Nrf2 as a regulator of health span and aging

描述（由申请人提供）：Nrf2转录因子是解毒和抗氧化机制的主要调节因子。越来越多的证据表明Nrf2依赖的基因表达程序保持了生物体的完整性和体内平衡。因此，Nrf2的功能是衰老研究的热点。这一建议基于两个主要假设：Nrf2信号反应性的丧失促进了衰老相关的功能下降。随着生物体年龄的增长，Nrf2靶基因的精确调控正在失效。染色质组织者和Nrf2二聚化伙伴MafS对这种与年龄相关的退行性表型的贡献将被研究。2. Nrf2的促长寿功能可以通过专门的信号通路调节。Nrf2功能的调控是复杂且不完全了解的。特别是延长生命的代谢信号（热量限制/白藜芦醇）与Nrf2之间调节相互作用的分子机制尚未得到很好的描述。利用新开发的实验工具监测Nrf2在体内和组织培养中的功能，以及自动化高通量RNAi筛选，提出了Nrf2调控机制的全面研究。该项目的长期目标是：(i)利用Nrf2作为一个具体的、实验可处理的例子，提供关于衰老一般原理的新信息；（ii）为延迟或逆转年龄相关的退行性表型制定合理的策略；（iii）获得系统层面对影响寿命和健康寿命的不同应激和代谢信号通路之间相互作用的理解。

DESCRIPTION (provided by applicant): The Nrf2 transcription factor is master regulator of detoxification and antioxidant mechanisms. Accumulating evidence indicates that Nrf2 dependent gene expression programs preserve organismic integrity and homeostasis. Therefore, Nrf2 function is a topic of high interested for aging research. This proposal is based on two principal hypotheses: 1. Aging associated functional decline is promoted by loss of Nrf2 signal responsiveness. The precise regulation of Nrf2 target genes is failing as organisms age. The contribution of the chromatin organizer and Nrf2 dimerization partner MafS to this age-associated degenerative phenotype will be investigated. 2. Longevity promoting functions of Nrf2 can be regulated by dedicated signaling pathways. The regulation of Nrf2 function is complex and incompletely understood. Especially the molecular mechanisms underlying the regulatory interplay between life extending metabolic signals (caloric restriction / resveratrol) and Nrf2 are not well described. Using newly developed experimental tools for the monitoring of Nrf2 function in vivo and in tissue culture, and automated high throughput RNAi screens a comprehensive study of Nrf2 regulatory mechanism is proposed. The long-term goals of this project are (i) to provide new information on general principles of aging using Nrf2 as a specific, experimentally tractable example, (ii) to develop rational strategies for the delay or reversal of age associated degenerative phenotypes, (iii) to gain a systems level understanding of the interactions between different stress and metabolic signaling pathways that influence lifespan and healthspan. PUBLIC HEALTH RELEVANCE: Oxidative damage to macromolecules, cells and tissues is considered a driver of aging and a major contributor to many diseases that predominantly afflict the elderly. Mechanisms that prevent or delay the progressive accumulation of oxidative damage in the aging organism can promote longevity and allay age-associated diseases. This project will investigate why such defense mechanisms break down as organisms grow old and tries to find ways to prevent or delay that decline.