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A Framework study of the NF-kB signalling pathway

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Abstract: The study of complex biological systems requires an interplay between theory, experimentation, modelling and simulation. Hypotheses are tested by experimental observations which are integrated into theoretical models that are then amenable to simulations for predicting the responses to perturbations made to a biological model. Thus, detailed understanding of these systems cannot be achieved by modelling or experiments alone but requires a tight integration between the two. This type of scientific approach is required for investigating the dynamic relationships between components, their organisation and regulation in cellular signal transduction networks. Mathematical modelling can further facilitate the understanding of these networks by enabling quantified relationships between components to be studied. The nuclear factor-kB (NF-kB) signalling pathway is an example of a complex signal transduction network. NF-kB is a transcription factor which has crucial roles in inflammation, immunity, cell proliferation and apoptosis. Proteins involved in the NF-kB signalling pathway undergo phosphorylation which ultimately leads to the activation of the transcription factor and expression of genes involved in various cellular processes. This work investigates how NF-kB oscillations depend on the kinetics of phosphorylation by IKK ; and describes a “trial” to analyze temporal behaviour of NF-kB signalling pathway in a frame work of combined experimental and in silico approach. We show that in the population average one finds damped oscillations upon IL1 -alpha treatment. We then characterise the kinetics of IkB-alpha phosphorylation by IKK and use the measured values to refine the insilico model. Finally, we use an inhibitor of IKK to show the effect of decreased phosphorylation by IKK on NF-kB oscillations experimentally and subsequently compared them to simulation. Results of which were used to explain the contribution of IKK2 to the control of frequency and amplitude of the observed NF-kB oscillations.

Biography: Adaoha Ihekwaba graduated with a BSc. in Pharmaceutical Sciences from the University of Greenwich, London, 2001 (thesis title – Symmetric & Asymmetric Synthesis of 4-Aryl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate and their conversion to pyridine by the process of Oxidation ) and a Ph.D degree in 2006 from The University of Manchester (thesis title – Modelling of Cellular Signal Transduction Process (NF-kB signalling pathway) using Numerical Simulation Techniques) under the supervision of Prof. DB Kell and Dr. Neil Benson (Pfizer). One of the main focus of the research was to explore the effectiveness of numerical simulation techniques to better understand the implications of complex and kinetics of cellular signal transduction events – with the intension to use existing data, state-of the art Cellular Fluorescence reader technology and standard inhibitors to generate data sets that would then be used to build and test computer models. For her postdoctoral research, a Wain International Fellowship was awarded to Adaoha Ihekwaba through obtained support from the BBSRC in 2006 (which was carried out at the Virginia Bioinformatics Institute under the guidance of Prof. Pedro Mendes) to establish a methodology for developing computational models of cellular biochemistry based on genome-wide molecular profiling data. The methods were applied to existing time course data sets of metabolite, protein and transcript profiles of the forage crop Medicago truncatula after elicitation with the hormone methyl-jasmonic acid.

This talk is part of the CoSBi Computational and Systems Biology Series series.

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