The use of newly discovered inhibitors to identify novel components of the ER associated degradation pathway.

生物是由一个或多个细胞组成的，细胞需要膜在细胞内提供屏障，保护细胞免受外部世界的伤害。虽然形成这些屏障的生物膜在性质上是令人难以置信的复杂和多样化的，但它们的特征通常是含有许多蛋白质的脂双层。为了制造新的膜，细胞必须将新的蛋白质放入脂双层，在高等细胞中，这是被称为内质网的特殊隔室的关键功能之一。内质网包含许多分子机器，它们将新的蛋白质缝合到脂质双层中，形成功能膜。近年来，越来越明显的是，这个过程有时会出错，例如，由于正在制造的蛋白质的突变或缺陷。为了将这些坏蛋白质从好蛋白质中分离出来，内质网还配备了一套分子机器，检查它制造的所有蛋白质，只使用好蛋白质，破坏有缺陷的蛋白质。这种所谓的“质量控制”过程特别令人感兴趣，因为它与某些疾病有关，例如囊性纤维化，它还可能限制用于生物技术应用的蛋白质的生产。这个项目的目的是使用一种新发现的药物来阻止两种不同类型的缺陷蛋白质的破坏，从而使我们能够识别识别它们的细胞机器。这将帮助我们理解细胞如何识别好的蛋白质和坏的蛋白质之间的区别，从长远来看，这可能有助于我们操纵这一过程，使其对我们有利。

Living things are made up of one or more cells, and cells need membranes to provide barriers inside the cell and to protect them from the outside world. Whilst the biological membranes that form these barriers are incredibly complex and diverse in nature, they are generally characterised by a lipid bilayer studded with many proteins. In order to make new membranes, the cell has to put new proteins into the lipid bilayer and in higher cells this is one of the key functions of a specialised compartment known as the endoplasmic reticulum. The endoplasmic reticulum contains a number of molecular machines that stitch new proteins into the lipid bilayer to make functional membranes. It has become increasing clear over recent years that sometime this process goes wrong, for example because of a mutation or defect in the protein being made. In order to sort such bad proteins from the good ones, the endoplasmic reticulum also has a set of molecular machines that check all the proteins it has made, only the good proteins are used and the defective ones are destroyed. This so called 'quality control' process is of particular interest because it linked to some kinds of disease, for example cystic fibrosis, and it can also restrict the production of proteins for biotechnology applications. The aim of this project is to use a newly discovered drug to block the destruction of two different kinds of defective proteins allowing us to identify the cellular machines that recognise them. This will help us understand how the cell knows the difference between good proteins and bad proteins, and in the longer term may help us to manipulate this process to our benefit.