A strategy to study pathway cross-talks of cells under repetitive exposure to stimuli
A strategy to study pathway cross-talks of cells under repetitive exposure to stimuli
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DOI：
10.1186/1752-0509-6-s3-s6
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发表时间：
2012-12-17
影响因子：
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通讯作者：
Xing, Jianhua
中科院分区：
文献类型：
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作者：
Fu, Yan;Jiang, Xiaoshan;Xing, Jianhua
背景：细胞在其自然环境中受到波动和多种刺激。信号通路经常相互串扰，并产生复杂的非线性动力学。具体地说，细胞反复暴露于相同的刺激有时会导致增强的细胞反应。实例是用亚阈值然后高剂量的内毒素或细胞因子刺激预处理的先天免疫细胞的放大的促炎反应。这种现象，在文献中称为启动效应，具有重要的病理和临床意义。结果：在以前的研究中，我们列举了可能的机制，使用三节点网络模型启动。分析揭示了三种机制。基于这些结果，在这项工作中，我们开发了一个简单的程序来确定分子候选人的启动效应和相应的机制。该过程涉及时间过程测量，e。例如，在一个实施例中，在低、高和低+高剂量刺激下的基因表达水平或蛋白质活性，然后对动力学模式进行计算分析，并在调控网络的背景下识别功能作用。我们将该程序应用于一组已发表的干扰素-γ介导的人巨噬细胞启动效应的微阵列数据。该分析确定了许多可能有助于干扰素-γ启动的网络基序。一个进一步详细的数学模型分析进一步揭示了如何结合不同的机制导致的priming effect.Conclusions：一个可以进行系统的筛选，使用所提出的程序结合高通量测量，在转录组和蛋白质组水平。它适用于各种启动现象。
Background: Cells are subject to fluctuating and multiple stimuli in their natural environment. The signaling pathways often crosstalk to each other and give rise to complex nonlinear dynamics. Specifically repetitive exposure of a cell to a same stimulus sometime leads to augmented cellular responses. Examples are amplified proinflammatory responses of innate immune cells pretreated with a sub-threshold then a high dose of endotoxin or cytokine stimulation. This phenomenon, called priming effect in the literature, has important pathological and clinical significances.Results: In a previous study, we enumerated possible mechanisms for priming using a three-node network model. The analysis uncovered three mechanisms. Based on the results, in this work we developed a straightforward procedure to identify molecular candidates contributing to the priming effect and the corresponding mechanisms. The procedure involves time course measurements, e. g., gene expression levels, or protein activities under low, high, and low + high dose of stimulant, then computational analysis of the dynamics patterns, and identification of functional roles in the context of the regulatory network. We applied the procedure to a set of published microarray data on interferon-gamma-mediated priming effect of human macrophages. The analysis identified a number of network motifs possibly contributing to Interferon-gamma priming. A further detailed mathematical model analysis further reveals how combination of different mechanisms leads to the priming effect.Conclusions: One may perform systematic screening using the proposed procedure combining with high throughput measurements, at both transcriptome and proteome levels. It is applicable to various priming phenomena.