Development of a Heuristic Machine Analogy Method for Model Simplification With an Application to a Large-Scale Model of Gi/Gs Signaling.

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Liang Yang, David Finlay, Michelle Glass, Stephen Duffull
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Abstract

Model simplification is a process to simplify large-scale mathematical models to enable easy applications such as simulation and parameter estimation. A novel heuristic machine analogy method of model simplification was developed and applied to a motivating example of a model for cAMP signaling switch induced by Gi/Gs pathway competition for the CB1 receptor (consisting of 31 species and 76 parameters) to enable its use in estimation. The method first acquired an understanding of the mechanism by full model simulation, and then the mechanism was abstracted to a machine analogy. The machine analogy included signal start, signal mode selector, signal size regulator, and final effector, representing functions of different parts of the full model. The simplified minimal model (consisting of 11 species and 13 estimated parameters) was used for parameter estimation for Gi/Gs signaling of six CB1 agonists. The results of the minimal model suggested that six CB1 agonists have similar ratios of Gi/Gs activation, indicating Gi/Gs preference was more of a system effect rather than a ligand-specific effect. In conclusion, the novel machine analogy method can be used to heuristically simplify a larger-scale model while maintaining the important mechanisms. In the example here, the full Gi/Gs model of CB1 was successfully simplified, and the results indicated Gi/Gs preference is a system-dependent effect.

模型简化的启发式机器类比方法及其在大尺度Gi/Gs信号模型中的应用。
模型简化是一种简化大规模数学模型的过程,以使模拟和参数估计等应用变得容易。提出了一种新的启发式机器类比模型简化方法,并将其应用于Gi/Gs通路竞争诱导的cAMP信号转换模型的激励示例,使其能够用于估计CB1受体(由31个物种和76个参数组成)。该方法首先通过全模型仿真获得对机构的理解,然后将机构抽象为机器类比。机器类比包括信号启动、信号模式选择、信号大小调节和最终效应器,代表了全模型不同部分的功能。采用简化最小模型(包含11个物种和13个估计参数)对6种CB1激动剂的Gi/Gs信号进行参数估计。最小模型的结果表明,六种CB1激动剂具有相似的Gi/Gs激活比例,表明Gi/Gs偏好更多的是系统效应,而不是配体特异性效应。总之,这种新的机器类比方法可以在保留重要机理的同时,启发式地简化更大规模的模型。在本例中,我们成功地简化了CB1的完整Gi/Gs模型,结果表明Gi/Gs偏好是一种系统依赖效应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
5.00
自引率
11.40%
发文量
146
审稿时长
8 weeks
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