miR-199a信号网络调控胰腺纤维化的研究

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。

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.