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

该项目的目的是为了更好地了解诱导程序性细胞死亡（凋亡）在克隆来源的细胞群。凋亡诱导剂是分子TRAIL （TNF相关的凋亡诱导配体），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死亡受体起作用。TRAIL是目前临床研究中最有前途的抗肿瘤药物之一。我们将在实验中：1)研究细胞群在TRAIL刺激下的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)在我们的模型细胞系NCI-H460中，详细确定细胞凋亡诱导的内在（线粒体）信号通路的作用，重点研究由Smac/DIABLO分子组成的调控网络；XIAP和caspases 9和3,3)，从而为建立trail介导的细胞凋亡的预测数学模型提供了全面的定量数据和动力学，包括单个和细胞群体反应。重要的是，这个实验项目是与斯图加特大学系统理论与自动控制研究所的系统科学家跨学科合作项目的一部分。虽然这里描述的实验工作可以独立存在，并期望取得重要的科学成果，但期望从这种特殊的合作中获得特殊的剩余价值。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处理诱导大多数细胞凋亡，但不是所有细胞。特别是在该合作项目的后期阶段（第三年），模型推导的预测将通过优化实验设计和预测分子关键成分及其行为来支持实验工作。因此，我们期望实验科学家和理论科学家之间的高协同效应，在许多循环中通过两个组进行迭代过程。

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.