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，衰老率由激素调节。在线虫中，一些细胞中胰岛素/IGF途径的突变足以缓慢衰老。我们在D. melanogaster中发现了一个类似的系统，其中突变胰岛素/IGF受体（INR）导致少年激素（JH）缺乏。这些突变体是矮人，无菌和长寿的，这显然是由于JH不足所致。这些发现引起了矮小鼠的共鸣，这些小鼠长寿且缺乏几种垂体激素。这是一个共同的主题，其中一小部分细胞调节二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是非常重要的。 该拟议项目中的研究将利用果蝇的强大工具来开发有关INR突变如何增加寿命的基本见解。 首先，分子分析将剖析赋予寿命增加的特定INR突变等位基因的质量。这些等位基因仅影响INR蛋白的数量，它们是否改变了INR转录的组织特异性，还是会改变INR产物的特定衰老相关质量？这些研究将比较多种类型等位基因的序列，描述表达模式和转录质量，并检查P元素重新启动等位基因营救表型的能力。 其次，该项目将研究JH缺乏症是否出现，因为INR突变基因型延迟了内分泌组织的发育或成熟的内分泌组织无法接收足够的激活信号。这项工作将使用带有胰岛素样配体或INR的条件表达的GAL4/UAS线。我们的第三个目标将通过使用新的提顿系统开发受调节的JH阴性菌株来直接解决JH假设，以驱动青少年激素酯酶。这些研究将确定INR如何调节JH以及JH缺乏是否足以增加INR突变体成年人的寿命。 最后，借助JH阴性试剂和INR突变等位基因的集合，该项目将探讨JH和INR如何影响塑造寿命的体细胞特征。在全面的实验设计中，我们将评估应力抵抗力，中央代谢和线粒体功能的限定，以确定哪种特征最能预测寿命的差异