Targeting MicroRNA miR-122 for the Treatment of Perioperative Liver Injury

项目总结 这项提议的目标是确定microRNA(MiRNA)靶点作为创新的治疗方法。 肝缺血再灌注损伤的治疗。肝脏缺血和再灌注损伤是一种重要的 大范围肝切除和肝移植期间的发病率和死亡率来源。MiRNAs 组成一个长度为20到25个核苷酸的非编码RNA分子家族，调节基因表达 在转录后水平上。为了识别在肝脏缺血和再灌注过程中具有重要功能的miRNAs 在小鼠肝脏缺血模型中，我们进行了有针对性的miRNA筛选。我们观察到 MiR-122-一种肝脏特异的功能上的miRNA的miRNA表达最显著的增加 与丙型肝炎病毒的传播有关。肝脏缺血和再灌注的后续研究 在肝细胞特异性缺失miR-122的小鼠中，损伤显示肝组织损伤显著增加。 利用慢病毒介导的miR-122过表达的肝细胞系使我们能够鉴定 氧敏感的脯氨酸羟基酶PhD1作为miR-122的新靶基因。因此，我们假设 依赖于HIF1a的miR-122的诱导代表了一种前馈肝保护途径，该途径增强了 低氧通过抑制其靶基因phd1发挥肝保护作用。

PROJECT SUMMARY The goal of this proposal is to identify microRNA (miRNA) targets as innovative therapeutic approach for the treatment of hepatic ischemia and reperfusion injury. Hepatic ischemia and reperfusion injury is a significant source of morbidity and mortality during major hepatic resection and during liver transplantation. MiRNAs constitute a family of noncoding RNA molecules of 20 to 25 nucleotides in length that regulate gene expression at the posttranscriptional level. In order to identify functionally important miRNAs during hepatic ischemia and reperfusion, we performed a targeted miRNA screen in a murine model of liver ischemia. We observed the most dramatic increase in miRNA expression for miR-122 – a liver-specific miRNA that is functionally implicated in the propagation of the hepatitis C virus. Subsequent studies of hepatic ischemia and reperfusion injury in mice with hepatocyte-specific deletion of miR-122 revealed dramatic increases in hepatic tissue injury. Utilization of a hepatocyte cell line with lentiviral-mediated overexpression of miR-122 allowed us to identify the oxygen-sensing prolyl-hydroxylase PHD1 as a novel target gene for miR-122. Thus, we hypothesize that HIF1A-dependent induction of miR-122 represents a feed-forward pathway for liver protection that enhances hypoxia-elicited liver protection via repression of its target gene PHD1.