与人类脂代谢紊乱高度相似的基因工程仓鼠模型的构建

项目名称： 与人类脂代谢紊乱高度相似的基因工程仓鼠模型的构建

项目编号： No.81470555

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘国庆

作者单位： 北京大学

项目金额： 170万元

中文摘要： 基因工程小鼠是当前用于脂代谢研究的主要模式动物，但其脂代谢与人类有很大的差异。仓鼠则与人类脂代谢高度相似，曾广泛应用于相关研究。由于存在技术瓶颈，国内外以往没有关于基因工程仓鼠的报道，由此限制了仓鼠的充分利用。申请人近年来成功构建了多种基因工程小鼠、家兔和小型猪脂代谢紊乱模型；并根据过去应用仓鼠进行脂代谢研究所积累的经验，开展了构建基因工程仓鼠的探索工作。在研发出专利技术，解决了仓鼠受精卵发育阻滞这一特殊难题后，应用透明带下显微注射慢病毒方法，构建成功了GFP转基因仓鼠品系。论文发表于Cell Res后，在国际上引起了强烈反响。在此突破的基础上，本课题拟构建ApoC3和PCSK9转基因仓鼠，以获得高胆固醇和高甘油三酯血症两种与人类最常见的脂代谢紊乱高度相似的基因工程仓鼠品系；并通过系统的表型分析，明确其脂代谢紊乱和动脉硬化发病特点，开创和引领一个应用基因工程仓鼠研究代谢性心血管病的新领域。

中文关键词： 疾病模式动物；仓鼠；高脂血症；心血管病；动脉粥样硬化

英文摘要： Genetically engineered mice are currently the choice of model animals for studies on lipid metabolism. However, the differences in lipid metabolism between mice and humans are enormous. Hamsters, on the other hand, are highly similar to human in lipid metabolism and have been widely used in related research. Due to technical difficulties, no genetic engineered hamsters have been reported in the literatures thus far, limiting the full use of hamsters. In recent years, we have generated several types of genetically engineered mice, rabbits and miniature swine models of lipid metabolism. We have also accumulated extensive experiences in past years using hamsters for studies on lipid metabolism. Therefore, we sought to work on creating genetically engineered hamstersto fully capitalize this unique useful animal model. After perfecting a patented technology to solve the major problem, the blockade of fertilized egg division, we developed a specific procedure for hamster superovulation, fertilized egg harvesting, perivitelline space microinjection and embryo transfer. By using lentiviral vector carrying green fluorescence protein (GFP) gene transgenic hamsters overexpressing GFP were successfully generated and the work was published in highly reputable journal Cell Research.Based on this breakthrough in transgenic hamster technology we proposed to generate ApoC3 and PCSK9 transgenic hamsters to develop 2 models for hypercholesterolemia and hypertriglyceridemia, the 2 types of the most common disorders in human lipid metabolism. These 2 genetically engineered hamsters will be fully characterized through the systemic phenotypic analysis and theirmajor characteristics in lipid metabolism and atherosclerosis will be identified. The results of proposed study would therefore open and lead a new research field of genetically engineered hamsters as disease models for metabolic cardiovascular research.

英文关键词： human disease model;golden hamster;hyperlipidemia;cardiovascular disease;atheroscelrosis