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

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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.