The physiology and pathophysiology of unfolded protein responses. (360G-Wellcome-084812_Z_08_Z)

This project s overarching goal is to understand the molecular mechanisms involved in signaling unfolded protein stress from organelles in hope of identifying unique features that may enable manipulation of these signaling pathways to useful ends. In the better-understood endoplasmic reticulum (ER) unfolded protein response (UPRer) studies will focus on three potentially malleable aspects: A detailed molecular understanding of regulated phosphorylation and dephosphorylation of translation initia tion factor 2 will be sought, alongside a search for chemical probes to manipulate these activities in cells. These probes and genetic tools will be applied to test the hypothesis that tuning the level of phosphorylated eIF2 can promote secretion of mutant proteins and alter susceptibility of cells to ER stress. Genetic manipulation of the ER oxidase ERO1 will be applied to test the hypothesis that a hyperoxidizing ER contributes to dysfunction of mammalian cells experiencing severe ER stress an d the molecular basis of the regulation of intermediary metabolism by ER stress will be studied in effort to understand the physiological links to diseases of aging. Studies on the mitochondrial UPR will follow clues that matrix proteolysis contributes to stress signal generation and unbiased genetic screens will identify components of this signal transduction cascade.