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A systematic survey of the response of a model NF-κBκB signalling pathway to TNFαTNFα stimulation

Wang, Yunjiao and Paszek, Pawel and Horton, Caroline A. and Yue, Hong and White, Michael R.H. and Kell, Douglas B. and Muldoon, Mark R. and Broomhead, David S. (2012) A systematic survey of the response of a model NF-κBκB signalling pathway to TNFαTNFα stimulation. Journal of Theoretical Biology, 297. pp. 137-147. ISSN 0022-5193

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Abstract

White's lab established that strong, continuous stimulation with tumour necrosis factor- (TNF ) can induce sustained oscillations in the subcellular localisation of the transcription factor nuclear factor B (NF- B). But the intensity of the TNF signal varies substantially, from picomolar in the blood plasma of healthy organisms to nanomolar in diseased states. We report on a systematic survey using computational bifurcation theory to explore the relationship between the intensity of TNF stimulation and the existence of sustained NF- B oscillations. Using a deterministic model developed by Ashall et al. in 2009, we find that the system's responses to TNF are characterised by a supercritical Hopf bifurcation point: above a critical intensity of TNF the system exhibits sustained oscillations in NF-kB localisation. For TNF below this critical value, damped oscillations are observed. This picture depends, however, on the values of the model's other parameters. When the values of certain reaction rates are altered the response of the signalling pathway to TNF stimulation changes: in addition to the sustained oscillations induced by high-dose stimulation, a second oscillatory regime appears at much lower doses. Finally, we define scores to quantify the sensitivity of the dynamics of the system to variation in its parameters and use these scores to establish that the qualitative dynamics are most sensitive to the details of NF- B mediated gene transcription.

Item type: Article
ID code: 40614
Keywords: gene transcription , subcellular localisation , computational bifurcation theory , bifurcation analysis, systematic survey, model nf-kappa b, signalling pathway, tnf alpha stimulation, Electrical engineering. Electronics Nuclear engineering, Agricultural and Biological Sciences(all), Biochemistry, Genetics and Molecular Biology(all), Modelling and Simulation, Applied Mathematics, Statistics and Probability, Immunology and Microbiology(all), Medicine(all)
Subjects: Technology > Electrical engineering. Electronics Nuclear engineering
Department: Faculty of Engineering > Electronic and Electrical Engineering
Related URLs:
    Depositing user: Pure Administrator
    Date Deposited: 31 Jul 2012 16:30
    Last modified: 05 Sep 2014 12:57
    URI: http://strathprints.strath.ac.uk/id/eprint/40614

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