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: 8087651
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8087651
• 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. 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.

描述（由申请人提供）：NRF2转录因子是排毒和抗氧化剂机制的主要调节剂。积累的证据表明，NRF2依赖基因表达程序可以保留有机体完整性和稳态。因此，NRF2功能是对衰老研究的高度兴趣的话题。该提案基于两个主要假设：1。与衰老相关的功能下降是通过NRF2信号响应能力丢失来促进的。随着生物的年龄，NRF2靶基因的确切调节是失败的。将研究染色质组织者和NRF2二聚合作伙伴MAFS对与年龄相关的退行表型的贡献。 2。延长NRF2的延长功能可以通过专用信号通路来调节。 NRF2功能的调节是复杂的，尚不完全理解。尤其是未充分描述了延长代谢信号（热量限制 /白藜芦醇）和NRF2之间调节性相互作用的分子机制。使用新开发的实验工具在体内和组织培养中监测NRF2功能，并自动化高吞吐量RNAi筛选了NRF2调节机制的全面研究。该项目的长期目标是（i）提供有关使用NRF2作为衰老一般原则的新信息，作为一个特定的，实验性的可处理的例子，（ii），以制定合理策略，以延迟或逆转与年龄相关的退化表型（III），以获得对不同压力信号和代理信号途径之间的相互作用的系统水平，以影响LifeSpan和SealthSpan Shearty Spans。 公共卫生相关性：对大分子，细胞和组织的氧化损害被认为是衰老的驱动因素，也是许多主要遭受老年人的疾病的主要贡献者。预防或延迟衰老生物体氧化损伤逐渐积累的机制可以促进寿命并减轻与年龄相关的疾病。该项目将调查为什么随着生物的生长变老，并试图找到防止或延迟下降的方法，这种防御机制是为何崩溃的。