Thioredoxin Peroxidases, Oxidative Stress, and Aging

描述：(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，它们 以硫氧还蛋白为电子源，还原过氧化氢和有机过氧化氢。 这些无处不在的物种被认为在 昆虫，因为这些动物中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了 硫氧还蛋白过氧化物酶活性会降低氧化应激水平， 从而减缓老化过程的速度，同时减少活动 会增加氧化应激水平，加快衰老速度。 这项研究的具体焦点将是两种不同的硫氧还蛋白过氧化物酶 果蝇成虫组织中高水平表达的基因 黑猩猩。其中一个定位于线粒体(DPx-5037)， 另一种已被鉴定为分泌型(DPx-4156)。 果蝇体内硫氧还蛋白过氧化物酶活性的降低将完成 通过表达不足，通过RNA干扰和/或通过使用 用标准遗传方法分离的突变等位基因。增强了 硫氧还蛋白过氧化物酶的活性将通过以下方式过度表达来实现 转基因方法学，要么使用原生生物控制下的转基因 促进剂或设计成可通过抗生素给药诱导的。这个 这些基因的过度表达和表达不足对寿命和年龄的影响 与衰老过程有关的各种生化/生理变化 将会被确定。结果应(I)提供对 老化过程中的硫氧还蛋白过氧化物酶，(Ii)允许进一步评估 衰老的氧化应激假说的有效性，以及(Iii)有助于 在哺乳动物身上设计类似的研究。

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.