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

项目概要 该提案的目标是确定 microRNA (miRNA) 靶点作为创新治疗方法 治疗肝脏缺血和再灌注损伤。肝脏缺血再灌注损伤是一个重要的 主要肝切除术和肝移植期间发病率和死亡率的来源。 miRNA 构成调节基因表达的长度为 20 至 25 个核苷酸的非编码 RNA 分子家族 在转录后水平。为了鉴定肝缺血期间功能重要的 miRNA 再灌注后，我们在小鼠肝缺血模型中进行了靶向 miRNA 筛选。我们观察到 miR-122 的 miRNA 表达显着增加，miR-122 是一种肝脏特异性 miRNA，具有功能性 与丙型肝炎病毒的传播有关。肝缺血和再灌注的后续研究 肝细胞特异性删除 miR-122 的小鼠的损伤表明，肝组织损伤显着增加。 利用慢病毒介导的 miR-122 过表达肝细胞系使我们能够鉴定 氧敏感脯氨酰羟化酶 PHD1 作为 miR-122 的新靶基因。因此，我们假设 miR-122 的 HIF1A 依赖性诱导代表了一种增强肝脏保护的前馈途径 缺氧通过抑制其靶基因 PHD1 引起肝脏保护。

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.