ß-catenin Signaling in the hepatocyte stress response

• Applicant: Dr. Nadja Lehwald
• Subject Area: General and Visceral Surgery
• Term: from 2010 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 166465124

The liver is subject to a variety of congenital, acquired and neoplastic diseases that cover the human life span. A common feature of liver disease is an increase in cellular oxidative stress that can damage DNA, protein and lipid resulting in hepatocellular injury. The liver is predisposed to fluctuations in oxidative balance and has evolved a number of protective mechanisms in order to mitigate oxidative injury. It is well known that Wnt signaling pathway is a critical molecular regulator of hepatic development, regeneration and carcinogenesis. The role of β-catenin in hepatic regeneration following partial hepatectomy has been well documented and reveals that although there is a delay in cell cycle entry, β- catenin null hepatocytes do proliferate to restore liver volume. Given our previous studies demonstrating a critical role for Wnt/β-catenin signaling in the chronic regenerative response, this proposal is to investigate molecular signaling pathways through which Wnt signaling via β-catenin exerts its effect. Our preliminary findings suggest a novel role for β-catenin in altering the hepatocyte response to environmental conditions as dictated by alterations in cellular redox balance. Under favorable conditions, β-catenin/TCF signaling predominates thus promoting cell proliferation. Under unfavorable conditions, β-catenin/TCF signaling is repressed in favor of a β-catenin switch to promoting stress adaptation pathways and survival, specifically to binding to FOXO and HIF. In order to test these hypotheses, we have created several murine in vivo and in vitro models that are amenable to genetic manipulation. Further knowledge on cellular mechanisms controlling the hepatocyte injury response to oxidative stimuli is of clinical and scientific relevance to identify targets for the development of novel therapies to treat liver disease. Due to the shortage of organ transplantations and the limited success of hepatocyte transplantation, hepatocellular therapies would benefit greatly from a molecular strategy aimed at either improving their in situ survival or augmenting their survival during manipulation and transplantation.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Karl G. Sylvester