A03: Functional genetic dissection of hepatocarcinogenesis in NASH

It is expected that the incidence of liver disease will further rise due to the rapid increase of non-alcoholic fatty liver disease (NAFLD), which e.g. affects 20% of all Americans. NAFL often progresses to nonalcoholic steatohepatitis (NASH), which is predicted to become the most important risk factor for HCC development in the future. The pathogenesis of the various types of chronic liver diseases is complex and multifactorial, but a common feature are repetitive waves of hepatocyte death and compensatory regeneration, which finally lead to an exhaustion of the regenerative capacity of the liver, the development of liver cirrhosis, ending either directly in liver failure or the development of hepatocellular carcinoma (HCC). We will use innovative mouse models and stable RNAi technology to i) functionally test inhibition of the kinases MKK4 and p38alpha (Mapk14) as new therapeutic options for the treatment of NASH and ii) to conduct functional genetic screens to dissect NASH pathogenesis with a particular emphasis on NASH driven HCC development.


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