微小RNA-382与肝再生的关系

The extraordinary liver regeneration ability can be impaired in severe hepatic injuries such as liver cirrhosis and liver failure, highlighting the importance of investigating novel therapeutic strategies to promote liver regeneration after injury. MicroRNAs (miRs) participate in many essential biological processes including cellular proliferation, apoptosis, differentiation and migration. Increasing evidence has indicated that dysregulation of miRs contributed to multiple liver diseases. However, the role of miRs in liver regeneration remains largely unclear.. Our preliminary data showed that miR-382 level was significantly increased in liver tissue 48 h after partial hepatectomy (PH) in mice using miR arrays and qRT-PCR. In addition, overexpression of miR-382 promoted the proliferation of hepatocytes in vitro, suggesting that up-regulated miR-382 may be responsible for liver regeneration after PH. . In the present project, firstly, we will investigate the role of miR-382 in liver regeneration after PH through gain-of-function and loss-of-function experiments in vitro and in vivo. Secondly, we will clarify its molecular mechanisms through identifying the target genes of miR-382 in promoting liver regeneration after PH. Finally, we will further evaluate the potential therapeutic value of miR-382 in acute liver failure. . Our project may provide important information helping develop a novel miR-target therapeutic approach to promote liver regeneration..

在肝硬化、肝功能衰竭等情况下，肝脏的再生能力受损。寻找新的促进肝再生的方法对于治疗肝脏疾病具有重大意义。微小RNA（miR）参与调节细胞增殖、凋亡、分化、移行等功能，其功能失调与肝脏疾病密切相关，然而miR失调在肝再生中的作用及分子机制尚未完全明确。本课题组前期已通过微小RNA芯片技术和实时定量PCR法筛选并确认miR-382在小鼠肝大切48 h后的肝组织中显著上调，且增加miR-382的表达可以促进肝细胞增殖，提示miR-382上调可能参与肝大切后的肝再生过程。在本项目中，我们拟结合细胞及动物水平的功能获得性和功能缺失性实验，明确miR-382与肝大切后肝再生的关系；通过研究相关靶基因从而阐明miR-382上调促进肝大切后肝再生的分子机制；并评估miR-382上调对急性肝功能衰竭可能存在的治疗作用。本项目将有望为研发出一种新的促进肝再生的靶向miR治疗药物提供重要的理论与实验依据。

诱导肝再生对于治疗肝脏疾病具有重要的意义。微小RNA（microRNA，miRNA，miR）功能失调与肝脏疾病的发生密切相关，然而微小RNA在肝再生中的作用尚未完全清楚。我们首先运用微小RNA芯片技术和实时定量PCR法筛选并确认miR-382在小鼠肝大切48小时后的肝组织中显著上调。在小鼠NCTC1469及人HL7702正常肝细胞系水平，运用CCK-8细胞计数、EdU细胞增殖或Ki67免疫荧光染色及流式细胞仪检测细胞周期后发现，miR-382模拟物可促进肝细胞的增殖，并促使细胞周期从G1期向S期的转化，而miR-382抑制物具有相反的作用。进一步研究证实，miR-382在肝细胞内负调控PTEN的蛋白表达，PTEN下调及Akt通路的激活参与介导了miR-382的促肝细胞增殖作用。综上，miR-382促进肝细胞的增殖，PTEN是miR-382的一个靶基因。miR-382有望成为一个新的促进肝再生的治疗靶点。