteins that apparently works by dramatically reducing their secretion from the liver and/or intestine. This mouse model will be exploited to further the basic understanding of lipoprotein production. This proposal aims to answer some very basic questions as to mechanism of action. Using primary hepatocytes of mutant animals and established tissue culture cell lines, the precise step in the production of lipoproteins that is perturbed by this mutation will be investigated. Secondly, the action of this novel gene in the whole animal will be explored using newly generated tools, including a transgenic mouse line and recombinant adenovirus, which is a very versatile means of expressing foreign genes in a variety of cell lines and tissues and in live mice. These tools will then be used for several experiments, including rescue of the mutant phenotype in vitro and in vivo. Rescue is important in that it proves beyond any doubt that we have identified the mutant gene responsible for the phenotype. Lipoprotein metabolism in rescued mice and cells will then be studied for a full exploration of this novel pathway in lipoprotein production.