慢性HBV肝损伤修复过程中miR-194的作用及功能研究

This study aims to discover dynamic changes of microRNA expression in plasma and tissue of chronic hepatitis B (CHB) related liver damage, and to explore mechanism of miR-194 with its target gene ACVR2B during histological liver damage and fibrosis. In our previous experiments, we discovered 9 significantly differential expressed microRNA in plasma of 22 CHB patients and 33 healthy controls using genome-wide microRNA analysis. In 118 plasma and 66 tissue samples of CHB patients, quantitative RT-PCR revealed that expression levels of 6 candidate microRNA (miR-122, miR-192, miR-194, miR-148a, miR-215, miR-27b) in plasma and tissue declined with the aggravation of liver damage and fibrosis. Through analysis of miRecords and KEGG databases, we found that the target genes of 5 candidate microRNA all include activin A receptor genes. There are A、B and AB three subtypes of activin , thereof activin A is most closely with liver . Though combining with receptors, activin A play a role in pathology and physiology process of liver. This implies that these 5 candidate microRNA may regulate hepatocyte apoptosis ，proliferation and liver fibrosis by combining activin A receptors. Based on our recent discoveries, we will establish a liver partial hepatectomy rat model and carbon tetrachloride induced liver fibrosis mice model to observe the expression changes of 5 human-mouse homologous microRNA in plasma and tissue. Through the in vitro and in vivo studies, we will investigate the regulation role and mechanism of key candidate miR-194 and its target gene ACVR2B during the liver damage and fibrosis process. The outcomes in this study will provide the scientific basis for exploring new mechanism of chronic hepatitis B related liver damage.

本项目旨在对慢性HBV肝损伤相关microRNA在血浆和组织中的变化规律及miR-194调节靶基因ACVR2B在肝损伤过程发挥的作用进行研究。我们已在22个慢乙肝患者和33个健康人血浆中进行全基因组microRNA差异表达分析，并通过定量RT-PCR在慢乙肝患者118例血浆及66例肝穿刺组织中验证，得到6个候选microRNA。发现伴随肝脏炎症及纤维化程度的加重血浆和组织中6个候选microRNA的表达逐渐下降。 其中5个microRNA的靶基因均包括了激活素A受体基因。我们推测microRNA通过调节激活素A受体影响肝脏的损伤修复过程。本研究在我们发现的基础上，通过大鼠部分肝切除再生模型以及小鼠慢性肝损伤模型，观察血浆及组织5个人鼠同源microRNA在肝细胞再生以及慢性纤维化过程中的表达变化，并结合细胞实验探索miR-194通过调节AVCR2B对肝细胞增殖和凋亡以及纤维化的影响。