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An automated in vivo screening platform for the UK zebrafish research community

英国斑马鱼研究界的自动化体内筛选平台

基本信息

批准号：
BB/M012239/1
负责人：
Catherina Becker
金额：
$ 67.11万
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM012239%2F1
关键词：
automated vivo screening platform UK

项目摘要

Much of what we know about the function of genes and drugs has arisen from so-called screens. Screens are unbiased methods to test gene and chemical compound function. For example, scientists can test how disruption of large numbers of genes affects a biological process of interest to discover which gene controls a given process. Similarly one can test how large numbers of chemical compounds affect specific biological events and discover, for example, how future drugs might affect different cells. Carrying out screens on living animals is very difficult, because one cannot manipulate genes or use chemicals in a sufficiently large number of animals in a time, cost, or ethically reasonable manner. Zebrafish, however, are a laboratory organism in which genetic and chemical screens can be carried out readily. This is because their embryos are available in very large numbers (1000s per day), they develop very rapidly, going from a fertilized egg to a tiny entity with the majority of organs that humans have in under 3 days- before they are technically considered animals. These young organisms are also transparent, such that one can directly observe biological events as they happen over time. New genetic technologies have further refined the ability to visualize in living zebrafish, e.g. by creating fish strains in which cell types of interest fluoresce. Genetic and chemical screens in zebrafish have already taught us a great deal about the fundamental molecular and cellular mechanisms of life and have even led to new clinical trials for the treatment of disease. However, despite being possible, such screens have remained very laborious, manual procedures, that take extended periods of time and that often rely on immediate experimenter's ability to link a gene or chemical treatment with biology. Therefore there is a great need to increase the efficiency of such screens because this will translate directly into new knowledge and insights of importance to health. Our proposal combines two elements, an electronically controlled system that can automatically transfer large numbers of embryonic zebrafish from their dishes via small capillaries onto a microscope stand in a rapid and uniform manner one by one. The second element is the microscope itself, which can carry out high-speed imaging of the individual zebrafish as they pass through the system. One can take overview snapshots of the entire animal to assess general health or organ function, or very detailed 3D images of specific cells of interest. Therefore it is possible to use this system to automatically image and screen hundreds of zebrafish throughout a day in a systematic manner and create a permanent record of the data, all of which represents an enormous increase in the efficiency of current approaches.This new system will be installed at the University of Edinburgh, where there is a concentration of world-experts in the use of zebrafish as a laboratory model. During the funding period of this award, the applicants will install the system in Edinburgh, and launch it to the wider community. In Edinburgh, the system will support projects focused on understanding the development of motor neurons and glial cells in the nervous system- cell types that are important for normal nervous system function and disrupted in diseases such as motor neuron disease and MS. The system will also be used to gain new insights into pigment cell development and how these cells are transformed in melanoma. Further screening studies will be carried out to better understand how our immune system can sometimes promote tumour growth and to learn how the resident network of immune cells in our brain develops and responds to injury. The wider UK community of zebrafish researchers who have already expressed great interest will use this new technology to elucidate yet further aspects of biology. Thus this new automated screening system for zebrafish will greatly strengthen UK Bioscience for health.

我们对基因和药物功能的许多了解都来自于所谓的筛选。筛查是测试基因和化合物功能的公正方法。例如，科学家可以测试大量基因的破坏如何影响感兴趣的生物过程，以发现哪个基因控制着给定的过程。同样，人们可以测试大量的化合物如何影响特定的生物事件，并发现，例如，未来的药物可能如何影响不同的细胞。对活着的动物进行筛查是非常困难的，因为一个人不能在足够多的动物中以合理的时间、成本或伦理方式操纵基因或使用化学品。然而，斑马鱼是一种实验室生物，可以很容易地进行遗传和化学筛选。这是因为它们的胚胎数量非常多(每天1000个)，发育非常迅速，从受精卵发育成一个微小的实体，在技术上被认为是动物之前，人类在3天内就拥有了大部分器官。这些年轻的生物体也是透明的，因此人们可以直接观察到随着时间的推移发生的生物事件。新的基因技术进一步提高了在活斑马鱼中可视化的能力，例如通过创造感兴趣的细胞类型荧光的鱼类品系。斑马鱼的遗传和化学筛选已经教会了我们许多关于生命的基本分子和细胞机制，甚至还导致了治疗疾病的新的临床试验。然而，尽管有可能，这样的筛查仍然非常费力，手动程序，需要很长一段时间，而且通常依赖于直接实验人员将基因或化学治疗与生物学联系起来的能力。因此，极有必要提高这类筛查的效率，因为这将直接转化为对健康具有重要意义的新知识和见解。我们的方案结合了两个元素，一个电子控制系统，可以快速而统一地将大量胚胎斑马鱼通过小毛细血管从盘子中自动转移到显微镜支架上。第二个元素是显微镜本身，它可以在斑马鱼通过系统时对它们进行高速成像。人们可以拍摄整个动物的概貌快照，以评估总体健康或器官功能，或者对感兴趣的特定细胞进行非常详细的3D图像。因此，使用该系统可以系统地全天自动对数百条斑马鱼进行成像和筛选，并创建永久的数据记录，所有这些都代表着当前方法效率的极大提高。这一新系统将安装在爱丁堡大学，那里是使用斑马鱼作为实验室模型的世界专家的集中地。在该奖项的资助期内，申请者将在爱丁堡安装该系统，并向更广泛的社区推出该系统。在爱丁堡，该系统将支持专注于了解神经系统中运动神经元和神经胶质细胞发育的项目-这些细胞类型对正常神经系统功能非常重要，并在运动神经元病和MS等疾病中受到干扰。该系统还将用于获得对色素细胞发育以及这些细胞在黑色素瘤中如何转化的新见解。将进行进一步的筛查研究，以更好地了解我们的免疫系统有时如何促进肿瘤生长，并了解大脑中常驻的免疫细胞网络如何发展和对损伤做出反应。已经表达了极大兴趣的更广泛的英国斑马鱼研究人员社区将使用这项新技术来阐明生物学的更多方面。因此，这一新的斑马鱼自动筛查系统将极大地加强英国生物科学公司的健康。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Myelination of Neuronal Cell Bodies when Myelin Supply Exceeds Axonal Demand.

DOI：
10.1016/j.cub.2018.02.068
发表时间：
2018-04-23
期刊：
Current biology : CB
影响因子：
0
作者：
Almeida RG;Pan S;Cole KLH;Williamson JM;Early JJ;Czopka T;Klingseisen A;Chan JR;Lyons DA
通讯作者：
Lyons DA

A Drug-Inducible Transgenic Zebrafish Model for Myelinating Glial Cell Ablation.