Novel Protective Mechanism against Liver Damage in Liver Transplant Patients

Principal Investigator: Xiaoying Liu, PhD The term cholestasis describes any condition that impairs normal bile flow from the liver into the bile ducts and then into the intestine. This disease state can cause chronic liver damage, cirrhosis, end-stage liver disease (requiring a liver transplant), and death. Cholestatic liver diseases include primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Cholestasis also occurs frequently after liver transplantation, which can result in the need for repeat liver transplantation or death. Unfortunately, the molecular drivers of cholestasis are still poorly understood with few effective medical therapies. The liver unfolded protein response (UPR) is a molecular pathway that protects cells from injury. UPR has been demonstrated to be important in many liver diseases, although its role in cholestasis remains unknown. Dr. Liu intends to investigate the activation of the liver UPR pathways in liver transplant patients with cholestasis. Identifying new UPR protein and gene targets will ultimate aid in developing novel drug therapies and improving liver transplant...

A Novel Protective Mechanism in the Bile Ducts of Patients with Primary Sclerosing Cholangitis

Principal Investigator: Richard M. Green, MD A chronic bile duct and liver disease, Primary Sclerosing Cholangitis (PSC) affects more than 50,000 Americans and can progress to cirrhosis, liver failure, and bile duct cancer. Currently, the only effective therapy is liver transplantation. Better understanding the pathogenesis of PSC is urgently needed to develop new therapies. In recent cell culture and animal studies, Dr. Green and his colleagues focused on a protective cell signaling pathway: the unfolded protein response (UPR). They found that the UPR is activated when bile flow is impaired, and mice lacking UPR genes in their liver are highly susceptible to injury from bile duct obstruction. Now moving forward with the first human investigations examining UPR, Dr. Green aims to determine how it is activated in the bile ducts of patients with PSC. The team plans to study bile duct tissues obtained during endoscopic procedures performed for bile duct obstruction. The identification of “protective” genes and proteins could lead to new drug targets and, ultimately, the development of novel medical...