Regulatory systems of Drosophila aging

果蝇衰老的调节系统

• 批准号: 7038301
• 负责人: MARC TATAR
• 金额: $ 37.37万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7038301
• 关键词: Drosophilidae; alleles; animal old age; cytochrome oxidase; endocrine gland /system; enzyme activity; genetic polymorphism; genetic transcription; genotype; growth factor receptors; hormone regulation /control mechanism; insulinlike growth factor; juvenile hormones; longevity; metabolism; mitochondria; nucleic acid sequence; phenotype; phosphorus; polymerase chain reaction; stress; thin layer chromatography; transfection /expression vector

DESCRIPTION (provided by applicant): Among nematodes, flies and mice, the rate of aging is modulated by hormones. In nematodes, mutation at the insulin/IGF pathway in a few cells is sufficient to slow aging. We found an analogous system in D. melanogaster where mutant insulin/IGF receptor (InR) leads to deficiency in juvenile hormone (JH). These mutants are dwarf, sterile and long-lived, all apparently due to deficient JH. These findings resonate with dwarf mice that are long-lived and deficient in several pituitary hormones. Here is a common theme where the a small set of cells regulate secondary hormones with the potential to modulate aging. It is now of great importance to discover how insulin/IGF regulates these secondary hormones, and how these endocrines affect senescence. Research in this proposed project will exploit the powerful tools of Drosophila to develop fundamental insights on how mutation of InR increases life span. First, molecular analysis will dissect the qualities of the specific InR mutant alleles that confer increased life span. Do these alleles merely affect the quantity of INR protein, do they alter the tissue specificity of InR transcription, or do they alter a specific senescence related quality of the INR product? These studies will compare sequences of many types of alleles, describe expression patterns and transcript quality, and examine the ability of P-element remobilized alleles to rescue phenotypes. Second, the project will investigate whether JH deficiency arises because InR mutant genotypes have delayed development of endocrine tissue or because a mature endocrine tissue fails to receive adequate activation signals. This work will use Gal4/UAS lines with conditional expression of insulin-like ligands or of InR. Our third aim will address the JH hypothesis directly by developing a regulated JH-negative strain with a new TetOn system to drive juvenile hormone esterase. These studies will establish how InR modulates JH and whether JH deficiency is sufficient to increase life span of InR mutant adults. Finally, with the JH-negative reagents and the set of InR mutants alleles, the project will explore how JH and InR affect somatic features that shape life span. In a comprehensive experimental design, we shall assess qualifies of stress resistance, central metabolism and mitochondria function to determine which feature best predicts variance in life span

描述（由申请人提供）：在线虫、苍蝇和小鼠中，衰老速度受激素调节。在线虫中，少数细胞中胰岛素/IGF途径的突变足以减缓衰老。我们在黑腹果蝇中发现了一个类似的系统，其中突变的胰岛素/IGF 受体 (InR) 导致保幼激素 (JH) 缺乏。这些突变体矮小、不育且寿命长，显然都是由于 JH 缺陷所致。这些发现与长寿且缺乏多种垂体激素的侏儒小鼠产生了共鸣。这是一个共同的主题，即一小部分细胞调节次级激素，具有调节衰老的潜力。现在发现胰岛素/IGF如何调节这些次级激素以及这些内分泌如何影响衰老非常重要。 该项目的研究将利用果蝇的强大工具来深入了解 InR 突变如何延长寿命。 首先，分子分析将剖析特定 InR 突变等位基因的特性，这些突变等位基因可延长寿命。这些等位基因是否仅仅影响 INR 蛋白的数量，它们是否改变了 InR 转录的组织特异性，或者它们是否改变了 INR 产物的特定衰老相关质量？这些研究将比较多种等位基因的序列，描述表达模式和转录质量，并检查 P 元素重新动员等位基因拯救表型的能力。 其次，该项目将调查 JH 缺陷的出现是否是因为 InR 突变基因型延迟了内分泌组织的发育，或者是因为成熟的内分泌组织未能接收到足够的激活信号。这项工作将使用条件表达胰岛素样配体或 InR 的 Gal4/UAS 系。我们的第三个目标是通过开发一种受调节的 JH 阴性菌株来直接解决 JH 假说，该菌株具有新的 TetOn 系统来驱动保幼激素酯酶。这些研究将确定 InR 如何调节 JH 以及 JH 缺乏是否足以延长 InR 突变体成年人的寿命。 最后，利用 JH 阴性试剂和一组 InR 突变体等位基因，该项目将探索 JH 和 InR 如何影响影响寿命的体细胞特征。在全面的实验设计中，我们将评估抗压能力、中枢代谢和线粒体功能的质量，以确定哪个特征最能预测寿命的变化