Aging-Specific Gene Expression in Drosophila

热休克蛋白(HSPs)在所有物种中都被诱导，以响应热和其他压力。热休克蛋白似乎参与了蛋白质损伤的预防和修复，并能增强许多细胞对热和氧化应激的抵抗力。果蝇HSP70和HSP22在衰老过程中以一种特有的组织特异性模式被诱导。这种与衰老相关的上调涉及转录和转录后机制，似乎部分是对氧化损伤的反应。Hsp22在已知的真核基因中表现出最大的与衰老相关的上调(超过150倍)。同源HSPs的表达在人类正常衰老和许多病理生理和衰老相关疾病状态中上调。在果蝇和哺乳动物中，HSP基因在衰老过程中的慢性上调与机体过度诱导基因和在急性热应激中生存的能力降低有关。我们假设，HSP基因表达的改变是衰老和寿命的物种通用生物标志物，并与蛋白质合成和周转减少的物种通用现象有关。我们建议详细研究果蝇HSP70和HSP22与衰老相关的转录和转录后调控。这项研究涉及对果蝇HSP基因表达和衰老的遗传和转基因操作。这些实验将测试几个与衰老和HSP基因表达相关的特定假说。

Heat shock proteins (hsps) are induced in all species in response to heat and other stresses. hsps appear to be involved in prevention and repair of protein damage and can confer increased heat and oxidative stress resistance to many cell types. Drosophila hsp70 and hsp22 are induced in a characteristic, tissue-specific pattern during aging. This aging associated upregulation involves both transcriptional and posttranscriptional mechanisms, and appears to be in part a response to oxidative damage. hsp22 exhibits the largest aging- related upregulation known for any eukaryotic gene (greater than 150-fold). The expression of homologous hsps is upregulated in humans during normal aging and in numerous pathophysiological and aging-related disease states. In both Drosophila and mammals the chronic upregulation of hsp genes during aging is associated with a reduced ability of the organism to hyper-induce the genes and survive an acute heat stress. We hypothesize that altered hsp gene expression is a species-general biomarker of aging and life span, and is related to the species-general phenomena of decreased protein synthesis and turnover. We propose to study the aging-related transcriptional and posttranscriptional regulation of Drosophila hsp70 and hsp22 in detail. The research involves genetic and transgenic manipulation of hsp gene expression and aging in Drosophila. The experiments will test several specific hypotheses relating aging and hsp gene expression.