A systems biology approach to explore the dynamics and interactions of the NF-κB signalling pathway

• Main Author: Boyd, James
• Other Authors: See, Violaine; Bearon, Rachel; Sanderson, Chris
• Published: University of Liverpool 2012
• Subjects: 570; QH301 Biology
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.579309

The family of nuclear factor kappa B (NF-κB) transcription factors controls diverse mammalian signalling responses that mediate cell survival, inflammation, and immune response. Complex spatial and temporal dynamics observed in the NF-κB pathway are believed to determine gene expression profiles, which confer different physiological responses. The intricate and non-linear nature of the NF-κB system has benefited from the application of mathematical modelling methods which provide non-intuitive insights into the mechanism of cellular regulation. It has become apparent that responses in signalling networks are influenced by complex spatial and temporal dynamics, which arise from a diverse range of competitive and combinatorial interactions. The systematic collection of quantitative data allows the application of a systems biology approaches to investigate and model complex biological systems. Through reiterative cycles of experimental and mathematical analysis it is possible to make predictions which generate testable hypotheses and guide future research. The primary aim of this work is to consider ways in which understanding of the core NF-κB system can be expanded to include a wider array of dynamic interactions using both theoretical and experimental approaches. From a modelling perspective, the goal of the project was to consider methods of how the network presented by Ashall et al. could be adapted and expanded to incorporate new data on the interactions of NF-κB with other signalling pathways. The main technique was to explore different network topologies and parameter set spaces in order to elucidate key features of the system structure. In experimental terms the goal was to consider methods and techniques of observing molecular dynamics and interactions in live cells and to define the potential and limitations of these tools for studying the NF-κB signalling pathway. In particular, fluorescence fluctuation microscopy approaches are explored. By combining both experimental and theoretical approaches, a new model of NF-κB signalling is proposed, with statements on the dynamics of protein complex formation in live cells made.