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.
Our studies are designed to lay the groundwork for novel therapeutic approaches for treating patients who are suffering from acute hepatic ischemia and reperfusion injury, for example during cadaveric liver transplantation, living-donor-related liver transplantation or major liver resection. Our studies point towards a novel therapeutic role for the microRNA miR-122 via repression of its target gene PHD1 in liver protection. If successful, our studies will contribute to preventing or treating hepatic ischemia and repefusion injury ? one of the leading causes of morbidity and mortality of liver surgery and liver transplantation.
