Nrf2 as a regulator of health span and aging

Nrf2 作为健康跨度和衰老的调节因子

• 批准号: 8707921
• 负责人: Dirk Bohmann
• 金额: $ 31.67万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707921
• 关键词: Acute; Address; Adult; Affect; Age; Aging; Animal Model; Antioxidants; Blood Vessels; Caloric Restriction; Cell Culture Techniques; Cells; Chromatin; Complex; Data; Defense Mechanisms; Dimerization; Disease; Drosophila genus; Drug Metabolic Detoxication; Elderly; Epigenetic Process; Gene Expression; Gene Targeting; Genetic; Goals; Health; Heart; Homeostasis; Incidence; Life; Longevity; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic stress; Methods; Modeling; Molecular; Monitor; Organism; Oxidative Stress; Parkinson Disease; Pathology; Pathway interactions; Performance; Phenotype; Publishing; RNA Interference; Regulation; Research; Resveratrol; Role; Signal Pathway; Signal Transduction; Stimulus; System; Systems Analysis; Testing; Tissues; acute stress; age related; base; fly; functional decline; in vivo; interest; macromolecule; overexpression; oxidative damage; prevent; programs; research study; response; tissue culture; tool; transcription factor

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.

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 依赖性基因表达程序可以维持机体的完整性和体内平衡。因此，Nrf2功能是衰老研究高度关注的课题。该提议基于两个主要假设： 1. Nrf2 信号响应能力的丧失会促进与衰老相关的功能衰退。随着生物体年龄的增长，Nrf2 靶基因的精确调控逐渐失效。我们将研究染色质组织者和 Nrf2 二聚化伙伴 MafS 对这种与年龄相关的退行性表型的贡献。 2. Nrf2的长寿功能可以通过专门的信号通路进行调节。 Nrf2 功能的调节非常复杂且不完全清楚。尤其是延长生命的代谢信号（热量限制/白藜芦醇）和 Nrf2 之间调节相互作用的分子机制尚未得到很好的描述。使用新开发的实验工具来监测体内和组织培养中的 Nrf2 功能，以及自动化高通量 RNAi 筛选，提出了对 Nrf2 调控机制的全面研究。该项目的长期目标是（i）使用 Nrf2 作为具体的、实验上易于处理的例子，提供有关衰老一般原理的新信息，（ii）制定延迟或逆转与年龄相关的退行性表型的合理策略，（iii）获得对影响寿命和健康的不同压力和代谢信号通路之间相互作用的系统水平理解。