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24-nor-ursodeoxycholic acid as novel therapeutic approach to sclerosing cholangitis
- Abstract
- The overall aim of the proposed research project is to identify novel therapeutic strategies for chronic cholangiopathies which are important indications for liver transplantation and causes of liver-related death. A side chain-shortened bile acid such as 24-nor-ursodeoxycholic acid (norUDCA) has been chosen since this biochemical modification results in cholehepatic shunting and targeting to the bile duct epithelium, effects which should provide the distinct pharmacological properties required for the treatment of cholangiopathies such as sclerosing cholangitis. The effects of norUDCA on biochemical, histological and molecular markers of liver and bile duct injury and biliary fibrosis will be tested in the recently established Mdr2-/- cholangiopathy model with features of sclerosing cholangitis. The effects of norUDCA will be compared with UDCA (as current standard treatment of cholangiopathies in humans) and sulindac (a non-steroidal anti-inflamatory drug also undergoing cholehepatic shunting and targeting to the bile duct epithelium). Potential therapeutic (anti-cholestatic and anti-fibrotic) mechanisms will be addressed both in in vivo (animal model) and in vitro (hepatocytes, cholangiocytes). To allow mechanistic insights across species differences, both human and mouse liver tissue/cells will be investigated. A major innovative aspect of this project lies in the attempt to link the research areas of hepatobiliary transport/cholestasis and hepatic fibrogenesis/biliary fibrosis. Current medical treatment options for cholestatic liver diseases and cholangiopathies ultimately resulting in biliary fibrosis and cirrhosis are unsatisfactory and of limited efficacy. The results of this study should contribute to novel therapeutic strategies against cholestatic liver diseases and biliary fibrosis. Moreover, the expected finding should have major general implications for hepatic fibrogenesis beyond the area of cholestasis.
- Keywords
- medical molecular biology
- pharmacology
- cancer research
- hepatology
- ABC transporters
- Bile acids
- Biliary Fibrosis
- Cholangitis
- Cholestasis
- Hepatocellular carcinoma
- Project Leader:
- Trauner Michael
- Duration:
- 01.06.2006-31.07.2010
- Programme:
- Einzelprojekt
- Type of Research
- basic research
- Staff
- Trauner, Michael, Project Leader
- MUG Research Units
- Center for Medical Research (ZMF)
- Division of Gastroenterology and Hepatology
- Funded by
- FWF, Fonds zur Förderung der Wissenschaftlichen Forschung, Wien, Austria
FWF-Grant-DOI: 10.55776/P19118
- Project results published
- > norUDCA protects common bile duct ligated mice fro... Doctoral Day 2012; DEC 7, 2012; Graz, AUSTRIA. 2012.
- > Expression of the nuclear bile acid receptor/farne... Int J Cancer. 2012; 130(10): 2232-2239.