Partner: A. Horton Caroline |
Recent publications
1. | Yunjiao W.♦, Paszek P., Horton Caroline A.♦, Hong Y.♦, White M.♦, Kell Douglas B.♦, Muldoon M.♦, Broomhead David S.♦, A systematic survey of the response of a model NF-kB signalling pathway to TNFa stimulation, JOURNAL OF THEORETICAL BIOLOGY, ISSN: 0022-5193, DOI: 10.1016/j.jtbi.2011.12.014, Vol.297, pp.137-147, 2012 Abstract: White's lab established that strong, continuous stimulation with tumour necrosis factor- () can induce sustained oscillations in the subcellular localisation of the transcription factor nuclear factor (NF-). But the intensity of the 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 stimulation and the existence of sustained NF- oscillations. Using a deterministic model developed by Ashall et al. in 2009, we find that the system's responses to are characterised by a supercritical Hopf bifurcation point: above a critical intensity of the system exhibits sustained oscillations in NF-kB localisation. For 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 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- mediated gene transcription. Keywords:NF-kB signalling pathway, Parameter sensitivity, Bifurcation analysis, Oscillations Affiliations:
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2. | Yunjiao W.♦, Paszek P., Horton Caroline A.♦, Kell Douglas B.♦, White M.♦, Broomhead David S.♦, Muldoon M.♦, Interactions among oscillatory pathways in NF-kappa B signaling, BMC SYSTEMS BIOLOGY, ISSN: 1752-0509, DOI: 10.1186/1752-0509-5-23, Vol.5, pp.23-1-11, 2011 Abstract: Background
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3. | Turner D.♦, Paszek P., Woodcock D. J.♦, Nelson David E.♦, Horton Caroline A.♦, Yunjiao W.♦, Spiller David G.♦, Rand D. A.♦, White M.♦, Harper C. V.♦, Physiological levels of TNFalpha stimulation induce stochastic dynamics of NF-kappaB responses in single living cells, Journal of Cell Science, ISSN: 0021-9533, DOI: 10.1242/jcs.069641, Vol.123, No.16, pp.2834-2843, 2010 Abstract: Nuclear factor kappa B (NF-kappaB) signalling is activated by cellular stress and inflammation and regulates cytokine expression. We applied single-cell imaging to investigate dynamic responses to different doses of tumour necrosis factor alpha (TNFalpha). Lower doses activated fewer cells and those responding showed an increasingly variable delay in the initial NF-kappaB nuclear translocation and associated IkappaBalpha degradation. Robust 100 minute nuclear:cytoplasmic NF-kappaB oscillations were observed over a wide range of TNFalpha concentrations. The result is supported by computational analyses, which identified a limit cycle in the system with a stable 100 minute period over a range of stimuli, and indicated no co-operativity in the pathway activation. These results suggest that a stochastic threshold controls functional all-or-nothing responses in individual cells. Deterministic and stochastic models simulated the experimentally observed activation threshold and gave rise to new predictions about the structure of the system and open the way for better mechanistic understanding of physiological TNFalpha activation of inflammatory responses in cells and tissues. Keywords:NF- Affiliations:
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4. | Ashall L.♦, Horton Caroline A.♦, Nelson David E.♦, Paszek P.♦, Harper Claire V.V.♦, Sillitoe K.♦, Ryan S.♦, Spiller David G.♦, Unitt John F.♦, Broomhead David S.♦, Kell Douglas B.♦, Rand David A.A.♦, Sée V.♦, White Michael R.R.♦, Pulsatile Stimulation Determines Timing and Specificity of NF-κB-Dependent Transcription, Science, ISSN: 0036-8075, DOI: 10.1126/science.1164860, Vol.324, No.5924, pp.242-246, 2009 Abstract: The nuclear factor κB (NF-κB) transcription factor regulates cellular stress responses and the immune response to infection. NF-κB activation results in oscillations in nuclear NF-κB abundance. To define the function of these oscillations, we treated cells with repeated short pulses of tumor necrosis factor–α at various intervals to mimic pulsatile inflammatory signals. At all pulse intervals that were analyzed, we observed synchronous cycles of NF-κB nuclear translocation. Lower frequency stimulations gave repeated full-amplitude translocations, whereas higher frequency pulses gave reduced translocation, indicating a failure to reset. Deterministic and stochastic mathematical models predicted how negative feedback loops regulate both the resetting of the system and cellular heterogeneity. Altering the stimulation intervals gave different patterns of NF-κB–dependent gene expression, which supports the idea that oscillation frequency has a functional role. Affiliations:
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