GLUTATHIONE, OXIDATIVE STRESS, AND AGING

谷胱甘肽、氧化应激和衰老

• 批准号: 6124242
• 负责人: WILLIAM C. ORR
• 金额: $ 20.79万
• 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 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6124242
• 关键词: Drosophilidae; aging; alleles; catalase; enzyme activity; functional ability; gene expression; genetically modified animals; glutathione; glutathione reductase; longevity; oxidative stress; protein metabolism

DESCRIPTION (Adapted from the Applicant'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 the aging process. Specifically, this study will determine the effects of an increased, or a decreased ability of cells to synthesize and regenerate reduced glutathione, on the aging process of Drosophila melanogaster. Flies that have an increased ability to synthesize and regenerate glutathione will be created by the transgenic overexpression of gamma-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione synthesis) and glutathione reductase (which converts oxidized glutathione to reduced glutathione), respectively. In contrast, flies with a decreased ability to synthesize and regenerate glutathione 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 two genes, along with other antioxidative genes (Cu/Zn-SOD, Mn-SOD, and catalase), on the aging process of the flies will be determined. It is suggested that the results should provide a direct test of (i) the validity of the oxidative stress hypothesis of aging, and (ii) the role of the genes, involved in the maintenance of glutathione, in the aging process.

描述（改编自申请人的摘要）： 拟议的研究是测试氧化应激的有效性 衰老的假设，该假设假定与年龄相关的损失 功能能力基本上是由于分子的应计 氧化损伤。 这项研究的重点是研究主要 对这一假设的预测，即 氧化应激，由抗氧化剂的实验改变引起 防御应相应地影响衰老过程的速度。 具体而言，这项研究将确定增加或 细胞合成和再生谷胱甘肽的能力降低， 关于果蝇的衰老过程。 苍蝇 将创建提高合成和再生谷胱甘肽的能力 通过γ-谷氨酰半胱氨酸合成酶的转基因过表达（ 谷胱甘肽合成中的限速酶和谷胱甘肽还原酶 （分别将氧化的谷胱甘肽转化为还原的谷胱甘肽）。 相反，苍蝇具有降低的合成能力和再生能力 谷胱甘肽将通过分离这些基因的突变等位基因获得。 这些基因过度表达和表达不足对寿命和a的影响 与衰老有关的多种生化/生理改变 过程将被确定。 随后，共同表达的影响 在这两个基因以及其他抗氧化基因（Cu/Zn-Sod，Mn-Sod， 和过氧化氢酶），将确定苍蝇的衰老过程。 这是 建议结果应直接测试（i）有效性 衰老的氧化应激假说，以及（ii）基因的作用， 参与谷胱甘肽的维持，在衰老过程中。