细胞存活与死亡之间的平衡：肿瘤坏死因子α细胞毒性的最小定量模型
Balance between cell survival and death: a minimal quantitative model of tumor necrosis factor alpha cytotoxicity
摘要：
肿瘤坏死因子α（TNF）在与其R1型受体（TNF-R1）结合后在细胞中启动一系列复杂的生化事件。最近的实验工作已经揭示了导致细胞存活或死亡的初始信号复合物的募集的分子调节。存活信号通过TNF与细胞膜上的TNF-R1的直接结合而激活，而凋亡信号通过内吞的TNF/TNF-R1复合物而激活。在这里，我们调查这些方面的发展TNF结合，内化和细胞内信号的定量数学模型。模型输出与实验数据相比较有利，并允许计算TNF介导的细胞毒性，如在不同的细胞系统中观察到的。我们广泛地研究了参数空间，以表明该模型在广泛的参数值范围内具有结构稳定性和鲁棒性。因此，我们的模型适合于在多尺度模拟程序中实现，这些程序目前正在开发中，以研究大型肿瘤细胞群体的行为。
英文摘要：
Tumor Necrosis Factor alpha (TNF) initiates a complex series of biochemical events in the cell upon binding to its type R1 receptor (TNF-R1). Recent experimental work has unravelled the molecular regulation of the recruitment of initial signaling complexes that lead either to cell survival or death. Survival signals are activated by direct binding of TNF to TNF-R1 at the cell membrane whereas apoptotic signals by endocytosed TNF/TNF-R1 complexes. Here we investigate these aspects by developing a quantitative mathematical model of TNF binding, internalization and intracellular signaling. Model outputs compare favorably with experimental data and allow to compute TNF-mediated cytotoxicity as observed in different cell systems. We extensively study the space of parameters to show that the model is structurally stable and robust over a broad range of parameter values. Thus, our model is suitable for implementation in multi-scale simulation programs that are presently under development to study the behavior of large tumor cell populations.
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