TRAIL诱骗受体DcR2介导糖尿病肾病衰老肾小管上皮细胞凋亡逃逸的作用及机制

项目名称： TRAIL诱骗受体DcR2介导糖尿病肾病衰老肾小管上皮细胞凋亡逃逸的作用及机制

项目编号： No.81470962

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： 何娅妮

作者单位： 中国人民解放军第三军医大学

项目金额： 73万元

中文摘要： 细胞应激衰老是糖尿病肾病（DN）的重要病理基础，衰老细胞凋亡逃逸是其损害放大和迁延的中心环节，但机制不明。TNF相关凋亡诱导配体（TRAIL）是加速DN进展最主要致凋亡炎症因子，但我们意外地发现DN患者衰老肾小管细胞高表达其拮抗型受体DcR2，推测DcR2可能与衰老肾小管细胞凋亡逃逸有关。为此，本项目拟进一步求证DN小鼠和培养肾小管细胞TRAIL及其激动型受体和DcR2表达变化与细胞衰老和凋亡之间的关系；拮抗DcR2是否可以促进DN衰老肾小管细胞凋亡；探明DcR2介导衰老肾小管细胞凋亡逃逸的关键信号通路是否为PI3K/Akt/FoxO1; 改变信号通路关键分子活性对DN衰老肾小管细胞凋亡逃逸的影响。本项目提出并证明DN进展中衰老细胞凋亡逃逸新机制，为以清除衰老细胞治疗DN的新策略奠定理论基础.

中文关键词： 诱骗受体DcR2；肾小管上皮细胞；应激性衰老；凋亡逃逸；糖尿病肾病

英文摘要： Stress-induced senescence plays a fundamental role in the pathogenesis of diabetic nephropathy (DN), and its harmful effects could be amplified and prolonged due to the escape of senescent cell from apoptosis. Nevertheless its mechanism is unknown. It has been proven that TNF-related apoptosis-inducing ligand (TRAIL) is one of the main inflammatory cytokines accelerating the progression of DN through inducing cellular apoptosis.Howere, we unexpectly found that DcR2,the TRAIL antagonist receptor, was highly expressed on the senescent renal tubular cells.We supposed that this paradoxical phenomenon might be linked to the escape of senescent tubular cell from apoptosis. This project intends to verify the relationships between TRAIL receptors including DcR2 and celluar senescence or apotosis invivo and in vitro, and whether inhibing DcR2 could enhance the senescent cell apoptosis. Then, to explore whether PI3K/Akt/FoxO1is the key signal pathway for DcR2-mediated apoptosis escape of senescent renal tubular cells. finaly , to observe whether alteration of the key molecules of this pathway could influnce apoptosis escape of senescence cells in DN. By this project, a novel mechanism could how senescent tubular cells escaped from apoptosis, which was fundamental for the therapy based on clearance of senscent cells in DN.

英文关键词： Decoy receptor2;Renal tubular epithelial cell;Stress-induced senescence;Apoptosis escape;Diabetic nephropathy