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: 6604134
• 负责人: WILLIAM C. ORR
• 金额: $ 32.19万
• 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/6604134
• 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 最近确定的抗氧化网络组成部分，该组成部分 使用硫氧还蛋白作为电子源降低H2O2和有机过氧化物。 这些无处不在的物种被认为在 考虑到这些动物中缺乏谷胱甘肽过氧化物酶活性，昆虫。 本研究的目的是确定是否增强 硫氧还蛋白的过氧化物酶活性将降低氧化应激水平， 从而减慢衰老过程的速度，而活动的降低 会增加氧化应激水平并加速衰老速率。 这项研究的具体重点将是两个不同的硫氧还蛋白过氧化物酶 基因，在果蝇的成人组织中以高水平表达 Melanogaster。其中一个已定位到线粒体（DPX-5037）， 而另一个已被确定为分泌形式（DPX-4 156）。 硫氧还蛋白过氧化物酶活性的降低将在果蝇中完成 通过表达不足，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 转基因方法论，要么使用原天然控制的转基因 启动子或设计为抗生素施用。这 这些基因过度表达和表达不足对寿命和一个 与衰老过程有关的多种生化/生理变化 将确定。结果应（i）直接测试 硫氧还蛋白过氧化物酶在衰老过程中，（ii）允许进一步评估 氧化应激假说的衰老的有效性，以及（iii）有助于 哺乳动物类似研究的设计。