Modelling the intracellular NF-KB signalling pathway

NF-nB is a transcription factor which is central to the regulation of genes involved in inflammatory and immune responses. Understanding the operation of NF-KB and its associated intracellular signalling pathway is essential in order to control a wide range of chronic inflammatory diseases, including asthma and rheumatoid arthritis. Abnormalities in the pathway are present in a variety of human cancersa nd may also affect the pathogenesiso f Alzheimer's disease. Computational modelling of the signalling pathway is necessary to overcome the practical limitations of biological experiments and to facilitate a more comprehensive understanding of the system. The thesis begins by outlining existing understanding of the NF-rdB signalling pathway, which in conjunction with a review of modelling methods is used to inform a different approach to model the pathway, using computational agents to represent individual molecules and receptors. The agent-based model is tested with well-understood chemical reactions before being used to describe the pathway. This provides a good appreciation of the system as a whole, offering a detailed description of events at every step in the pathway and allowing investigation of stochastic, spatial and structural parameters. The modelling process and simulation help to provide a prediction about the role of actin filaments of the cytoskeleton in regulating the unstimulated pathway; this is quantitatively validated by biological experiment. The effect of cell shape on the pathway is also investigated.