Regulation of TRAIL-mediated apoptosis: Mechanisms and quantitative assessment of response heterogeneity at the cell population level

该项目的目的是更好地了解克隆来源的细胞群中程序性细胞死亡（凋亡）的诱导。凋亡诱导剂是分子TRAIL（TNF相关凋亡诱导配体），其是TNF（肿瘤坏死因子）超家族的成员，通过刺激其各自的膜表达的死亡受体起作用。TRAIL是目前在临床研究中作为抗肿瘤剂测试的最有前途的分子之一。我们将通过实验1）研究TRAIL刺激后细胞群凋亡反应的异质性是否与单个肿瘤细胞的细胞周期状态有关，2）详细确定内源性凋亡因子的作用，3）确定肿瘤细胞的凋亡状态。本发明人的模型细胞系NCI-H460中的细胞凋亡诱导的（线粒体）信号传导途径，重点在于包含分子Smac/DIABLO的调节网络，XIAP和半胱天冬酶9和3，3），从而提供全面的定量数据和动力学，建立一个预测的数学模型的TRAIL介导的细胞凋亡，涵盖单一以及细胞群体的反应。重要的是，这个实验项目是一个跨学科的合作项目的一部分，系统科学家从系统理论和自动控制研究所，斯图加特大学。虽然这里所描述的实验工作可以独立存在，并有望取得重要的科学成果，但这种特殊的合作预计会产生特殊的剩余价值。基于我们产生的这些实验数据，系统科学家将构建、分析和验证一个数学模型，该模型描述了一个增殖的NCI-H460细胞群，其中TRAIL治疗诱导了大多数但不是所有细胞的凋亡。特别是在该合作项目的后期（第三年），模型衍生的预测将通过优化实验设计和预测分子关键组分及其行为来支持实验工作。因此，我们预计实验和理论科学家之间的高协同效应，在一个迭代的过程中运行在许多周期通过两个群体。

The aim of this project is to better understand the induction of programmed cell death (apoptosis) in a clonally derived cell population. Apoptosis inducer is the molecule TRAIL (TNF-related apoptosis inducing ligand), a member of the TNF (tumor necrosis factor) superfamily, acting via stimulation of its respective membrane expressed death receptors. TRAIL is one of the most promising molecules currently tested in clinical studies as an antitumoral agent. We will experimentally1) investigate whether the heterogeneity in the apoptotic response of a cell population upon TRAIL stimulation is linked to the cell cycle status of individual tumor cells,2) determine in details the role of the intrinsic (mitochondrial) signaling pathway of apoptosis induction in our model cell line NCI-H460 with the focus on the regulatory network comprising the molecules Smac/DIABLO, XIAP and the caspases 9 and 3,3) and thereby provide comprehensive quantitative data and kinetics for establishing a predictive mathematical model of TRAIL-mediated apoptosis covering both single as well as the cell population responses.Importantly this experimental project is part of an interdisciplinary cooperation project with systems scientist from the Institute for Systems Theory and Automatic Control, University of Stuttgart. Although the experimental work described here can stand on its own and important scientific results are expected, a special surplus value is expected from this particular cooperation. Based on these experimental data produced by us the systems scientists will construct, analyze and verify a mathematical model describing a proliferating NCI-H460 cell population where TRAIL treatment induces apoptosis in most, but not all cells. Especially at later stages of this cooperation project (year three) model-derived predictions will support experimental work via optimization of experimental design and predictions regarding molecular key components and their behavior. We therefore expect high synergy effects between the experimental and the theoretical scientists in terms of an iterative process running in many cycles through both groups.