GLUTATHIONE, OXIDATIVE STRESS, AND AGING

谷胱甘肽、氧化应激和衰老

• 批准号: 6266174
• 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 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6266174
• 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（改编自研究者摘要）：主要目的 拟议的研究是为了测试氧化应激假说的有效性， 衰老，这假设与年龄相关的功能丧失是 这主要是由于分子氧化损伤的累积。的焦点 这项研究是为了调查这一假设的主要预测之一， 即氧化应激水平的变化， 抗氧化防御的实验性改变， 影响衰老的速度。具体来说，这项研究将确定 细胞合成和再生能力的增强或减弱 还原型谷胱甘肽（GSH）对果蝇衰老过程的影响。GSH 可与多种自由基物质反应， 超氧化物歧化酶，提供的主要机制或衰减 氧化应激苍蝇的合成能力增强， 再生的GSH将通过转基因过表达产生， γ-谷氨酰半胱氨酸合成酶（GSH合成的限速酶） 和葡萄糖-6-磷酸脱氢酶（产生NADPH， 将氧化型谷胱甘肽还原为GSH）。相反，苍蝇 合成和再生GSH的能力降低， 分离这些基因的突变等位基因。过度和的影响 这些基因的表达不足对寿命和各种 与衰老过程有关的生物化学/生理学变化， 测定随后，这些基因的共过表达与 其他抗氧化基因（e. Cu，Zn-超氧化物歧化酶和过氧化氢酶）对 确定果蝇的衰老过程。结果应（i）提供 直接测试基因的作用，参与GSH的维持， 老化过程，（二）允许进一步评估的有效性， 老化的氧化应激假说，和（iii）在类似的设计援助 哺乳动物的研究。