Systems biology of the oxidative stress response

描述（由申请人提供）：本项目研究细胞如何调节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外部条件对细胞造成的OS与多种与衰老相关的疾病密切相关，包括神经退行性疾病、炎症、癌症和糖尿病的血管并发症。已知OS触发主要面向恢复的转录程序，但如果损害无法修复，则触发细胞死亡。尽管该程序在mRNA丰度水平上具有相对较好的特征，但几乎不知道与基因表达控制的转录后层的协调。该应用程序探索了一个总体假设，即基因表达对OS的反应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。目的是定量地描述这些机制，并通过获取全球基因表达数据集和用数学术语形式化连接来实验验证它们。具体来说，本文提出了一种新的综合控制模型，该模型受到了一些初步研究的启发，这些研究强调了从mRNA水平变化预测蛋白质变化的局限性。数学模拟表明，在应激过程中mRNA水平的控制和蛋白质稳定性的关键作用，导致以下命题：a)应激诱导蛋白质合成的增加与氧化损伤的增加相一致，因此蛋白质水解清除的增加是一种质量控制机制。b) os触发的快速翻译关闭导致os抑制的mrna而非蛋白质下调，从而释放核糖体能力，用于os诱导的mrna的有效翻译。在提议的项目范围内，这些预测将通过获取独特的系统范围的数据集来进行审查，这些数据集将输入数学建模和实验验证的迭代过程，以达到压力调节基因表达的综合框架。这些研究还解决了OS模型在应对其他形式的环境压力和哺乳动物细胞中的基因表达的一般适用性。

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.