Thioredoxin Peroxidases, Oxidative Stress, and Aging

描述：（由申请人提供）硫氧还蛋白过氧化物酶代表一种 一组最近确定的抗氧化网络的组成部分， 使用硫氧还蛋白作为电子源还原H2 O2和有机过氧化物。 这些无处不在的物种被认为在以下方面发挥着特别关键的作用： 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增强 硫氧还蛋白过氧化物酶活性将降低氧化应激水平， 从而减缓衰老过程的速度， 会增加氧化应激水平，加速衰老速度。 本研究的具体重点将是两种不同的硫氧还蛋白过氧化物酶 基因，在果蝇的成体组织中高水平表达 黑腹菌其中之一已定位于线粒体（DPx-5037）， 而另一种已被鉴定为分泌形式（DPx-4156）。 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 通过标准遗传学方法分离的突变等位基因。加强 硫氧还蛋白过氧化物酶活性将通过过量表达来实现， 转基因方法，或者使用在天然植物控制下的转基因， 启动子或工程化以通过抗生素施用诱导。的 这些基因的过度表达和表达不足对寿命的影响， 与衰老过程相关的各种生化/生理变化 将被确定。结果应（i）提供对 硫氧还蛋白过氧化物酶在老化过程中，（ii）允许进一步评估 老化的氧化应激假说的有效性，和（iii）援助， 在哺乳动物中进行类似的研究。

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.