A Drosophila single-cell resource for brain metabolism research

用于脑代谢研究的果蝇单细胞资源

• 批准号: NC/V001272/1
• 负责人: Alex Gould
• 金额: $ 32.62万
• 依托单位: The Francis Crick Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FV001272%2F1
• 关键词: Drosophila; single; cell; resource; brain

A healthy human fetus grows at an impressive rate as it develops inside the mother's uterus. In about 5% of pregnancies, however, nutrients and oxygen cannot be efficiently supplied from mother to fetus. When this metabolic stress occurs, it is not always possible for the fetal body to continue to grow at the normal rate. Nevertheless, in many of these cases, the growth of the fetal brain remains remarkably unperturbed. Our research aims to identify, as yet unknown, protective processes that spare the growth of the brain over that of the body. Towards this goal, our previous work has modelled some aspects of brain sparing in the fruit fly Drosophila, which shares many genes with humans - including about three-quarters of those linked to human diseases. Although the brain of Drosophila is much smaller and less complex than that of humans, they both contain very similar cell types - neural stem cells, neurons and glia. We therefore propose that Drosophila, with its relatively simple nervous system, can be used to replace a proportion of the brain sparing experiments that would otherwise be carried out in mice or other animals. Our research plan has three main aims. In the first aim, we will use a technology called single-cell sequencing to produce a map or atlas of the genes active in every one of the tens of thousands of cells in the normal versus the metabolically stressed Drosophila brain. In this way, we will identify which genes are most active during Drosophila brain sparing, anticipating that some of the equivalent genes will also be active during mammalian brain sparing. In the second aim, we will use the sophisticated genetics possible in Drosophila to test which of the highly active genes are the most essential for the growth processes that drive brain sparing. In the third and final aim, we will use the results of the sequencing and genetic approaches to pinpoint how the different cell types in the brain use genes to communicate with each during brain sparing. An enduring legacy of this project will be a Drosophila brain atlas, an open-access web resource that can be used by all scientists interested in brain sparing and brain research. This atlas may also help researchers to work out how metabolism in the mammalian brain is linked to health and disease.

健康的人类胎儿在母亲子宫内发育时以惊人的速度生长。然而，在大约 5% 的妊娠中，营养物质和氧气无法有效地从母亲供应给胎儿。当这种代谢应激发生时，胎儿身体并不总是能够继续以正常速度生长。然而，在许多这样的情况下，胎儿大脑的生长仍然不受干扰。我们的研究旨在确定目前未知的保护过程，使大脑的生长优于身体的生长。为了实现这一目标，我们之前的工作对果蝇大脑保护的某些方面进行了建模，果蝇与人类共享许多基因，其中大约四分之三与人类疾病相关。尽管果蝇的大脑比人类的大脑小得多，复杂性也低得多，但它们都含有非常相似的细胞类型——神经干细胞、神经元和神经胶质细胞。因此，我们建议，果蝇以其相对简单的神经系统，可以用来代替部分在小鼠或其他动物中进行的大脑保留实验。我们的研究计划有三个主要目标。在第一个目标中，我们将使用一种称为单细胞测序的技术来生成正常果蝇大脑与代谢应激果蝇大脑中数万个细胞中每一个细胞中活跃的基因图谱或图谱。通过这种方式，我们将确定哪些基因在果蝇大脑保留期间最活跃，并预计一些等效基因在哺乳动物大脑保留期间也将活跃。在第二个目标中，我们将利用果蝇中可能的复杂遗传学来测试哪些高度活跃的基因对于驱动大脑保护的生长过程最为重要。在第三个也是最后一个目标中，我们将利用测序和遗传方法的结果来查明大脑中的不同细胞类型在大脑保护期间如何使用基因相互通信。该项目的持久遗产将是果蝇大脑图谱，这是一种开放访问的网络资源，可供所有对大脑保护和大脑研究感兴趣的科学家使用。该图谱还可以帮助研究人员弄清楚哺乳动物大脑中的新陈代谢如何与健康和疾病相关。