DJ-1 function and oxidative stress

DJ-1 功能和氧化应激

• 批准号: 8552528
• 负责人: Mark Cookson
• 金额: $ 34.98万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552528
• 关键词: Aerobic; Aging; Animals; Bacteria; Breeding; Cells; Clinical; Escherichia coli; Family; Gene Mutation; Genes; Goals; Human; Molecular; Mus; Mutation; Oxidative Stress; PARK7 protein; Parkinson Disease; Parkinsonian Disorders; Phenotype; Play; Proteins; System; Work; age related neurodegeneration; dopaminergic neuron; interest; man; molecular phenotype; response

DJ-1 is one of the rarest gene mutations associated with recessive parkinsonism. Although the function of the DJ-1 protein, which is conserved in aerobic species from E coli to man, is unknown, several observations suggest that it plays a key role in cellular responses to oxidative stress. Several previous studies have suggested that oxidative stress is associated with aging in most aerobic systems. Therefore, our aim in this project is to understand why mutations in such an evolutionarily ancient protein would be associated with age related neurodegeneration of dopaminergic neurons, as seen in Parkinsons disease. Our current work has been to extend our previous observations that DJ-1 expression levels determine cellular responses to oxidative stress. We are characterizing the cellular and molecular phenotypes of cells deficient in DJ-1 using both directed and large scale approaches. We have also begun breeding DJ-1 deficient mice to animals that have accelerated aging phenotypes in an attempt to increase basal phenotypes.

DJ-1是与隐性帕金森氏症相关的最罕见的基因突变之一。虽然DJ-1蛋白的功能尚不清楚，但一些观察表明，它在细胞对氧化应激的反应中发挥着关键作用。DJ-1蛋白在从大肠杆菌到人类的需氧物种中都是保守的。先前的几项研究表明，在大多数有氧系统中，氧化应激与衰老有关。因此，我们在这个项目中的目的是了解为什么这种进化上古老的蛋白质的突变会与多巴胺能神经元的年龄相关神经退化有关，就像帕金森病中所看到的那样。 我们目前的工作是扩展我们之前的观察，即DJ-1的表达水平决定了细胞对氧化应激的反应。我们正在使用直接和大规模的方法来表征DJ-1缺陷细胞的细胞和分子表型。我们还开始将DJ-1缺陷小鼠培育成加速衰老表型的动物，试图增加基础表型。