Systems biology of the oxidative stress response

描述(由申请人提供)：这个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)以确保生存的根本问题。OS作为有氧代谢的内在代价或外部条件对细胞造成的影响，与各种与衰老有关的疾病密切相关，包括神经退行性疾病、炎症条件、癌症和糖尿病的血管并发症。众所周知，OS会触发一个转录程序，主要是为了恢复，但如果损伤是不可修复的，就会触发细胞死亡。虽然该程序在mRNA丰度水平上具有相对较好的特征，但几乎对基因表达控制的转录后层次的协调知之甚少。这项应用探索了一个重要的假设，即对OS的反应是由一个整合的多层程序塑造的，该程序精确地协调转录和转录后机制，以最大限度地提高存活率。其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通过数学术语形式化这些联系来实验验证它们。具体地说，提出了一种新的集成控制模型，该模型受到初步研究的启发，这些研究强调了根据mRNA水平的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，在mRNA和蛋白质稳定性水平上的控制起着关键作用，这导致了下列命题：a)应激诱导蛋白质的合成增加与氧化损伤的增加相一致，因此作为一种质量控制机制，蛋白质降解清除增加。B)OS触发的快速翻译关闭导致OS抑制的mRNAs的下调，而不是蛋白质的下调，以释放核糖体能力，以便有效地翻译OS诱导的mRNAs。在拟议的项目范围内，这些预测将通过获取独特的系统范围的数据集进行审查，这些数据集将提供给数学建模和实验验证的迭代过程，以得出压力调节基因表达的综合框架。这些研究还讨论了OS模型在应对其他形式的环境压力和哺乳动物细胞时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.