Tisp40在肾缺血再灌注损伤中的作用及机制研究

项目名称： Tisp40在肾缺血再灌注损伤中的作用及机制研究

项目编号： No.81470923

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： 张杰

作者单位： 武汉大学

项目金额： 73万元

中文摘要： 肾缺血再灌注（I/R）所致的肾小管损伤和异常修复伴随的间质纤维化贯穿于急、慢性肾损伤的全过程，但机制尚未完全阐明。Tisp40属于CREB/CREM家族转录因子，与细胞稳态和炎症相关。我们最近研究首次发现，敲除Tisp40可以减轻I/R所致的小鼠肾小管损伤和肾功能恶化。本项目拟从细胞、动物和分子水平阐明Tisp40在I/R所致的肾小管损伤和异常修复中的双重作用和机制：1）通过缺氧和TGFβ1刺激Tisp40基因缺失或过表达的肾小管原代细胞，研究Tisp40在肾小管损伤和修复中的作用和机制；2）通过在Tisp40基因敲除和肾小管特异性转基因小鼠建立肾I/R模型，进一步从体内研究Tisp40在肾小管坏死和异常修复所致间质纤维化中的作用和机制；3）拟通过药物或基因工程手段抑制或激活Tisp40下游关键分子以期逆转Tisp40敲除和转基因所致的表型；为急、慢性肾脏疾病的防治策略提出新思路.

中文关键词： Tisp40；凋亡；纤维化；转基因；信号通路

英文摘要： Tubular injury and abnormal repairment are predominant factors for development of renal ischemia-reperfusion injury to chronic kidney injury , but the mechanisms involved are not fully understood. Tisp40 belongs to CREB/CREM transcription factor superfamily, which are associated with cell apoptosis and inflammation. The project intends to clarify the roles of Tisp40 in tubular apoptosis and interstitial fibrosis and its underlying mechanisms after renal ischemia-reperfusion injury at cell, animal and molecular levels. The first aim: we explore the roles of Tisp40 in renal tubular apoptosis and interstitial fibrosis in vitro with primary culture of renal tubular epithelial cells treated with hypoxia/reoxygen and TGFβ1 by knowdown or expression of Tips40.the second aim: we will employ Tisp40 knocknout mice and tubular specific Tisp40 transgenic mice to study its roles in renal tubular apoptosis and abnornal repairment induced interstitial fibrosis using a renal ischemia-reperfusion injury animal model. The third aim,we will block or activate the key downstream protein of Tisp40 via drugs or genetic engineering aproaches to reverse the phenotype caused by Tisp40 knockout or overexpression and try to clearify the mechanisms involved.

英文关键词： Tisp40;apoptosis;fibrosis;Trangene;signalling pathway