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Achievements

Biological achievements

  • Peptide array experiments have identified the binding regions of Raf-1, ARaf, B-Raf, MEK, ERK to wild-type RKIP and RKIP mutants.
  • Several experiments allowed the identification of new potential binding partners of the Raf kinase inhibitor protein (RKIP).
  • New experiments confirmed that RKIP downregulation affects the dynamics of the NF?B-pathway in breast epithelial cells.

Methodological achievements

  • An strategy to use kinetic models based on power-law terms in cell signaling modeling has been implemented and applied.
  • A new method hybrid method (global+local search) for parameter estimation has been developed and implemented.
  • An strategy for the reduction of dimensionality in non-linear kinetic models of cellular signal transduction systems was designed and applied to the investigated pathways.
  • A MATLAB toolbox for parameter estimation has been developed and implemented. This tool includes global optimisation methods for parameter estimation as well as numerical tools for parametric sensitivity analysis.
  • A Matlab addon for the MATLAB Systems Biology Toolbox for the analysis of power-law models was desgined and implemented.
  • A toolbox for optimal experimental design toolbox has been extended and tested with applications for the JAK2/STAT5 and Ras/RAF/MEK/ERK pathways.

Modelling achievements

  • Non linear kinetic models have been set up to describe the JAK2-STAT5, RAS/RAF1/MEK/ERK and NFkB pathway in the biological conditions investigated in the project.
  • A plethora of quantitative experimental techniques have been tested and adapted for the purpose of modeling these pathways, including quantitative western blots, life cell imaging, ELISA kits and radioactive labeling.
  • Extensive sets of quantitative experimental data of sufficient quality to be used in mathematical modeling have been produced for the three pathways investigated
  • An strategy for modeling ERK and STAT cross talk by using reaction-diffusion distributed models has been developed and implemented.
  • Theoretical and experimental techniques to investigate protein gradients and diffusion effects in the JAK2/STAT5 pathway has been designed, implemented and tested.