Role of glutathione transferases in life span extension of C. elegans

谷胱甘肽转移酶在延长线虫寿命中的作用

基本信息

批准号：
8038380
负责人：
Piotr Zimniak
金额：
$ 27.15万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2012-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8038380
关键词：
4 hydroxynonenal Address Affect Age Aging Aging-Related Process Agonist Aldehyde Reductase Aldehydes Alleles Animal Model Animals Antioxidants Autologous Biochemical Biochemical Process Biological Biological Phenomena Caenorhabditis elegans Cells Cessation of life Chemicals Disease Drug Metabolic Detoxication Drug or chemical Tissue Distribution Eating Enzymes Functional disorder Future Genes Genetic Genetic Epistasis Glutathione S-Transferase Goals Heat Stress Disorders Homeostasis Human Hydrogen Peroxide Insulin Intestines Life Life Expectancy Light Link Lipid Peroxidation Longevity MAPK8 gene Measures Mediating Messenger RNA Metabolism Methods Mission Molecular Mus Muscle Mutation National Institute on Aging Nature Nematoda Neurons Organism Outcome Oxidants Oxidoreductase Paraquat Pathway interactions Process Production Proteins RNA Interference Reactive Oxygen Species Regulation Regulatory Pathway Research Personnel Resistance Role Series Shock Signal Pathway Signal Transduction Sirtuins Somatomedins Stress Structure Taxes Techniques Testing Time Tissues Transgenic Organisms Ursidae Family Work adduct aldehyde dehydrogenases base carbonyl compound congenic dietary restriction genetic manipulation genetic variant insight knock-down mGSTA4-4 mutant overexpression physical process prevent promoter protein function public health relevance repaired research study synergism therapy design

项目摘要

DESCRIPTION (provided by applicant): The goal of the project is to elucidate, in the model organism Caenorhabditis elegans, a biochemical process that contributes to organismal aging. Except for oxidants, the chemical or physical processes which have the capacity to disturb biological homeostasis and promote aging have not been characterized in detail. We propose that electrophilic products of lipid peroxidation, such as 4-hydroxynonenal (4-HNE), exert such an effect. We have found that expression of CeGSTP2-2, a glutathione transferase able to metabolize 4-HNE, correlates inversely with life span among natural genetic variants and among long-lived mutants, and that its expression is regulated by insulin-like growth factor signaling. By genetic manipulation of C. elegans, we have further shown that the level of CeGSTP2-2 and life span extension not only correlate, but are causally linked. The aim of the proposal is to define the mechanisms underlying that relationship. Specifically: (1) The hypothesis will be tested that life-span extension by CeGSTP2-2 is mediated by 4-HNE or similar aldehydes, rather than by unrelated substrates of CeGSTP2-2. (2) The functional significance of the very limited tissue distribution of CeGSTP2-2 will be defined. (3) The mechanism of inducibility of CeGSTP2-2 will be characterized, with special emphasis on regulation by insulin-like growth factor signaling. (4) By analysis of epistasis, the hypothesis will be tested that CeGSTP2-2 is not only a downstream effector counteracting the stochastic damage by electrophiles which leads to aging, but that it also modulates high-level signaling pathways that regulate aging. The project will combine biochemical techniques centered on electrophile metabolism with powerful genetic approaches available for C. elegans. The synergism of these two methods is expected to yield new insights into a fundamental mechanism that contributes to the aging process. Public Health Relevance: The focus of the proposed work is to define a basic mechanism which contributes to aging, a topic central to the mission of the National Institute on Aging. Closely similar pathways have been found to underlie aging in diverse species, and it is likely that the chemical processes that determine life span are also conserved. Therefore, understanding the process in the roundworm (in which experiments are much easier and faster) will help to shed light on human aging. The type of damage to be studied here could become the target of future interventions designed to slow aging and deter age-associated diseases.

描述（由申请人提供）：该项目的目标是阐明模式生物秀丽隐杆线虫中导致生物体衰老的生化过程。除氧化剂外，具有扰乱生物稳态和促进衰老能力的化学或物理过程尚未得到详细表征。我们认为脂质过氧化的亲电子产物，例如 4-羟基壬烯醛 (4-HNE)，可以发挥这种作用。我们发现，CeGSTP2-2（一种能够代谢 4-HNE 的谷胱甘肽转移酶）的表达与自然遗传变异体和长寿突变体中的寿命呈负相关，并且其表达受到胰岛素样生长因子信号传导的调节。通过对秀丽隐杆线虫的基因操作，我们进一步表明，CeGSTP2-2 的水平与寿命延长不仅相关，而且存在因果关系。该提案的目的是定义这种关系背后的机制。具体来说： (1) 将检验以下假设：CeGSTP2-2 的寿命延长是由 4-HNE 或类似的醛介导的，而不是由 CeGSTP2-2 的不相关底物介导的。 (2) 将定义 CeGSTP2-2 非常有限的组织分布的功能意义。 (3) 将表征CeGSTP2-2的诱导机制，特别强调胰岛素样生长因子信号传导的调节。 (4)通过上位性分析，将检验以下假设：CeGSTP2-2不仅是抵消亲电子试剂导致衰老的随机损伤的下游效应子，而且还调节调节衰老的高水平信号通路。该项目将以亲电子代谢为中心的生化技术与可用于线虫的强大遗传方法相结合。这两种方法的协同作用有望对促进衰老过程的基本机制产生新的见解。公共卫生相关性：拟议工作的重点是确定一种有助于老龄化的基本机制，这是国家老龄化研究所使命的核心主题。人们已经发现，不同物种的衰老过程有着非常相似的途径，而且决定寿命的化学过程很可能也是保守的。因此，了解蛔虫的过程（实验更容易、更快）将有助于揭示人类衰老的情况。这里要研究的损伤类型可能成为未来旨在减缓衰老和预防与年龄相关的疾病的干预措施的目标。