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

• 批准号: 7569441
• 负责人: Piotr Zimniak
• 金额: $ 28.53万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569441
• 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; Pan Genus; 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

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）：该项目的目的是阐明秀丽隐杆线虫模型中的生物化学过程，有助于有机体衰老。除氧化剂外，尚未详细表征具有干扰生物稳态和促进衰老的能力的化学或物理过程。我们提出脂质过氧化的亲电产物，例如4-羟基烯烯（4-hne），发挥了这种作用。我们发现，CEGSTP2-2的表达是一种能够代谢4-HNE的谷胱甘肽转移酶，与自然遗传变异和长寿命突变体之间的寿命相反，并且其表达受胰岛素样生长因子信号的调节。通过对秀丽隐杆菌的遗传操纵，我们进一步表明，CEGSTP2-2和寿命延长的水平不仅相关，而且是有因果关系的。该提案的目的是定义这种关系的基础机制。具体：（1）将测试假设，即CEGSTP2-2的寿命延伸是由4-HNE或类似醛介导的，而不是由CEGSTP2-2的无关底物介导的。 （2）将定义CEGSTP2-2组织分布非常有限的功能意义。 （3）将表征CEGSTP2-2诱导性的机制，并特别强调通过胰岛素样生长因子信号传导调节。 （4）通过对上学的分析，将检验假设CEGSTP2-2不仅是下游效应器，可抵消导致老化的电力的随机损害，而且还调节调节老化的高级信号通路。该项目将将以电力代谢为中心的生化技术与可用于秀丽隐杆线虫的强大遗传方法相结合。这两种方法的协同作用有望产生对有助于衰老过程的基本机制的新见解。公共卫生相关性：拟议工作的重点是定义有助于衰老的基本机制，这是美国国家衰老研究所任务的核心。已经发现在各种物种的衰老基础上非常相似，并且确定寿命的化学过程也很可能是保守的。因此，了解round虫中的过程（其中实验更容易且更快）将有助于阐明人类衰老。这里要研究的损害类型可能成为旨在减缓衰老和阻止年龄相关疾病的未来干预措施的目标。