Modelling regulatory pathways and applications to cancer therapy

MAPK signalling pathways are central to cell physiology and adaptation to the environment. These are regulated by phosphorylation and dephosphorylation of a large variety of cytosolic and nuclear targets to transduce external stimuli into a specific response. In these complex systems, the type, duration and localisation of the signals are relevant to the final response, producing a network of interactions that require precise integration and fine-tuning. Key players in such pathways are protein kinases and phosphatases that keep the balance in protein phosphorylation. MAPKs are responsible for controlling cell proliferation and differentiation and both their enzyme activity and cellular localisation are influenced by the action of many protein phosphatases. Malfunction of either kinases or phosphatases are the basis for many diseases, in particular in cancer processes such as leukemia. Efficient treatment of such diseases is still challenged by the multifactorial nature of the underlying molecular mechanisms and our limited knowledge of their regulation. Furthermore, current single target therapies, result inevitably in disease relapse and poor prognosis, due to complex feedback loops and unexpected up-regulation of pathway components.
The complexity of such signalling networks is a major obstacle to the elucidation of the relative contribution of their partners by traditional experimental methods. A more sensible way is to apply a systems biology approach to dissect the underlying mechanisms in such networks. A true understanding of the network dynamics will then provide a much more robust tool for modelling suitable drug therapy regimens and individualised treatments.

Aim:
Our aim is to undertake an integrated systems biology approach to better understand the role of MAPK signalling in hematopoietic cell differentiation and malignant transformation. We will use mathematical modelling of the network dynamics to generated hypotheses that can be then tested experimentally, in vitro first and in animal systems later.