B3_Wnt/ß-Catenin Signalling

Project Summary:

Wnt/beta-catenin signaling takes part in the regulation of proliferation, differentiation, survival and metabolic activities of liver cells. b-Catenin and its upstream regulator glycogen synthase kinase-3beta (GSK3beta) are integral components of complex and interdigitated signaling systems which control these processes. The aim of the project is to model gene regulatory networks centred around and emanating from beta-catenin signaling activity. Special emphasis will be given to a molecular dissection of mechanisms underlying beta-catenin signaling in normal hepatic gene expression, to the role of beta-catenin in controlling hepatocyte proliferation in regenerative processes, and to the cross-regulation of Wnt/beta-catenin and other signaling cascades. Time-resolved quantitative data, such as genome-wide transcriptome and proteome data, as well as molecular monitoring of pathway components and their posttranslational modifications will be used to generate an extensive mathematical model of the Wnt/beta-catenin signaling pathway and beta-catenin-related gene regulatory networks. Dynamic properties of the network will be investigated on the basis of the data- and knowledge-based models. Methods of model-based optimal experimental design will be applied to improve and validate the model by directed experiments. Crosstalk between beta-catenin signaling and other pathways will be investigated and modeled in collaboration with other HepatoSys network partners.