SIRT1对IGF-1诱导的肠上皮细胞间质转化的作用机制及其在肠纤维化中的意义

项目名称： SIRT1对IGF-1诱导的肠上皮细胞间质转化的作用机制及其在肠纤维化中的意义

项目编号： No.81500426

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 李平

作者单位： 南京医科大学

项目金额： 18万元

中文摘要： 肠纤维化是克罗恩病（CD）严重并发症之一。文献提示：上皮间质转化（EMT）是肠纤维化中成纤维细胞的重要来源；胰岛素样生长因子1（IGF-1）是肠纤维化中重要的生长因子；Ⅲ型组蛋白去乙酰化酶SIRT1在肾纤维化中具有抗EMT作用，其激动剂白藜芦醇（RSV）具有抗肠纤维化作用，但其确切机制尚不清楚。我们前期研究发现：IGF-1可通过IGF-1R/MAPK/ERK通路诱导肠上皮细胞EMT，RSV可阻断IGF-1对肠上皮细胞中E-cadherin的下调作用。本课题拟：通过细胞实验和结肠炎动物模型，探讨SIRT1对IGF-1介导的肠上皮细胞EMT的作用及机制，在肠上皮细胞SIRT1特异性敲除小鼠中研究SIRT1对肠纤维化的保护作用，为CD肠纤维化的防治和干预提供新的方法和研究思路。

中文关键词： 肠纤维化；上皮间质转化；胰岛素样生长因子1；SIRT1

英文摘要： Intestinal fibrosis is a serious complication of Crohn's disease for which there is no effective treatment. Latest research has confirmed that intestinal epithelial mesenchymal transition (EMT) is a key process influencing intestinal fibrosis. Insulin-like growth factor 1 (IGF-1) is a potent profibrogenic agent involved in intestinal fibrosis. Many studies have shown that type III histone deacetylase SIRT1 reduces EMT in kidney fibrosis, and that the SIRT1 activator resveratrol (RSV) has antifibrotic effects in cultured cells and colitis animal models. However, the effect of RSV on EMT in intestinal epithelial cells has not been reported. Our preliminary data show that IGF-1 induces EMT in intestinal epithelial cells through IGF-1R/MAPK/ERK pathway, and that RSV could restore the expression of E-cadherin inhibited by IGF-1. The present study aims to further explore the mechanism whereby SIRT1 regulates EMT in intestinal epithelial cells induced by IGF-1. We also will examine its relevance in intestinal fibrosis by using intestinal epithelial-specific SIRT1 knockout mice. This study may provide novel insight to prevention and intervention strategies for CD-associated intestinal fibrosis.

英文关键词： intestinal fibrosis;epithelial mesenchymal transition;Insulin-like growth factor-1;SIRT1