Bentele M, Lavrik I, Ulrich M, Stösser S, Heermann D W, Kalthoff H, Krammer P H, Eils R
Division Theoretical Bioinformatics,German Caner Research Center DKFZ, Heidelberg 69120, Germany.
J Cell Biol. 2004 Sep 13;166(6):839-51. doi: 10.1083/jcb.200404158.
Mathematical modeling is required for understanding the complex behavior of large signal transduction networks. Previous attempts to model signal transduction pathways were often limited to small systems or based on qualitative data only. Here, we developed a mathematical modeling framework for understanding the complex signaling behavior of CD95(APO-1/Fas)-mediated apoptosis. Defects in the regulation of apoptosis result in serious diseases such as cancer, autoimmunity, and neurodegeneration. During the last decade many of the molecular mechanisms of apoptosis signaling have been examined and elucidated. A systemic understanding of apoptosis is, however, still missing. To address the complexity of apoptotic signaling we subdivided this system into subsystems of different information qualities. A new approach for sensitivity analysis within the mathematical model was key for the identification of critical system parameters and two essential system properties: modularity and robustness. Our model describes the regulation of apoptosis on a systems level and resolves the important question of a threshold mechanism for the regulation of apoptosis.
理解大型信号转导网络的复杂行为需要数学建模。以往对信号转导途径进行建模的尝试往往局限于小型系统或仅基于定性数据。在此，我们开发了一个数学建模框架，用于理解CD95（APO-1/Fas）介导的细胞凋亡的复杂信号行为。细胞凋亡调控缺陷会导致诸如癌症、自身免疫和神经退行性变等严重疾病。在过去十年中，细胞凋亡信号传导的许多分子机制已得到研究和阐明。然而，对细胞凋亡的系统理解仍然欠缺。为了解决细胞凋亡信号传导的复杂性，我们将该系统细分为具有不同信息质量的子系统。数学模型中一种新的敏感性分析方法是识别关键系统参数以及两个基本系统特性（模块化和稳健性）的关键。我们的模型在系统层面描述了细胞凋亡的调控，并解决了细胞凋亡调控阈值机制这一重要问题。
