Mathematical modelling and systems analysis of intracellular signalling networks and the budding yeast cell cycle

摘要

Cellular signalling networks are responsible for coordinating a cell’s response to internaludand external perturbations. In order to do this, these networks make use of a wide varietyudof molecular mechanisms, including allostery, gene regulation, and post-translationaludmodifications. Mathematical modelling and systems approaches have been useful in understandingudthe signal processing capabilities and potential behaviours of such networks.udIn this thesis, a series of mathematical modelling and systems investigations are presentedudinto the potential regulation of a variety of cellular systems. These systems rangeudfrom ubiquitously seen mechanisms and motifs, common to a wide variety of signallingudpathways across many organisms, to the study of a particular process in a particular celludtype - the cell cycle in Saccharomyces cerevisiae.udThe first part of the thesis involves the analysis of ubiquitous signalling mechanismsudand behaviours. The potential behaviours of these systems are examined, with particularudattention paid to properties such as adaptive and switch-like signalling. This series ofudinvestigations is followed by a study of the dynamic regulation of cell cycle oscillators byudexternal signalling pathways. A methodology is developed for the study of mathematicaludmodels of the cell cycle, based on linear sensitivity analysis, and this methodology is thenudapplied to a range of models of the cell cycle in Saccharomyces cerevisiae. This allows theuddescription of some interesting generic behaviours, such as nonmonotonic approach of celludcycle characteristics to their eventual values, as well as allowing identification of potentialudprinciples of dynamic regulation of the cell cycle.