Grant: China-Canada Joint Health Research Initiative

Genetic defects in bile formation are found in children with Progressive Familial Intrahepatic Cholestasis types 2 and 3 (PFIC2 and PFIC3). PFIC is a devastating liver disease, the most severe form of cholestasis, often resulting in jaundice, growth retardation, cirrhosis, liver failure, and death. Bile acids are one of the main constituents of bile and BSEP is a bile acid pump responsible for driving bile flow. MDR3 is a similar protein that transports lipids to protect liver cells from the toxic detergent effects of bile acids. These two genes work together to produce healthy bile. PFIC2 and PFIC3 are associated with mutated BSEP and MDR3 genes, respectively. Mouse models with mutations similar to PFIC2 and PFIC3 have been created. They show that the mouse liver has the amazing ability to alleviate the toxic effects of cholestasis by making use of genes not normally involved in bile flow. The goal of this application is to determine if the livers of PFIC patients also have similar compensatory mechanisms to alleviate cholestasis in people. We will use the mouse models as a guide to investigate compensatory bile forming-genes in patients. Any new bile acids found in patients will be studied using the mouse models of cholestasis to determine how they might protect liver cells. We expect that findings from this study will result in the identification of diagnostic and prognostic biomarkers to improve clinical management of patients with severe PFIC-like liver diseases. This proposed research is synergistic because of collaboration between the Fudan University Pediatric Liver Diseases Centre, headed by Dr Jian She Wang in Shanghai, with the laboratory of Dr Victor Ling in Vancouver. Dr Wang's centre is a major referral centre for PFIC patients in China and clinical material can be obtained readily for this study. Dr Ling's lab is recognized as the world authority on the experimental mouse models of PFIC.