肥胖与糖尿病猕猴代谢组织及其脂滴的组学研究

项目名称： 肥胖与糖尿病猕猴代谢组织及其脂滴的组学研究

项目编号： No.U1402225

项目类型： 联合基金项目

立项/批准年度： 2015

项目学科： 管理科学

项目作者： 刘平生

作者单位： 中国科学院生物物理研究所

项目金额： 222万元

中文摘要： 糖尿病是严重危害人类健康的重大慢性代谢性疾病。大量的基础和临床医学研究表明，肥胖和胰岛素抵抗是导致2型糖尿病的主要因素，而脂质的异位储存可能是直接引起胰岛素抵抗的原因。机体组织里的中性脂质储存在细胞脂滴里。研究代谢组织脂滴蛋白的变化，就能促进脂质异位储存引起胰岛素抵抗的机理研究。由于糖尿病人主要代谢组织采集困难，以及这些组织的代谢因药物使用而产生的变化，使得利用糖尿病病人组织进行脂质储存代谢研究，具有相当的难度和不确定性。因此，我们选用与人类非常接近的猕猴作为研究模式，筛选正常、2型糖尿病和肥胖病猴，采集它们组织，血液样品，从组织中纯化脂滴，进行比较蛋白组学和脂质组学分析研究，发现脂滴差异蛋白和脂质。从差异蛋白中寻找可能影响胰岛素信号的目标。用对应组织的细胞株，改变蛋白表达及脂滴定位，检测脂滴动态变化和细胞的胰岛素抵抗，然后用小鼠加以验证，找出参与脂质异位储存和引起胰岛素抵抗的关键蛋白。

中文关键词： 脂滴；2型糖尿病；猕猴；脂质代谢；蛋白质组学

英文摘要： Diabetes mellitus is a group of chronic metabolic diseases that severely affect human health. Accumulated evidence from both basic and clinical researches demonstrates that obesity and insulin resistance are the major causes of type 2 diabetes (T2D). Aberrant lipid accumulation in metabolic tissues has been directly linked to insulin resistance and metabolic syndromes. Neutral lipids are stored in a cellular organelle, lipid droplet (LD). Therefore, study of LD formation and dynamic change in metabolic tissues can facilitate the dissection of molecular mechanisms of T2D. Due to availability of T2D patients as well as uncertainty of their medication, it is almost impossible to obtain enough comparable human metabolic tissues for LD study. Thus, we decide to use monkey (Macaca) that is very closed to humans as the research model. We have collected normal, obese, and diabetic monkeys, three each. We are then going to collect their metabolic tissues, isolate LDs, analyze the LDs using proteomics and lipidomics, identify the differences between normal and obese or diabetes. Finally, we will verify these differences using cell lines and mouse model, and identify the protein(s) that are involved in the accumulation of lipids in LDs of these metabolic tissues.

英文关键词： Lipid droplets;Type 2 diabetes;Macaca;Lipid metabolism;Proteomics