毒素蓄积诱导慢性肾脏病胰岛素抵抗的分子机制研究

项目名称： 毒素蓄积诱导慢性肾脏病胰岛素抵抗的分子机制研究

项目编号： No.81471027

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： 魏日胞

作者单位： 中国人民解放军总医院

项目金额： 73万元

中文摘要： 慢性肾衰患者毒素蓄积会诱发胰岛素抵抗，氧化应激可能在其中起重要作用，但具体机制不明。本研究分为三部分，第一部分体内研究：建立5/6肾切除大鼠慢性肾衰模型，通过对各组大鼠肾功能及尿蛋白检查、肾脏及胰腺病理检查、糖代谢相关检查、胰岛素信号通路相关检查和氧化应激水平检查明确慢性肾衰胰岛素抵抗的发生机制以及缬沙坦和普罗布考缓解慢性肾衰胰岛素抵抗的作用效应和分子机制。第二部分体外研究：建立尿素诱导骨骼肌细胞胰岛素抵抗模型，观察各组细胞糖代谢、胰岛素信号通路及氧化应激水平的改变，明确尿素诱导骨骼肌胰岛素抵抗的机制以及在这一过程中氧化应激的作用。第三部分：利用蛋白组学、生物信息学、RNAi、免疫共沉淀和免疫印迹技术筛选并验证与慢性肾衰胰岛素抵抗新的分子标志物。研究结果将为今后临床干预慢性肾衰患者胰岛素抵抗提供理论依据和实验数据支持。

中文关键词： 慢性肾脏病；胰岛素抵抗；氧化应激；分子机制

英文摘要： The accumulation of toxins in patients with chronic renal failure induced insulin resistance, oxidative stress may play an important role in these, but the specific mechanism is unknown. This study contains three parts, the first part is the in vivo experiments: establish the 5/6 nephrectomized model of rats, and the parameters of renal function, urinary protein, renal and pancreatic pathology, glucose metabolism, insulin signaling pathway and oxidative stress would be collected to clarify the mechanism of insulin resistance in chronic renal failure, and also the effects and molecular mechanism of valsartan and probucol. The second part is the in vitro experiments: the model of insulin resistance induced by urea in skeletal muscle cells would be established, the parameters of glucose metabolism, insulin signaling pathway and oxidative stress would be collected to clear the mechanism of urea induced insulin resistance of skeletal muscle, and also the role of oxidative stress in the process. The third part: use of proteomics, bioinformatics, RNAi, immunoprecipitation and immunoblotting techniques to find and validate the new biomarkers for the chronic renal failure patients with insulin resistance. The results of this research will provide a theoretical basis and experimental data for the future clinical intervention of insulin resistance in patients with chronic renal failure.

英文关键词： chronic kidney disease;insulin resistance;oxidative stress;molecular mechanism