The role of endoplasmic reticulum protein misfolding in cell death and disease

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.