Construction and analysis of a modular model of caspase activation in apoptosis
Construction and analysis of a modular model of caspase activation in apoptosis
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DOI：
10.1186/1742-4682-5-26
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发表时间：
2008-12-10
影响因子：
--
通讯作者：
Tung, K. C.
中科院分区：
文献类型：
--
作者：
Harrington, Heather A.;Ho, Kenneth L.;Tung, K. C.
背景：多细胞生物体使用的一个关键的生理机制是细胞凋亡，即程序性细胞死亡。细胞外(外在)和细胞内(内在)信号都能激活半胱氨酸氨基转移酶，从而触发细胞凋亡。外在途径和内在途径分别以死亡诱导信号复合体(Disk)和凋亡体的形成为特征，Disk和凋亡体都是具有复杂形成动力学的寡聚体。此外，外源性和内源性途径通过线粒体凋亡诱导通道通过Bcl2蛋白家族相互耦合。结果：构建并分析了caspase激活模型。通过模块化方法和对三个功能模块的均衡抽象，简化了细胞凋亡信号网络。该数学模型由一组常微分方程组组成，并用数值方法求解。多元线性回归分析研究了每个模块的作用，并构建了简化模型，以确定外在和内在途径在触发不同细胞系凋亡中的关键贡献。结论：通过线性回归技术，我们确定了反馈、复合体的解离和负调控因子是细胞凋亡的关键成分。对我们的模型公式的分析和简化模型表明，选定的细胞系主要表现出强烈的外源性caspase，这是I型细胞的典型行为。此外，在简化的模型框架下，所选择的细胞系呈现出可能发生caspase激活的不同模式。最后，所提出的模块化的细胞凋亡模型可能概括更多的细胞和组织的行为，特别是识别和预测负责从I型细胞行为向II型细胞行为转变的组件。
Background: A key physiological mechanism employed by multicellular organisms is apoptosis, or programmed cell death. Apoptosis is triggered by the activation of caspases in response to both extracellular (extrinsic) and intracellular (intrinsic) signals. The extrinsic and intrinsic pathways are characterized by the formation of the death-inducing signaling complex (DISC) and the apoptosome, respectively; both the DISC and the apoptosome are oligomers with complex formation dynamics. Additionally, the extrinsic and intrinsic pathways are coupled through the mitochondrial apoptosis-induced channel via the Bcl-2 family of proteins.Results: A model of caspase activation is constructed and analyzed. The apoptosis signaling network is simplified through modularization methodologies and equilibrium abstractions for three functional modules. The mathematical model is composed of a system of ordinary differential equations which is numerically solved. Multiple linear regression analysis investigates the role of each module and reduced models are constructed to identify key contributions of the extrinsic and intrinsic pathways in triggering apoptosis for different cell lines.Conclusion: Through linear regression techniques, we identified the feedbacks, dissociation of complexes, and negative regulators as the key components in apoptosis. The analysis and reduced models for our model formulation reveal that the chosen cell lines predominately exhibit strong extrinsic caspase, typical of type I cell, behavior. Furthermore, under the simplified model framework, the selected cells lines exhibit different modes by which caspase activation may occur. Finally the proposed modularized model of apoptosis may generalize behavior for additional cells and tissues, specifically identifying and predicting components responsible for the transition from type I to type II cell behavior.