The Role of Mia2 in Lipoprotein Biogenesis

Mia2 在脂蛋白生物发生中的作用

基本信息

批准号：
8445830
负责人：
William Edward Balch
金额：
$ 27.06万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8445830
关键词：
Adenoviruses Affect Alternative Splicing Animals Apolipoproteins Arterial Fatty Streak Atherosclerosis Biogenesis Blood Blood Vessels Capsid Proteins Cardiac Cardiovascular Diseases Cell Line Cells Cholesterol Cholesterol Homeostasis Co-Immunoprecipitations Disease Drosophila genus Ethylnitrosourea Family Gene Family Gene Transfer Techniques Genes Genetic Genetic Models Genetic Screening Golgi Apparatus Grant Heart Diseases Hepatocyte High Density Lipoproteins Homologous Gene In Vitro Intestines Investigation Label Life Lipids Lipoproteins Liver Mass Spectrum Analysis Measurement Measures Mediating Metabolism Methods Mission Mus Mutant Strains Mice Mutation National Heart, Lung, and Blood Institute Pathway interactions Phenotype Physiologic pulse Plasma Process Production Proteins Recombinants Role Site Small Intestines Structure Structure-Activity Relationship System Testing Tissues Transcript Transgenic Mice Travel Triglyceride Metabolism Triglycerides Uncertainty United States National Institutes of Health Very low density lipoprotein Vesicle Wild Type Mouse Work base combat in vivo member mouse model mutant novel prevent promoter public health relevance research study tissue culture tool

项目摘要

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.

描述（由申请人提供）：血浆胆固醇和甘油三酸酯与动脉粥样硬化有因果关系，动脉粥样硬化是心脏病的先驱，这是工业化世界中的主要杀手。因此，完全了解胆固醇和甘油三酸酯的代谢以及将它们携带在血液中的脂蛋白对于对抗这种疾病并履行NIH和NHLBI的使命至关重要。正向遗传筛选已经确定了一个非常低（约25％正常）胆固醇水平的小鼠家族。分析突变小鼠的大小分级血浆表明，两种主要小鼠脂蛋白（HDL和VLDL）的胆固醇和甘油三酸酯含量降低。负责这种低胆固醇表型的基因已被确定为MIA2。它是脂蛋白代谢的新颖玩家通过大大减少肝脏和/或肠的分泌作品。该小鼠模型将被利用，以进一步了解脂蛋白的产生。该建议旨在回答有关行动机制的一些非常基本的问题。使用突变动物的原发性肝细胞和已建立的组织培养细胞系，将研究脂蛋白的生产的确切步骤，该突变受到这种突变的干扰。其次，将使用新生成的工具（包括转基因小鼠系和重组腺病毒）来探索这种新型基因在整个动物中的作用，这是在多种细胞系和组织以及活小鼠中表达异物基因的一种非常通用的手段。然后，这些工具将用于多个实验，包括在体外和体内营救突变表型。救援很重要，因为它毫无疑问地证明了我们已经确定了负责表型的突变基因。然后，将研究救出的小鼠中的脂蛋白代谢，然后研究细胞，以充分探索脂蛋白生产中这种新型途径。