Identification of potential pathway mediation targets in Toll-like receptor signaling.
Identification of potential pathway mediation targets in Toll-like receptor signaling.
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DOI：
10.1371/journal.pcbi.1000292
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发表时间：
2009-02
影响因子：
4.3
通讯作者：
Palsson BØ
中科院分区：
文献类型：
--
作者：
Li F;Thiele I;Jamshidi N;Palsson BØ
信号网络重建和分析方法的最新进展促进了大规模模型的发展，这些模型包含了完整的功能和生物学相关特征。本文提出了人Toll样受体信号传导网络的扩展重建。这种重建包含大量的激酶、磷酸酶和其他相关蛋白质，这些蛋白质介导信号级联反应，沿着描绘它们相关的化学反应。一个计算框架的基础上的方法的大规模凸分析的发展和应用到这个网络来表征输入输出关系。输入-输出关系使网络模块化为10条路径。该分析确定了TLR信号传导的抑制性介导的潜在候选物，其特异性和效力。随后，我们能够通过基于约束的建模方法确定八个新的抑制目标。本研究的结果有望为进一步研究Toll样受体信号网络及其作用提供有意义的途径。人类先天免疫系统作为抵御病原体的第一道防线，是我们生存的重要组成部分。先天免疫系统的一个组成部分是Toll样受体信号网络，其负责将激活信号从细胞外部传递到细胞内的分子机制。先天免疫系统必须保持适当的平衡，因为过度激活可能导致潜在的致命性感染性休克。因此，人们对开发能够介导Toll样受体信号传导的药物以减轻过度激活的影响非常感兴趣。我们提出了一个在硅片上重建的Toll样受体信号网络，并将其转换成一个数学框架，适合于基于约束的建模和分析。这一方法有助于确定基于药物的调解的潜在候选人。除了确定Toll样受体网络的药物介导靶点外，我们还提供了一个可以不断更新和维护的网络模型。
Recent advances in reconstruction and analytical methods for signaling networks have spurred the development of large-scale models that incorporate fully functional and biologically relevant features. An extended reconstruction of the human Toll-like receptor signaling network is presented herein. This reconstruction contains an extensive complement of kinases, phosphatases, and other associated proteins that mediate the signaling cascade along with a delineation of their associated chemical reactions. A computational framework based on the methods of large-scale convex analysis was developed and applied to this network to characterize input–output relationships. The input–output relationships enabled significant modularization of the network into ten pathways. The analysis identified potential candidates for inhibitory mediation of TLR signaling with respect to their specificity and potency. Subsequently, we were able to identify eight novel inhibition targets through constraint-based modeling methods. The results of this study are expected to yield meaningful avenues for further research in the task of mediating the Toll-like receptor signaling network and its effects. The human innate immune system, as the first line of defense against pathogens, is a vital component of our survival. One component of the innate immune system is the Toll-like receptor signaling network, which is responsible for transmitting activation signals from the outside of the cell to molecular machinery inside the cell. The innate immune system must be properly balanced, as excessive activation can lead to potentially lethal septic shock. Therefore, there is much interest in developing drugs that can mediate Toll-like receptor signaling so as to alleviate effects of excess activation. We present an in silico reconstruction of the Toll-like receptor signaling network and convert it into a mathematical framework that is suitable for constraint-based modeling and analysis. This approach leads to the identification of potential candidates for drug-based mediation. In addition to identifying targets for drug mediation of the Toll-like receptor network, we also supply a network model that may be continually updated and maintained.
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DOI：
10.1038/nrmicro1949
发表时间：
2009-02
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
14.8
作者：
Becker, Scott A.;Feist, Adam M.;Herrgard, Markus J.
通讯作者：
Herrgard, Markus J.
影响因子：
3.4
作者：
Beard, DA;Liang, SC;Qian, H
通讯作者：
Qian, H
影响因子：
4.3
作者：
Lee, Jong Min;Gianchandani, Erwin P.;Eddy, James A.;Papin, Jason A.
通讯作者：
Papin, Jason A.
影响因子：
5.3
作者：
Feng, YF;Longmore, GD
通讯作者：
Longmore, GD