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: 9803243
• 负责人: Denise J. Montell
• 金额: $ 34.1万
• 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/9803243
• 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; Process; Proxy; Public Health; Recovery; Regulation; Rejuvenation; Reproduction; Resistance; Stem cells; Stress; System; Temperature; Testing; TimeLine; Tissues; Work; axonal pathfinding; circadian; cold temperature; day length; experience; feeding; female fertility; fertility preservation; fly; follow-up; genetic approach; genome wide association study; germline stem cells; healthspan; insight; knock-down; mutant; neurodevelopment; neuron development; novel; nutrient deprivation; preservation; programs; reproductive; response; 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，衰老的众多后果之一是 降低生育率，特别是女性生育率。有趣的是，有些物种 在特定的环境条件下，它们的生育能力比其他情况下更长。 例如，不同种类的果蝇进入一种称为成年生殖的状态， 滞育时，他们经历低温和短日照。根据这些 它们可以在保持生育能力的同时延长寿命。先前的工作已经 表明一些基因参与了成虫生殖滞育的正或负调控 在果蝇中。例如，胰岛素通路负调节滞育， 这表明代谢、生育力的调节是保守的机制， 和其他物种的寿命，包括C. elegans线虫，mice小鼠，and humans人.但我们的 滞育的机械理解是非常有限的，生育力是如何 保存是未知的。我们利用果蝇强大的遗传工具 进行滞育的全基因组关联研究。这种方法似乎是 非常成功，因为从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，最高度丰富的网络 与滞育相关的基因包括那些参与神经元发育的基因， 女性生殖神经元发育基因是惊人的，因为它们没有 以前与滞育有关，因此提供了新的分子和 细胞洞察力在这里，我们提出：1）确定基因控制的具体步骤， 滞育程序，如进入，维持，退出，保持繁殖力， 2）测试滞育基因是否需要在发育过程中准备 动物滞育，或功能，特别是在成年期;和3）调查 滞育期间生殖系干细胞保存的分子机制。我们 预期正如C. elegans dauer地层照明一般 调节动物代谢、生长、繁殖和衰老的途径， 从蠕虫到人类，果蝇滞育的研究提供了令人兴奋的潜力， 揭示干细胞保存、生育力维持 和寿命延长。