Thioredoxin Peroxidases, Oxidative Stress, and Aging

硫氧还蛋白过氧化物酶、氧化应激和衰老

• 批准号: 6464279
• 负责人: WILLIAM C. ORR
• 金额: $ 31.7万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6464279
• 关键词: Drosophilidae; RNA; aging; antioxidants; body movement; free radical oxygen; free radical scavengers; gene expression; genetically modified animals; high performance liquid chromatography; in situ hybridization; mitochondria; oxidative stress; peroxidases; polymerase chain reaction; superoxide dismutase; thioredoxin; western blottings

DESCRIPTION: (provided by applicant) The thioredoxin peroxidases represent a group of recently identified components of the antioxidative network, which reduce H2O2 and organic peroxides using thioredoxin as an electron source. These ubiquitous species are thought to play a particularly critical role in insects, given the lack of glutathione peroxidase activity in these animals. The purpose of the present study is to determine if the enhancement of thioredoxin peroxidase activity would lower the level of oxidative stress, thereby slowing the rate of the aging process, while a reduction in activity would increase the level of oxidative stress and accelerate the rate of aging. The specific focus of this study will be two distinct thioredoxin peroxidase genes, which are expressed at high levels in the adult tissues of Drosophila melanogaster. One of them has been localized to the mitochondria (DPx-5037), while the other has been identified as a secreted form (DPx-4 156). Reduction in thioredoxin peroxidase activity will be accomplished in Drosophila by under-expression, through RNA interference and/or the through the use of mutant alleles isolated by standard genetic approaches. Enhancement of thioredoxin peroxidase activity will be accomplished by over-expression by transgenic methodology, either using transgenes under control of the native promoters or engineered to be inducible by antibiotic administration. The effects of over- and under-expresssion of these genes on life span and a variety of biochemical/physiological alterations related to the aging process will be determined. Results should (i) provide a direct test of the role of the thioredoxin peroxidases 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：（由申请人提供）硫氧还蛋白过氧化物酶代表 一组最近发现的抗氧化网络成分， 使用硫氧还蛋白作为电子源还原 H2O2 和有机过氧化物。 这些普遍存在的物种被认为在 昆虫，因为这些动物缺乏谷胱甘肽过氧化物酶活性。 本研究的目的是确定是否可以增强 硫氧还蛋白过氧化物酶活性会降低氧化应激水平， 从而减缓衰老过程的速度，同时减少活动 会增加氧化应激水平并加速衰老速度。 这项研究的具体重点是两种不同的硫氧还蛋白过氧化物酶 基因，在果蝇成体组织中高水平表达 黑腹果蝇。其中之一已定位于线粒体（DPx-5037）， 而另一种已被确定为分泌形式（DPx-4 156）。 果蝇中硫氧还蛋白过氧化物酶活性的降低将实现 通过低表达、通过RNA干扰和/或通过使用 通过标准遗传方法分离的突变等位基因。增强 硫氧还蛋白过氧化物酶活性将通过过表达来实现 转基因方法，或者使用在天然控制下的转基因 启动子或被设计为可通过抗生素施用诱导。这 这些基因的过度表达和表达不足对寿命和 与衰老过程相关的各种生化/生理变化 将被确定。结果应该 (i) 提供对角色作用的直接测试 老化过程中的硫氧还蛋白过氧化物酶，(ii) 允许进一步评估 衰老氧化应激假说的有效性，以及（iii）有助于 在哺乳动物中设计类似的研究。