Computational approaches to systems biology: Applications in xenobiotic metabolism and cellular signaling

Systems biology attempts to identify interactions between the components of biological systems and understand how these interactions give rise to the physiological function of the system. This thesis describes the application of computational tools to study, on a system-wide level, metabolic reaction networks describing the biodegradation of xenobiotic compounds and a cellular signaling network involved in coordinating the cell's immune response to intracellular pathogens.;Microorganisms provide a wealth of potential in the reduction and elimination of xenobiotic compounds in the environment. In order to explore their biodedegradative capabilities, computational methods are needed to predict xenobiotic metabolism. In Part I, a framework for predictive biodegradation called BNICE is described and applied to generate novel xenobiotic biodegradation pathways. A thermodynamic analysis was used to estimate the relative energetic feasibility of the degradation routes. Additionally, metabolic flux analysis and thermodynamics-based metabolic flux analysis provided an estimate of the feasibility within the context of the cellular environment, probing how implementation of the novel pathways influences the physiology of the cell in a genomescale model of cellular metabolism. This work demonstrates the utility of computational tools to design and evaluate novel biodegradation pathways.;Mathematical models of cell signaling pathways provide insight into the system-level behavior of cellular signaling networks. In particular, it is important to understand the regulatory features of this network in order to design effective therapeutic interventions. Part II of this thesis describes the development and application of a model of the Interleukin-12 pathway, a cellular signaling network involved in mediating the cell's immune response. Chemical kinetic modeling, parameter estimation, and time scale analysis were applied to infer the regulatory mechanisms that govern signaling in the pathway. These tools provided insight into the biology of the cell signaling pathway and revealed the kinetic events that largely influenced the cellular immune response.