Objectif "BACKGROUNDNon–alcoholic steatohepatitis (NASH) is the hepatic event of the metabolic syndrome and is characterized by steatosis and inflammation. Although our understanding of the disease mechanisms has progressed, the therapy options for treatment of NASH remain poor. AMP-activated protein kinase (AMPK) is an important integrator of signals managing energy balance and acts as a protective response to energy stress during metabolic deregulations. Pharmacologic AMPK activation is a well-established treatment strategy against the metabolic syndrome and has been reported to ameliorate steatosis, but accumulating evidence suggests that global AMPK activation is undesirable, especially because of affecting appetite. Macrophage-stimulating protein (MSP) is a multifunctional serum factor secreted from liver cells and a ligand for Recepteur d'origine nantais (RON) receptor tyrosine kinase to initiate downstream signaling pathways in an autocrine fashion. MSP exhibits anti-inflammatory properties on macrophages. Interestingly, MSP-deficient mice on normal diet develop hepatic steatosis. However, the role of MSP in normal liver metabolism and metabolic syndrome remained underexplored. Previous studies by the applicant demonstrated MSP as a negative regulator of hepatic gluconeogenesis and of inflammatory responses, both via AMPK activation.HYPOTHESISMSP-mediated activation of AMPK is an effective treatment option against NASH.OBJECTIVES1) Investigate the molecular mechanism and metabolic/anti-inflammatory action of MSP-mediated AMPK activation in cultured hepatocytes and macrophages.2) Stimulate the MSP/AMPK pathway in liver to assess the potential of ameliorating NASH in relevant mouse models.DELIVERABLES1) Identification of novel upstream regulators of AMPK downstream of MSP/RON.2) Appraisal of MSP for possible treatment of NASH in humans." Champ scientifique natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health scienceshealth sciencesnutrition Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) FP7-PEOPLE-2012-IIF - Marie Curie Action: "International Incoming Fellowships" Appel à propositions FP7-PEOPLE-2012-IIF Voir d’autres projets de cet appel Régime de financement MC-IIF - International Incoming Fellowships (IIF) Coordinateur UNIVERSITEIT MAASTRICHT Contribution de l’UE € 183 469,80 Adresse MINDERBROEDERSBERG 4 6200 MD Maastricht Pays-Bas Voir sur la carte Région Zuid-Nederland Limburg (NL) Zuid-Limburg Type d’activité Higher or Secondary Education Establishments Contact administratif Dietbert Neumann (Dr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
