Chemical combination effects predict connectivity in biological systems
Chemical combination effects predict connectivity in biological systems
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DOI：
10.1038/msb4100116
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发表时间：
2007-02-01
影响因子：
9.9
通讯作者：
Keith, Curtis T.
中科院分区：
文献类型：
--
作者：
Lehar, Joseph;Zimmermann, Grant R.;Keith, Curtis T.
构建生物系统的治疗有用的模型的努力需要大量的和不同的数据集，其组件之间的功能连接。在这里，我们展示了细胞对化学物质组合的反应，揭示了它们的生物靶点是如何连接的。在不同剂量下对抑制剂进行的途径模拟预测了在酵母实验中再现的不同响应面形状，并得到了使用人类肿瘤细胞的更大屏幕的进一步支持。响应形态产生附近目标之间的详细连接约束，并且许多组合的协同概况显示整个网络中目标之间的相关性。来自化学组合的限制补充了遗传研究，因为它们探测不同的细胞成分，并可应用于不适合诱变的疾病模型。化学探针还提供了更大的灵活性，因为它们可以连续给药，时间控制，并易于组合。在扩展这一初步研究以涵盖更广泛的组合效应和途径拓扑结构后，化学组合可用于改进网络模型或识别新靶点。这种响应面方法甚至可以应用于非生物系统，其中可以测量对目标扰动的响应。
Efforts to construct therapeutically useful models of biological systems require large and diverse sets of data on functional connections between their components. Here we show that cellular responses to combinations of chemicals reveal how their biological targets are connected. Simulations of pathways with pairs of inhibitors at varying doses predict distinct response surface shapes that are reproduced in a yeast experiment, with further support from a larger screen using human tumour cells. The response morphology yields detailed connectivity constraints between nearby targets, and synergy profiles across many combinations show relatedness between targets in the whole network. Constraints from chemical combinations complement genetic studies, because they probe different cellular components and can be applied to disease models that are not amenable to mutagenesis. Chemical probes also offer increased flexibility, as they can be continuously dosed, temporally controlled, and readily combined. After extending this initial study to cover a wider range of combination effects and pathway topologies, chemical combinations may be used to refine network models or to identify novel targets. This response surface methodology may even apply to non-biological systems where responses to targeted perturbations can be measured.