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Chemical mapping of the PPIase interactome in C. elegans - development of a systems biology toolbox

线虫 PPIase 相互作用组的化学图谱 - 系统生物学工具箱的开发

基本信息

批准号：
BB/D006201/1
负责人：
Antony Page
金额：
$ 22.95万
依托单位：
University of Glasgow
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2006
资助国家：
英国
起止时间：
2006 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FD006201%2F1
关键词：
Chemical mapping PPIase interactome C.

项目摘要

Caenorhabditis elegans (C. elegans) is a free living round worm comprising only 959 cells. Its genome produces 19,000 proteins (compared with some 25,000 from the human genome). We will introduce chemicals into the worms and look to see how they respond, particularly in terms of changes in their proteins. Small molecules which might be hormones, drugs or toxins can have profound effects on biological systems. Changes are usually caused by the small molecules (ligands) binding directly to a particular 'target protein' and stopping it from performing its normal function. These types of molecules are known as inhibitors. Currently we have a very poor understanding of the 'knock-on' effects in the cell when a given protein is bound to a ligand. We want to design molecules that bind to particular families of proteins in C.elegans and then modify their behaviour. We will monitor the effect of the chemical on the whole worm and identify which of the other proteins are affected. In this project we will only look at one family of proteins, the immunophilins, for which we have considerable background knowledge. Over 20 different proteins belong to this family. We know that they can act as enzymes and also help protein folding. We have synthesised new classes of molecules that inhibit these immunophilins and also show biological activity in the C.elegans. We have already put fluorescent-labels on some of these inhibitor molecules so that we see (using an optical microscope) where the molecules are taken up by the worm. We will see how proteins in worm change when they are exposed to these inhibitor ligands. By testing the many hundreds of different inhibitors that will be made in this project, we will identify molecules that have specific biological effects. Many of the proteins in C. elegans are similar to those in mammals, and so we will also learn about the effect of these chemicals in animal systems. Our data from worms could have a major impact on human and veterinary biology in areas like gene regulation, developmental biology, and drug discovery.

秀丽隐杆线虫（Caenorhabditis elegans，C. elegans）是仅包含959个细胞的自由生活的圆形蠕虫。它的基因组产生19，000种蛋白质（而人类基因组约为25，000种）。我们将向蠕虫中引入化学物质，并观察它们的反应，特别是它们蛋白质的变化。可能是激素、药物或毒素的小分子可以对生物系统产生深远的影响。变化通常是由小分子（配体）直接结合到特定的“靶蛋白”并阻止其正常功能引起的。这些类型的分子被称为抑制剂。目前，我们有一个非常贫穷的理解'敲'在细胞中的影响时，一个给定的蛋白质结合到一个配体。我们希望设计出与秀丽隐杆线虫中特定蛋白质家族结合的分子，然后改变它们的行为。我们将监测化学物质对整个蠕虫的影响，并确定哪些其他蛋白质受到影响。在这个项目中，我们将只看一个家族的蛋白质，亲免疫素，我们有相当多的背景知识。超过20种不同的蛋白质属于这个家族。我们知道它们可以作为酶，也可以帮助蛋白质折叠。我们已经合成了新的类的分子，抑制这些immunophilins，也表现出生物活性的秀丽隐杆线虫。我们已经在一些抑制剂分子上贴上荧光标记，这样我们就可以（用光学显微镜）看到这些分子被蠕虫吸收的位置。我们将看到蠕虫中的蛋白质在暴露于这些抑制剂配体时是如何变化的。通过测试数百种不同的抑制剂，我们将确定具有特定生物效应的分子。C.秀丽隐杆线虫与哺乳动物的相似，因此我们也将了解这些化学物质对动物系统的影响。我们从蠕虫获得的数据可能对人类和兽医生物学在基因调控、发育生物学和药物发现等领域产生重大影响。