Systems biological analysis of mitochondrial apoptosis synergies evoked by 2nd generation TRAIL receptor agonists and cardic glycosides

第二代 TRAIL 受体激动剂和强心苷引起的线粒体凋亡协同作用的系统生物学分析

• 批准号: 324476878
• 负责人: Professor Dr. Markus Morrison
• 金额: --
• 依托单位: Institut für Zellbiologie und Immunologie (IZI)
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/324476878?language=en
• 关键词: Systems; biological; analysis; mitochondrial; apoptosis

TRAIL receptor agonists are cancer cell-selective agents that trigger mitochondrial apoptosis through the activation of the BH3-only protein Bid, but so far demonstrated limited clinical efficacy. We found that non-toxic concentrations of therapeutically relevant cardiac glycosides (CGs), such as digitoxin, cause complex changes in apoptosis protein amounts and synergistically enhance cell death via the mitochondrial Bcl-2 family-dependent pathway. Here, we will investigate these processes, using a systems biological approach of integrated experimental and mathematical analyses. We will develop prototype tools for case-specifically predicting responsiveness to combination treatments with a superior 2nd generation TRAIL receptor agonist (IZI1551) and CGs in cell lines and in vivo models of colorectal cancer (CRC). To this end, we will (i) study changes in the quantitative composition of the signalling networks that control TRAIL and Bcl-2 family signalling in well characterised CRC model cell lines upon CG exposure, (ii) investigate which signalling cascades drive CG-induced apoptosis protein deregulation, (iii) employ mathematical pathway models to predict the consequences that these changes will have for apoptosis signal transduction and to identify optimal treatment schedules, and (iv) validate mathematical predictions on apoptosis responsiveness by flow-cytometric and microscopic real-time measurements in cellulo and by CRC xenograft models in vivo. Besides detailed novel insight into the complexity of apoptosis signal transduction and cell death regulation, this work will also provide the basis for the optimal further development and exploitation of mitochondrial apoptosis synergies evoked by IZI1551/CG co-treatments for future translational studies.

TRAIL受体激动剂是癌细胞选择性试剂，其通过激活仅BH 3蛋白Bid来触发线粒体凋亡，但迄今为止显示出有限的临床功效。我们发现，无毒浓度的治疗相关的强心苷（CG），如洋地黄毒苷，引起细胞凋亡蛋白量的复杂变化，并协同增强细胞死亡通过线粒体Bcl-2家族依赖性途径。在这里，我们将调查这些过程中，使用系统生物学方法的综合实验和数学分析。我们将开发原型工具，用于在结直肠癌（CRC）的细胞系和体内模型中特异性预测对上级第二代TRAIL受体激动剂（IZI 1551）和CG的联合治疗的反应性。为此，我们将（i）研究CG暴露后在充分表征的CRC模型细胞系中控制TRAIL和Bcl-2家族信号传导的信号传导网络的定量组成的变化，（ii）研究哪些信号传导级联驱动CG诱导的凋亡蛋白失调，（三）采用数学途径模型来预测这些变化对细胞凋亡信号转导的影响，并确定最佳治疗方案。时间表，和（iv）通过流式细胞术和显微镜实时测量在cellulo和CRC异种移植模型在体内验证对细胞凋亡反应的数学预测。除了对细胞凋亡信号转导和细胞死亡调控的复杂性的详细的新见解之外，这项工作还将为进一步开发和利用IZI 1551/CG共处理引起的线粒体凋亡协同作用提供基础，用于未来的翻译研究。