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

为了生长，细胞含有称为细胞器的特殊结构。其中一种叫做内质网，它能产生蛋白质。当细胞不能正常分泌蛋白质时，就会受到内质网应激，这会阻碍它们的生长，甚至导致它们死亡。在许多人类疾病中，如糖尿病和中风，内质网应激会损害组织的存活。我们打算研究细胞、果蝇和小鼠的内质网应激。我们希望了解内质网应激如何影响细胞生长并导致死亡。我们之前证明了两种蛋白质，PERK和Gadd34，在这些现象中发挥着重要作用。现在，我们希望了解PERK和Gadd34是如何受到监管的。我们还希望识别参与内质网应激反应的新蛋白，改变细胞生长。有了这些信息，我们将试图在人类疾病模型中提高组织存活率。我们能够通过对果蝇或老鼠进行基因改造来制造在人类疾病中发生突变的蛋白质，从而导致果蝇或老鼠的组织损伤。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的有用药物靶点。

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.