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The Function of inflammatory signalling pathways in acute and chronic liver disease and liver cancer

Objective

The aim of this proposal is to examine the role of inflammatory signalling pathways in murine models of liver and biliary disease by application of conditional gene targeting using cre/loxP technology. Previous studies have provided evidence that the NF-kB pathway and its activating kinase complex – consisting of three subunits: IKK1, IKK2 and NEMO – are crucial regulators of liver physiology and pathology, but their differential, cell specific functions in the liver are currently only poorly understood. The first part of this proposal will focus on the evaluation of molecular mechanisms underlying the development of hepatocellular carcinoma in a setting of chronic hepatitis. By using a novel mouse model of spontaneous liver cancer based on conditional deletion of NEMO in hepatocytes, the functions of cytokines, specific intracellular signalling pathways, the innate and adaptive immune system and the role of hepatic stem cells in hepatitis and carcinogenesis will be examined. In the second part of this proposal, we will extend these studies by evaluating the function of NEMO/NF-kB in other hepatic cell compartments, specifically the function of NEMO in hepatic stellate cells and liver fibrosis, the endothelial function of NEMO/NF-kB in an in vivo model of hepatic ischemia-reperfusion injury and the role of the NF-kB pathway in biliary epithelial cells and inflammatory biliary diseases. Finally, in the third part of this proposal we will analyse the unknown intrahepatic role of non-canonical, IKK1-dependent signalling pathways and the function of TAK1 – a molecule at the interface between inflammatory and developmental pathways – in liver injury, fatty-liver-disease and insulin-resistance. Knowledge gained by these studies and the further understanding of the cell specific hepatic function of NF-kB and related pathways might build the basis for the development of novel pharmacological approaches for the future treatment of liver diseases and cancer in humans.

Field of science

  • /medical and health sciences/basic medicine/pathology
  • /medical and health sciences/medical biotechnology/cells technologies/stem cells
  • /medical and health sciences/basic medicine/immunology
  • /medical and health sciences/clinical medicine/oncology/cancer
  • /medical and health sciences/basic medicine/physiology
  • /medical and health sciences/clinical medicine/oncology/cancer/liver cancer

Call for proposal

ERC-2007-StG
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

UNIVERSITAETSKLINIKUM AACHEN
Address
Pauwelsstrasse 30
52074 Aachen
Germany
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 600 356
Principal investigator
Tom Luedde (Dr.)
Administrative Contact
Volker Legewie (Mr.)

Beneficiaries (1)

UNIVERSITAETSKLINIKUM AACHEN
Germany
EU contribution
€ 1 600 356
Address
Pauwelsstrasse 30
52074 Aachen
Activity type
Higher or Secondary Education Establishments
Principal investigator
Tom Luedde (Dr.)
Administrative Contact
Volker Legewie (Mr.)