THE ROLE OF ENDOPLASMIC RETICULUM PROTEIN MISFOLDING IN CELL DEATH AND DISEASE

在许多人类疾病中，会产生破坏细胞的缺陷蛋白质，即所谓的蛋白质错误折叠。为了应对这种情况，我们的细胞降低了制造新蛋白质的速度，以便纠正或破坏这些异常成分。当缺陷被纠正后，蛋白质合成再次增加。蛋白质合成的减少需要一种叫做PERK的蛋白质，而恢复需要一种叫做GADD34的蛋白质。我们之前已经展示了GADD34基因突变如何在蛋白质错误折叠的动物模型中保护肾脏免受损害。这让我们假设，通过开发阻断GADD34功能或激活PERK的药物，我们可能能够保护蛋白质错误折叠很重要的疾病中的组织，比如糖尿病和中风。为了帮助我们确定潜在的药物靶点，我们现在正在研究GADD34和PERK是如何被细胞的其他成分控制的。我们主要使用两种方法：第一，通过研究GADD34和PERK在培养的人和小鼠细胞中是如何调节的；第二，利用转基因果蝇（Drosophila melanogaster）快速识别与该系统相关的基因。

In many human diseases defective proteins are made that damage the cell, so-called protein misfolding. In response to this, our cells reduce the rate at which they make new proteins in order to allow correction or destruction of these abnormal components. When the defect is corrected, protein synthesis increases once again. The reduction of protein synthesis requires a protein called PERK, while the recovery involves a protein called GADD34. We have previously shown how mutations in the GADD34 gene protect against kidney damage in an animal model of protein misfolding. This led us to hypothesise that by developing drugs either to block GADD34 function or activate PERK, we might be able to protect tissues in diseases where protein misfolding is important, such as diabetes and stroke. To help us identify potential drug targets, we are now studying how GADD34 and PERK are controlled by other components of the cell. We are using two main approaches: First, by studying how GADD34 and PERK are regulated in cultured human and mouse cells; and second, using genetically modified fruit flies (Drosophila melanogaster) to allow rapid identification of genes involved in the this system.