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

为了生长，细胞包含被称为细胞器的特殊结构。其中一种叫做内质网，它产生蛋白质。当细胞不能正常分泌蛋白质时，它们就会遭受内质网应激，这可能会阻碍细胞的生长，甚至导致细胞死亡。在许多人类疾病中，如糖尿病和中风，内质网应激损害组织存活。我们打算在细胞、果蝇和小鼠中研究内质网应激。我们希望了解内质网应激是如何影响细胞生长并导致死亡的。我们之前的研究表明，PERK和GADD34两种蛋白在这些现象中起重要作用。我们现在希望了解PERK和GADD34是如何调控的。我们也希望确定新的蛋白质参与响应内质网应激改变细胞生长。有了这些信息，我们将尝试提高人类疾病模型中的组织存活率。我们可以通过对果蝇或老鼠进行基因改造，使它们产生在人类疾病中发生突变的蛋白质，从而造成它们的组织损伤。我们将在这些模型中操纵内质网应激信号，并确定哪些蛋白质最有可能成为人类疾病中有用的药物靶点。

In order to grow, cells contain specialised structures called organelles. One of these is called the endoplasmic reticulum, which produces proteins. Cells suffer ER-stress when they cannot make secreted proteins normally and this can hinder their growth and even cause them to die. In many human diseases, such as diabetes and stroke, ER-stress impairs tissue survival. We intend to study ER-stress in cells, fruit flies and mice. We hope to understand how ER-stress affects cell growth and causes death. We previously showed that two proteins, PERK and GADD34, play important roles in these phenomena. We now wish to understand how PERK and GADD34 are regulated. We wish also to identify new proteins involved in the response to ER-stress that alter cell growth.Armed with this information, we will attempt to improve tissue survival in models of human disease. We are able to cause tissue damage in fruit flies or mice by genetically modifying them to make proteins that are mutated in human diseases. We will manipulate ER-stress signaling in these models and determine which are the proteins most likely to be useful drug targets in human disease.