GLUTATHIONE, OXIDATIVE STRESS, AND AGING

谷胱甘肽、氧化应激和衰老

• 批准号: 6839917
• 负责人: WILLIAM C. ORR
• 金额: $ 25.72万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6839917
• 关键词: Drosophilidae; aging; catalase; enzyme activity; enzyme induction /repression; genetically modified animals; glucose 6 phosphate dehydrogenase; glutathione; glutathione reductase; oxidative stress; superoxide dismutase

DESCRIPTION (Adapted from the investigator's Abstract): The main purpose of the proposed studies is to test the validity of the oxidative stress hypothesis of aging, which postulates that the age-associated loss of functional capacity is substantially due to the accrual of molecular oxidative damage. The focus of this study is to investigate one of the main predictions of this hypothesis, namely that variations in the level of oxidative stress, induced by experimental alterations in antioxidative defenses, should correspondingly affect the rate of aging. Specifically, this study will determine the effects of an increased or a decreased ability of cells to synthesize and regenerate reduced glutathione (GSH) on the aging process of Drosophila melanogaster. GSH can react with a variety of free radical species and, in conjunction with superoxide dismutase, provide the main mechanism or the attenuation of oxidative stress. Flies that have an increased ability to synthesize and regenerate GSH will be created by the transgenic overexpression of gamma-glutamylcysteine synthetase (the rate-limiting enzyme in GSH synthesis) and glucose-6-phosphate dehydrogenase (which generates NADPH, required for reduction of oxidized glutathione to GSH), respectively. In contrast, flies with a decreased ability to synthesize and regenerate GSH will be obtained by isolating mutant alleles of these genes. The effects of over-and under-expression of these genes on life span and a variety of biochemical/physiological alterations, related to the aging process, will be determined. Subsequently, the effects of co-overexpression of these genes with other antioxidative genes (e. Cu,Zn-superoxide dismutase and catalase) on the aging process of the flies will be determined. Results should (i) provide a direct test of the role of the genes, involved in the maintenance of GSH, in the aging process, (ii) permit further assessment of the validity of the oxidative stress hypothesis of aging, and (iii) aid in the design of similar studies in mammals.

描述（根据研究者的摘要进行了改编）： 提出的研究是测试氧化应激假说的有效性 衰老，这表明与年龄相关的功能能力损失为 基本上是由于分子氧化损伤的应计。重点 这项研究是为了研究该假设的主要预测之一， 也就是说，氧化应激水平的变化是由 抗氧化防御的实验改变应相应地 影响衰老率。具体而言，这项研究将确定影响 细胞合成和再生能力的增加或降低的能力 谷胱甘肽（GSH）减少了果蝇的衰老过程。 GSH 可以与多种自由基物种反应，并结合 超氧化物歧化酶，提供主要机制或衰减 氧化应激。苍蝇的合成能力增加和 再生GSH将由转基因过表达产生 γ-谷氨酰半胱氨酸合成酶（GSH合成中的速率限制酶） 和6-磷酸葡萄糖脱氢酶（产生NADPH，需要） 分别还原氧化的谷胱甘肽至GSH）。相反，苍蝇 通过降低合成和再生GSH的能力，将获得 分离这些基因的突变等位基因。过度的影响和 这些基因在寿命和各种各样的表达不足 与衰老过程有关的生化/生理改变将是 决定。随后，这些基因共同表达与 其他抗氧化基因（例如Cu，Zn-塞氧化物歧化酶和过氧化氢酶） 将确定苍蝇的衰老过程。结果应（i）提供 直接测试与维持GSH有关的基因的作用， 衰老过程，（ii）允许进一步评估 衰老的氧化应激假说，（iii）有助于设计相似的设计 研究哺乳动物。