Systems biology of the oxidative stress response

描述（由申请人提供）：该项目解决了细胞如何调整其基因表达程序以应对氧化应激（OS）以确保生存的基本问题。作为有氧代谢的内在代价或由外部条件对细胞造成的OS与多种衰老相关疾病密切相关，包括神经退行性疾病、炎症性疾病、癌症和糖尿病的血管并发症。已知OS会触发一个主要面向恢复的转录程序，但如果损伤无法修复，则会触发细胞死亡。虽然这个程序是相对较好的特点，在mRNA丰度的水平，几乎没有什么是已知的协调与转录后层的基因表达控制。该应用程序探讨了总体假设，即响应OS的基因表达是由一个集成的多层程序形成的，该程序精确地协调转录和转录后机制，以最大限度地提高生存率。其目的是定量描述这些机制，并通过获取全球基因表达数据集和数学术语形式化的连接来实验验证它们。具体而言，一种新的模型的综合控制的解决，是由初步研究的启发，突出了预测蛋白质的变化，从mRNA水平的变化的局限性。数学模拟表明，在应激过程中，mRNA和蛋白质稳定性水平的控制起着关键作用，这导致了以下命题：a）应激诱导的蛋白质的合成增加与氧化损伤增加一致，因此增加了蛋白水解清除率作为质量控制机制。B）OS触发的快速翻译关闭导致OS抑制的mRNA而不是蛋白质的下调，以释放核糖体能力用于OS诱导的mRNA的有效翻译。在拟议项目的范围内，这些预测将通过获取独特的系统范围的数据集进行审查，这些数据集将输入到数学建模和实验验证的迭代过程中，以获得压力调节基因表达的全面框架。这些研究还解决了OS模型对其他形式的环境应激和哺乳动物细胞的基因表达的普遍适用性。

DESCRIPTION (provided by applicant): This project addresses the fundamental question of how cells adjust their gene expression program in response to oxidative stress (OS) in order to ensure survival. OS, inflicted upon cells either as an intrinsic cost of aerobic metabolism or by extraneous conditions, is intimately linked to a variety of ageing-related diseases, including neurodegenerative disorders, inflammatory conditions, cancer, and the vascular complications of diabetes. OS is known to trigger a transcriptional program primarily geared toward recovery, but triggering cell death if the damage is irreparable. Whereas this program is relatively well characterized at the level of mRNA abundance, almost nothing is known about the coordination with posttranscriptional layers of gene expression control. This application explores the overarching hypothesis that gene expression in response to OS is shaped by an integrated multi-layered program that precisely coordinates transcriptional and posttranscriptional mechanisms to maximize survival. The aim is to describe these mechanisms quantitatively and validating them experimentally both by acquiring global gene expression datasets and by formalizing the connections in mathematical terms. Specifically, a novel model of integrated control is addressed that was inspired by preliminary studies which highlighted the limitations of predicting protein changes from changes in mRNA levels. Mathematical simulations suggested critical roles for control at the levels of mRNA and protein stability during stress that lead to te following propositions: a) Increased synthesis of stress-induced proteins coincides with increased oxidative damage and hence increased proteolytic clearance as a quality control mechanism. b) OS-triggered rapid translational shutdown leads to downregulation of OS-suppressed mRNAs but not proteins in order to liberate ribosome capacity for the efficient translation of OS-induced mRNAs. Within the realm of the proposed project, these predictions will be put to scrutiny by acquiring unique system-wide datasets that will feed into an iterative process of mathematical modeling and experimental validation to arrive at a comprehensive framework of stress-regulated gene expression. The studies also address the general applicability of the OS models for gene expression in response to other forms of environmental stress and to mammalian cells.