miR-199a信号网络调控胰腺纤维化的研究

项目名称： miR-199a信号网络调控胰腺纤维化的研究

项目编号： No.81470883

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： 胡良皞

作者单位： 中国人民解放军第二军医大学

项目金额： 73万元

中文摘要： 慢性胰腺炎（CP）特征性病理变化为胰腺纤维化，目前缺少有效控制或逆转方法。申请人承担的青年基金项目（81100316，2012-2014）筛选并确定了miR-199a是促进胰腺纤维化的关键miRNA，并发现抑制miR-199a能改善CP大鼠的纤维化，进一步通过基因芯片和双荧光素酶标记发现SIRT1、HGF和mTOR是miR-199a重要靶基因。然而已有报道和我们的数据初步提示SIRT1和HGF抑制胰腺纤维化，而mTOR具有促进作用，这意味着miR-199a同时参与促进和抑制纤维化进程。本项目拟明确上述三个基因在介导miR-199a影响胰腺纤维化过程中的功能作用及信号机制，构建以miR-199a为中心的调控网络。并在CP大鼠上抑制miR-199a表达的同时激活SIRT1、HGF或抑制mTOR，采用多靶点干预模式增强单独抑制miR-199a的抗纤维化效果，为研发抗纤维化药物提供理论基础。

中文关键词： 微小RNA；慢性胰腺炎；胰腺星状细胞；胰腺纤维化；基因干预

英文摘要： Fibrosis is the major pathological feature of chronic pancreatitis (CP). There are few effective methods to control or reverse it. With the support of young scientist fund of NSFC (81100316; 2012-2014), we have identified miR-199a as a key miRNA for promotion of pancreatic fibrosis. Moreover, it has been found that inhibiting the expression of miR-199a could contribute to curing the fibrosis. Further studies discovered that SIRT1, HGF and mTOR are important targets of miR-199a via gene chip and dual-luciferase assay. However, our preliminary results in combination with the relevant literature indicate that SIRT1 and HGF inhibit pancreatic fibrosis while mTOR could promote it. This implies that miR-199a involve in the processes of both pro-fibrosis and anti-fibrosis. This project intends to make clear the involved biological processes and signal pathways through these targets, and exhibit the regulation network of miR-199a. Furthermore, intervention in expression of these genes will be implemented in the rat model; whose expression of miR-199a is down regulated. This multi-target strategy of combining miR-199a and its targets will be carried out to enhance the anti-fibrosis effects of the single miR-199a intervention. This project will provide a theoretical basis for the research and development of anti-fibrosis drugs.

英文关键词： miRNA;chronic pancreatitis;pancreatic stellate cells;pancreatic fibrosis;genetic intervention