Aging-Specific Gene Expression in Drosophila

热休克蛋白（hsps）在所有物种中都是对热和其他胁迫的反应。热休克蛋白似乎参与蛋白质损伤的预防和修复，并能增强许多细胞类型的热应激和氧化应激抵抗能力。果蝇hsp70和hsp22在衰老过程中以一种特殊的、组织特异性的模式被诱导。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。在所有真核基因中，Hsp22表现出最大的衰老相关上调（大于150倍）。同源热休克蛋白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，衰老过程中热休克蛋白基因的慢性上调与机体过度诱导这些基因和在急性热应激中存活的能力降低有关。我们假设hsp基因表达的改变是衰老和寿命的物种一般生物标志物，并且与蛋白质合成和周转减少的物种一般现象有关。我们拟详细研究果蝇hsp70和hsp22与衰老相关的转录和转录后调控。该研究涉及果蝇热休克蛋白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热休克蛋白基因表达有关的特定假设。

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.