Harrington Heather A, Ho Kenneth L, Ghosh Samik, Tung K C
Department of Mathematics, Imperial College London, London, SW7 2AZ, UK.
Theor Biol Med Model. 2008 Dec 10;5:26. doi: 10.1186/1742-4682-5-26.
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.
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.
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.
多细胞生物采用的一种关键生理机制是细胞凋亡，即程序性细胞死亡。细胞凋亡是由半胱天冬酶的激活引发的，以响应细胞外（外在）和细胞内（内在）信号。外在和内在途径分别以死亡诱导信号复合物（DISC）和凋亡小体的形成为特征；DISC和凋亡小体都是具有复杂形成动力学的寡聚体。此外，外在和内在途径通过线粒体凋亡诱导通道经由Bcl-2蛋白家族相互耦合。
构建并分析了一个半胱天冬酶激活模型。通过模块化方法和对三个功能模块的平衡抽象简化了细胞凋亡信号网络。数学模型由一个常微分方程组组成，并进行了数值求解。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作用。
通过线性回归技术，我们确定了反馈、复合物解离和负调节因子是细胞凋亡中的关键成分。我们模型公式的分析和简化模型表明，所选细胞系主要表现出强烈的外在半胱天冬酶活性，这是I型细胞的典型行为。此外，在简化模型框架下，所选细胞系表现出半胱天冬酶激活可能发生的不同模式。最后，所提出的细胞凋亡模块化模型可能概括其他细胞和组织的行为，具体识别和预测负责从I型细胞行为向II型细胞行为转变的成分。
