miR-155靶向CCN1调控肝纤维化的作用与分子机制研究

Molecular mechanisms and prevention & treatment of liver fibrosis are challenging problems in the world. Our previous studies found that 1) the expression of miR-155 in liver tissue of CCl4-induced mouse model of liver fibrosis was significantly up-regulated, and 2) The preliminary experimental results showed that the liver of miR-155 knockout mice is resistant to the chronic hepatic fibrosis induced by CCl4, suggesting that miR-155 might play a role in promoting liver fibrosis formation. Based on the previous work, the present project plans to carry out the following studies: 1) the functions of miR-155 in liver fibrosis formation will be completely examined by the combined use of miR-155 transgenic mice and conditional knockout mice; 2) Experimental Study to explore whether the function of miR-155 in liver fibrosis formation can be mediated by miR-155 target gene CCN1 in vitro and in vivo; 3) human clinical tissue specimens will be employed to reveal the expression profile of miR-155 and its target gene CCN1 in human liver fibrosis tissues, the correlation between the expression of miR-155 and CCN1, and clinical pathological significance. The expected findings will provide a new target for the prevention and treatment of liver fibrosis.

肝脏纤维化形成的分子机理及其预防治疗是一项富有挑战性的世界性难题。申请者前期研究发现：1) 肝纤维化小鼠模型肝组织中miR-155表达水平显著升高，2) 初步实验结果表明，miR-155基因敲除小鼠的肝脏对CCl4诱导的肝纤维化形成具有抵抗性，这些提示miR-155可能起促肝纤维化的功能。本项目拟在前期工作基础上开展如下研究：1) 综合运用miR-155转基因小鼠 和miR-155条件性基因敲除小鼠阐明miR-155在肝纤维化形成中的作用；2) 利用体内外实验确证miR-155对肝纤维化的调节作用可否由其靶基因CCN1介导；3) 利用人临床组织标本揭示miR-155和CCN1在肝纤维化组织中的表达谱、miR-155和CCN1等表达的相关性及临床病理意义。预期成果将为肝纤维化防治提供新的靶点。