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Mathematical modelling of beta-catenin and ras signalling in liver and its impact on proliferation, tissue organization and formation of hepatocellular carcinomas

Objective

The goal of the CANCERSYS project is to establish a multi-scale model for two major signalling pathways involved in the formation of hepatocellular carcinoma, the beta-catenin and ras signalling pathways. Integrative studies linking measurements in primary heptocytes with effects at the organ level will address the impact of these signalling networks on proliferation, tissue organization and formation of hepatocellular carcinoma. In a close collaboration of scientists from theoretical fields and life sciences, our approach will combine dynamic modelling of signalling networks with spatial-temporal modelling of the liver microarchitecture. For this purpose dynamic models of the beta-catenin and ras core modules and their interactions will be integrated into a single-cell based three-dimensional model of the liver lobule. This model will be used to predict the impact of beta-catenin and ras activation on tissue organization starting with the early events, such as enhanced proliferation as well as micromotility of single cells, followed by formation of nodules and finally of dedifferentiated hepatocarcinomas. Predictions obtained by the model will be validated by inducible Apclox/lox and Ha-rasQ61R mouse strains, which have already been established by members of our consortium and allow induction of hepatocellular carcinoma. In addition the model predictions of the combined influence of active beta-catenin and ras signalling will be validated using a mouse strain that allows induction of both pathways in hepatocytes. In an iterative process, the model will be validated and adjusted to the in vivo situation. The model aims at the identification of systems properties of beta-catenin and ras signalling exploited during carcinogenesis and will foster the prediction of strategies for effective intervention, thereby facilitating the design of novel therapeutic strategies to combat hepatocellular carcinoma.

Call for proposal

FP7-HEALTH-2007-B
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Coordinator

FORSCHUNGSGESELLSCHAFT FUR ARBEITSPHYSIOLOGIE UND ARBEITSSCHUTZ EV
Address
Ardeystrasse 67
44139 Dortmund
Germany
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 854 850
Administrative Contact
Michael Paul (Mr.)

Participants (8)

ALBERT-LUDWIGS-UNIVERSITAET FREIBURG
Germany
EU contribution
€ 250 800
Address
Fahnenbergplatz
79098 Freiburg
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Jens Timmer (Prof.)
INSTITUT NATIONAL DE RECHERCHE EN INFORMATIQUE ET AUTOMATIQUE
France
EU contribution
€ 273 300
Address
Domaine De Voluceau Rocquencourt
78153 Le Chesnay Cedex
Activity type
Research Organisations
Administrative Contact
Sandrine Lassout (Ms.)
DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Germany
EU contribution
€ 280 800
Address
Im Neuenheimer Feld 280
69120 Heidelberg
Activity type
Research Organisations
Administrative Contact
Bettina Crispin (Ms.)
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France
EU contribution
€ 280 800
Address
Rue De Tolbiac 101
75654 Paris
Activity type
Research Organisations
Administrative Contact
Annick Bertault (Ms.)
EBERHARD KARLS UNIVERSITAET TUEBINGEN
Germany
EU contribution
€ 280 800
Address
Geschwister-scholl-platz
72074 Tuebingen
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Michael Schwarz (Prof.)
UNIVERSITAET LEIPZIG
Germany
EU contribution
€ 280 800
Address
Ritterstrasse 26
04109 Leipzig
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Rolf Gebhardt (Prof.)
STIFTELSEN FRAUNHOFER-CHALMERS CENTRUM FOR INDUSTRIMATEMATIK
Sweden
EU contribution
€ 250 800
Address
Chalmers Science Park
41288 Goeteborg
Activity type
Research Organisations
Administrative Contact
Mats Jirstrand (Dr.)
CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Germany
EU contribution
€ 239 074
Address
Chariteplatz 1
10117 Berlin
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Eveline Fraessdorf (Ms.)