Research Interests

Mathematical modelling of specific networks (TANKs and WNT)

The Wnt family of proteins plays a major role in controlling cell proliferation, cell-fate determination and differentiation during embryonic development and adult homeostasis. It has also been suggested that the Wnts activate a number of different signalling pathways. The Wnt family of proteins does not act on its own – it forms many interactions with other families of proteins, such as the Frizzled family and other cofactors and proteins, such as β-catenin, as well as complexes, such as axin/GSK-3/APC. The mammalian Wnt signalling pathway has been, to some extent, decoded and has illustrated the importance of Wnts in cancer. Alterations of Wnts, APC, axin, and TCFs are all associated with carcinogenesis.

In this project we will study this pathway further, through protein-protein interactions and analyse its function through the use of systems biology (mathematical modelling) as well as experimental techniques. Systems biology aims at a system level and signal- oriented understanding of pathways by investigating ‘inter- relationships’ (organisation or structure) and ‘interactions’ (dynamics or behaviour) of RNA transcripts, proteins and metabolites. Most of the mathematical models that have been developed are based on reaction kinetics and employ non-linear ordinary differential equations. A major problem in understanding the Wnt pathway is that this network is regulated through complex dynamic interactions and this can only be investigated through the integration of large-scale information using mathematical models.

Since any particular method (e.g. microarrays) provides only a part of the whole picture, there is a need to fuse data by using different technologies, and to combine the information. For predictive mathematical models and simulation of inter- and intracellular dynamics it is therefore crucial to investigate the Wnt system with the full range of technologies and methodologies available.  Here at Breakthrough we have the means to do this.

Mathematical modelling and simulation will be employed to identify key components and subsystems in the Wnt network. Hybrid models that combine stochastic formalism (e.g. modelling at transcriptional level) with deterministic representations (e.g. By measuring both mRNA accumulation and degradation over a short time course) and qualitative or rule- based formalisms will be explored to provide sufficiently predictive models.

Find out more about Dr Marketa Zvelebil's research on the Breakthrough Breast Cancer website