Mechanisms of stem cell preservation and lifespan extension in Drosophila

果蝇干细胞保存和寿命延长的机制

• 批准号: 10399509
• 负责人: Denise J. Montell
• 金额: $ 31.88万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399509
• 关键词: Adult; Affect; Aging; Animal Model; Animals; Behavioral; Biological Assay; Caenorhabditis elegans; Candidate Disease Gene; Cues; Data; Development; Developmental Gene; Diapause; Drosophila genus; Feeding behaviors; Female; Fertility; Genes; Genetic; Genetic study; Goals; Growth; Human; Individual; Insulin; Insulin Receptor; Longevity; Maintenance; Metabolism; Methods; Molecular; Mus; Oogenesis; Organism; Pathway interactions; Persons; Process; Proxy; Public Health; Recovery; Regulation; Rejuvenation; Reproduction; Resistance; Stress; System; Temperature; Testing; TimeLine; Tissues; Work; axonal pathfinding; circadian; cold temperature; day length; experience; feeding; female fertility; fertility preservation; fly; follow-up; gene network; genetic approach; genome wide association study; germline stem cells; healthspan; insight; knock-down; mutant; neurodevelopment; neuron development; novel; nutrient deprivation; preservation; programs; reproductive; response; stem cells; tool

Across many species, including humans, one of the many consequences of aging is a reduction in fertility, particularly female fertility. Intriguingly some species can preserve fertility for longer than they otherwise would, under specific environmental conditions. For example, various species of Drosophila enter a state called adult reproductive diapause when they experience low temperatures and short day length. Under these conditions they can double their lifespan while maintaining fertility. Previous work has implicated a few genes in positive or negative regulation of adult reproductive diapause in Drosophila. For example, the insulin pathway negatively regulates diapause, suggesting mechanisms that are conserved with the regulation of metabolism, fertility, and lifespan in other species including C. elegans, mice, and humans. However, our mechanistic understanding of diapause is extremely limited, and how fertility is preserved is unknown. We have taken advantage of powerful genetic tools in Drosophila to carry out a genome-wide association study of diapause. This approach appears to be highly successful, as the few known genes emerged from the analysis, such as the insulin receptor. In addition, this screen revealed that the most highly enriched networks of genes associated with diapause include those involved in neuronal development and female reproduction. The neuronal development genes are striking, as they have not previously been associated with diapause and thus offer to provide new molecular and cellular insights. Here we propose to: 1) identify the genes controlling specific steps in the diapause program such as entry, maintenance, exit, preservation of fecundity, and lifespan; 2) test whether diapause genes are required during development to prepare the animals for diapause, or function specifically in adulthood; and 3) investigate the molecular mechanisms of germline stem cell preservation during diapause. We anticipate that just as studies of C. elegans dauer formation illuminated general pathways regulating metabolism, growth, reproduction and aging in animals ranging from worms to humans, studies of Drosophila diapause offer the exciting potential to uncover novel and general mechanisms of stem cell preservation, fertility maintenance, and lifespan extension.

在包括人类在内的许多物种中，衰老的许多后果之一是 降低生育能力，尤其是女性生育能力。有趣的是，有些物种可以保存 在特定的环境条件下，生育能力比以其他方式更长。 例如，各种果蝇种类进入一个称为成人生殖的状态 当他们经历低温和短日长度时。在这些 条件它们可以在维持生育能力的同时将其寿命加倍。以前的工作有 在成人生殖滞育的阳性或阴性调节中暗示了一些基因 在果蝇中。例如，胰岛素途径对肿瘤进行负调节， 建议通过调节新陈代谢，生育能力来保守的机制 以及其他物种中的寿命，包括秀丽隐杆线虫，小鼠和人类。但是，我们的 对滞育的机械理解非常有限，生育力的程度 保留是未知的。我们在果蝇中利用了强大的遗传工具 进行全基因组的结合研究。这种方法似乎是 非常成功，因为分析中出现了少数已知的基因，例如 胰岛素受体。此外，该屏幕显示了最丰富的网络 与肿瘤相关的基因包括参与神经元发育和 女性繁殖。神经元发育基因很引人注目，因为它们没有 以前与滞育有关，因此提供了新的分子和 细胞见解。在这里我们建议：1）确定控制特定步骤的基因 诊断计划，例如进入，维护，退出，繁殖力保存以及 寿命; 2）测试开发过程中是否需要抑郁基因来制备 育动的动物，或在成年期专门起作用； 3）调查 滞育过程中种系干细胞的分子机制。我们 预计，就像对秀丽隐杆线虫的研究dauer形成照亮了一般 调节动物的新陈代谢，生长，繁殖和衰老的途径 从蠕虫到人类，果蝇的研究为 发现干细胞保存，生育能力维护的新颖和一般机制， 和寿命扩展。