Objectif Hepatocellular carcinoma (HCC) is caused by chronic hepatitis and is the third most common cause of cancer-related death worldwide, with a rising incidence in first world countries. To date no effective therapies other than liver transplantation are available for this disease.Previous studies have provided evidence that inflammatory signalling pathways (e.g. the NF-b pathway) are crucial modulators of liver cancer development. However, the exact mechanisms driving hepatitis-induced liver damage and cancer formation remain elusive. Among others, aberrant expression of cytotoxic cytokines is thought to be critically involved.We have recently shown that the inflammatory cytokines lymphotoxin (LT) and are specifically upregulated in livers of patients suffering from hepatitis C and B virus-induced liver inflammation or HCC and that liver specific expression of LT and in mice (AlbLT) suffices to induce inflammation-induced liver cancer development. We could further demonstrate that this depended on the presence of functional lymphocytes.My proposal is pillared by three main approaches that all aim to elucidate the exact cellular and molecular mechanisms underlying chronic liver damage and HCC development in humans as well as in mouse models of inflammation- or carcinogen-induced liver cancer.First, we will identify the particular immune cell type(s) (e.g. B- or T-lymphocytes; macrophages; NK-T cells) involved in HCC development. Although inflammatory signalling and immune cells appear to be important in HCC development it remains elusive, which immune cell type(s) contribute to inflammation induced liver cancer development.Secondly, we will investigate how inflammatory signalling pathways induce chromosomal aberrations. It is known that inflammatory signalling cascades cause chromosomal aberrations; however, the detailed mechanisms by which this occurs are not fully understood. Additionally, we will determine how inflammatory signalling influences the pathways involved in DNA repair, replication and chromosomal segregation culminating in chromosomal aberrations and cancer.Finally, we will examine the role of oval cells in liver cancer formation. Oval cells, which are putative liver-cancer stem cells, differentiate into either hepatocytes or cholangiocytes, proliferate under inflammatory conditions, and are found within HCC. However, their exact functional role in liver carcinogenesis is unknown. We will biochemically characterize proliferating and HCC-associated ovals cells in mouse models of inflammation-induced HCC and in diseased human liver tissues. This will pave the way for the development of the first genetic tools to deplete or express genes in an oval cell-specific manner.The new scientific knowledge gained by these studies investigating how immune cells and inflammatory signalling induce chronic liver damage and cancer on a mechanistic level, and how oval cells contribute to HCC will provide the basis for future novel pharmacological approaches to treating inflammatory liver diseases and HCC in humans. Champ scientifique medical and health sciencesclinical medicineoncologyliver cancermedical and health scienceshealth sciencesinfectious diseasesmedical and health sciencesbasic medicineimmunologymedical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesclinical medicinehepatology Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) ERC-SG-LS4 - ERC Starting Grant - Physiology, Pathophysiology and Endocrinology Appel à propositions ERC-2010-StG_20091118 Voir d’autres projets de cet appel Régime de financement ERC-SG - ERC Starting Grant Institution d’accueil HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH Contribution de l’UE € 1 212 190,00 Adresse INGOLSTADTER LANDSTRASSE 1 85764 Neuherberg Allemagne Voir sur la carte Région Bayern Oberbayern München, Landkreis Type d’activité Research Organisations Contact administratif Juergen Ertel (Dr.) Chercheur principal Mathias Heikenwaelder (Dr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire HELMHOLTZ ZENTRUM MUENCHEN DEUTSCHES FORSCHUNGSZENTRUM FUER GESUNDHEIT UND UMWELT GMBH Allemagne Contribution de l’UE € 1 212 190,00 Adresse INGOLSTADTER LANDSTRASSE 1 85764 Neuherberg Voir sur la carte Région Bayern Oberbayern München, Landkreis Type d’activité Research Organisations Contact administratif Juergen Ertel (Dr.) Chercheur principal Mathias Heikenwaelder (Dr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée