Progression of chronic liver disease: Defining the contributions of hepatocytic JNK expression and gut microbiota

• Applicant: Professor Dr. Christian Trautwein
• Subject Area: Gastroenterology
• Term: from 2014 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 247690831

Chronic liver diseases (CLD) are serious health problems worldwide with increasing incidence and limited treatment options. Based on our own preliminary work we hypothesize that the outcome of CLD is substantially affected by JNK signaling in hepatocytes and by gut dysbiosis. Therefore, it is the overarching objective of this application to test whether a modulation of the hepatic JNK signaling or changes in gut microbiota may improve the outcome of CLD. To this end we will take advantage of two recently established mouse model of CLD and hepato-carcinogenesis referred to as the DEN/CCl4 and NEMO∆hepa model. Briefly, in mice after single DEN injection and subsequent repetitive CCl4 injection or in the NEMO∆hepa model with mice lacking NEMO in hepatocytes, animals undergo most stages of CLD. This includes basal inflammation, steatosis, fibrosis and liver cancer formation and thus serve as a well-suited platform to modulate additional factors involved in CLD. Modulations within the pathogenesis will be achieved using genetic approaches, RNA interference as well as microbiota modulation. Within this grant, these two topics will be addressed in two specific work packages: • In the first work package, we plan to unravel the JNK1 and/or JNK2-specific signaling in hepatocytes for CLD disease progression, namely fibrosis and hepato-carcinogenesis. • In the second work package, we aim in defining the functional role of gut microbiota and their modulation for CLD.In summary, our current grant application is very well suited to expand our knowledge about the mechanisms of CLD and to identify novel options for therapeutic interventions.

• DFG Programme: Research Grants