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一种最小的NF-κB信号通路时空模型展现出一系列行为。

A minimal spatio-temporal model of the NF-κB signalling pathway exhibits a range of behaviours.

作者信息

Terry Alan J

机构信息

Division of Mathematics, University of Dundee, Dundee, DD1 4HN, UK,

出版信息

Bull Math Biol. 2014 Oct;76(10):2363-88. doi: 10.1007/s11538-014-0011-2. Epub 2014 Sep 9.

Abstract

In animal cells, the transcription factor NF-κB regulates many stressful, inflammatory, and innate immune responses. Experiments have revealed that, in response to cell stimulation, NF-κB can exhibit oscillatory dynamics where the nature of these dynamics can influence the pattern of NF-κB-dependent gene expression. Oscillations in NF-κB are believed to depend on a negative feedback loop linking NF-κB and one of its downstream products, namely IκBα. This negative feedback loop is enhanced by cell stimulation. However, it also exists in the absence of cell stimulation. Here we propose a minimal spatio-temporal model of the NF-κB signalling pathway, composed of partial differential equations. Through numerical simulations, we find various combinations of behaviours before and during cell stimulation: equilibrium dynamics (rapid convergence to a solution that is everywhere constant) before cell stimulation, followed by oscillatory dynamics during cell stimulation; oscillatory dynamics before and during cell stimulation; oscillatory dynamics before cell stimulation, followed by equilibrium dynamics during cell stimulation; and equilibrium dynamics before and during cell stimulation. In each case, when cell stimulation ceases, the model quickly returns to its pre-stimulation behaviour. All of these different combinations of behaviours occur for similar sets of parameter values. Therefore, our results may help to explain why, in experiments on the NF-κB pathway involving populations of cells, only a certain fraction of the cells exhibit oscillatory dynamics.

摘要

在动物细胞中,转录因子NF-κB调节许多应激、炎症和先天性免疫反应。实验表明,响应细胞刺激时,NF-κB可呈现振荡动力学,这些动力学的性质会影响NF-κB依赖基因表达的模式。NF-κB的振荡被认为依赖于一个将NF-κB与其下游产物之一即IκBα相连接的负反馈环。这种负反馈环会因细胞刺激而增强。然而,在没有细胞刺激的情况下它也存在。在此,我们提出一个由偏微分方程组成的NF-κB信号通路的最小时空模型。通过数值模拟,我们发现了细胞刺激之前和期间行为的各种组合:细胞刺激之前是平衡动力学(迅速收敛到处处恒定的解),细胞刺激期间是振荡动力学;细胞刺激之前和期间都是振荡动力学;细胞刺激之前是振荡动力学,细胞刺激期间是平衡动力学;细胞刺激之前和期间都是平衡动力学。在每种情况下,当细胞刺激停止时,模型会迅速恢复到刺激前的行为。所有这些不同的行为组合都出现在相似的参数值集下。因此,我们的结果可能有助于解释为什么在涉及细胞群体的NF-κB通路实验中,只有一定比例的细胞呈现振荡动力学。

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