Department of Biosensors and Processing of Biomedical Signals, Silesian University of Technology, 41-800 Zabrze, Poland.
Department of Systems Biology and Engineering, Silesian University of Technology, 44-100 Gliwice, Poland.
Int J Mol Sci. 2022 Jun 13;23(12):6604. doi: 10.3390/ijms23126604.
Mathematical modeling of signaling pathways and regulatory networks has been supporting experimental research for some time now. Sensitivity analysis, aimed at finding model parameters whose changes yield significantly altered cellular responses, is an important part of modeling work. However, sensitivity methods are often directly transplanted from analysis of technical systems, and thus, they may not serve the purposes of analysis of biological systems. This paper presents a novel sensitivity analysis method that is particularly suited to the task of searching for potential molecular drug targets in signaling pathways. Using two sample models of pathways, p53/Mdm2 regulatory module and IFN-β-induced JAK/STAT signaling pathway, we show that the method leads to biologically relevant conclusions, identifying processes suitable for targeted pharmacological inhibition, represented by the reduction of kinetic parameter values. That, in turn, facilitates subsequent search for active drug components.
目前，信号通路和调控网络的数学建模已经在为一些实验研究提供支持。敏感性分析旨在找到那些模型参数发生变化会显著改变细胞反应的参数，这是建模工作的重要组成部分。然而，敏感性分析方法通常是直接从技术系统分析中移植过来的，因此，它们可能并不适用于生物系统的分析。本文提出了一种新的敏感性分析方法，特别适合于在信号通路中寻找潜在的分子药物靶点。我们使用了两个通路的模型，即 p53/Mdm2 调控模块和 IFN-β诱导的 JAK/STAT 信号通路，表明该方法可以得出具有生物学意义的结论，确定适合靶向药理抑制的过程，即通过降低动力学参数值来实现。这反过来又有助于后续寻找有效的药物成分。
