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）：Nrf 2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，Nrf 2依赖的基因表达程序保持器官的完整性和稳态。因此，Nrf 2的功能是衰老研究的一个热点。这一建议基于两个主要假设：1。Nrf 2信号反应性的丧失会促进衰老相关的功能衰退。Nrf 2靶基因的精确调控随着生物体的衰老而失败。将研究染色质组织者和Nrf 2二聚化伴侣MafS对这种年龄相关退行性表型的贡献。2. Nrf 2的长寿促进功能可以通过专门的信号通路来调节。Nrf 2功能的调节是复杂的且不完全理解。特别是延长寿命的代谢信号（热量限制/白藜芦醇）和Nrf 2之间的相互作用的分子机制没有得到很好的描述。使用新开发的实验工具在体内和组织培养中监测Nrf 2的功能，以及自动化高通量RNAi筛选，提出了对Nrf 2调控机制的全面研究。该项目的长期目标是（i）使用Nrf 2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）开发延迟或逆转年龄相关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。 公共卫生关系：对大分子、细胞和组织的氧化损伤被认为是衰老的驱动因素，也是主要困扰老年人的许多疾病的主要原因。预防或延缓衰老生物体中氧化损伤的进行性积累的机制可以促进长寿并减轻与年龄相关的疾病。该项目将研究为什么这种防御机制会随着生物体的衰老而崩溃，并试图找到防止或延迟这种衰退的方法。