Objective The progression from a healthy liver towards non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) serves as a model for chronic diseases in a solid organ, demonstrating how an initially stable stage undergoes critical transitions along several defined phases. Defining the molecular drivers of these phase transitions will open the road for the definition of warning signs, risk prediction approaches and prevention of disease decompensation in human liver disease. We recently made several ground-breaking findings indicating that the molecules RIPK3 and MLKL – which regulate a novel form of programmed cell death called necroptosis – are crucial mediators of these phase transitions, but they might have unexpected and cell-death-independent functions. Therefore, PhaseControl aims at exploring the specific functions of these molecules at the critical phase transitions towards NASH/HCC. Specifically, I propose to apply a systematic approach and innovative methods to 1) explore cell-type specific RIPK3- and MLKL-dependent regulatory networks in white adipose tissue (WAT), hepatocytes and myeloid cells in murine NASH development and define cell-death independent functions of MLKL in metabolic regulation;2) explore how inflammatory pathways in hepatocytes modulate the reactivity and specific responses towards necroptosis at the transition towards hepatocellular carcinoma (HCC);3) examine apoptosis- and necroptosis-specific genetic alterations and driver mutations that mediate the transition from chronic inflammation to HCC; 4) evaluate in a cohort of human patients if these newly discovered pathways can be used for risk-prediction approaches and might be chemoprevention targets against HCC.The expected results will establish a novel concept how programmed cell death, inflammation and metabolic pathways functionally interact in hepatocarcinogenesis with fundamental relevance for risk prediction and chemoprevention of human liver cancer. Keywords non-alcoholic fatty liver disease NAFLD non-alcoholic steatohepatitis NASH hepatocellular carcinoma HCC liver liver cancer cell-death alarmins necroptosis apoptosis RIPK3 MLKL Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2017-COG - ERC Consolidator Grant Call for proposal ERC-2017-COG See other projects for this call Funding Scheme ERC-COG - Coordinator HEINRICH-HEINE-UNIVERSITAET DUESSELDORF Net EU contribution € 1 825 340,00 Address Universitaetsstrasse 1 40225 Dusseldorf Germany See on map Region Nordrhein-Westfalen Düsseldorf Düsseldorf, Kreisfreie Stadt Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Beneficiaries (2) Sort alphabetically Sort by Net EU contribution Expand all Collapse all HEINRICH-HEINE-UNIVERSITAET DUESSELDORF Germany Net EU contribution € 1 825 340,00 Address Universitaetsstrasse 1 40225 Dusseldorf See on map Region Nordrhein-Westfalen Düsseldorf Düsseldorf, Kreisfreie Stadt Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 UNIVERSITAETSKLINIKUM AACHEN Germany Net EU contribution € 172 500,00 Address Pauwelsstrasse 30 52074 Aachen See on map Region Nordrhein-Westfalen Köln Städteregion Aachen Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
