Stress granules and Caprin-1 in the cochlea: towards a new understanding of how the cochlea copes with stress. . (360G-Wellcome-091092_Z_09_Z)

The main aim of this project is to understand the role that stress granules play in sensory hair cell survival in the inner ear. It will provide the first characterisation of stress granules, their components and their formation in the mammalian inner ear in vivo. Analysis of mice subjected to different clinically-relevant types of cochlear insult will reveal whether stress-granule assembly is a fundamental response of hair cells to injury and ageing. We have identified a number of hair-cell str ess genes through genetic screens using known essential hair-cell transcription factors. We will now determine whether those hair-cell transcription factors, Pou4f3 and Barhl1 act as stress sensors in hair cells. We have shown that Pou4f3 regulates Caprin-1, a recently identified component of RNA granules and that Caprin-1 is present in stress granules during hair cell damage. We will now identify Caprin-1 s binding partners, determine the role that Caprin-1 plays during hair-cell stress in vitr o and generate a conditional knockout mouse to determine whether Caprin-1 regulates hair-cell survival in vivo. We will utilise in vitro manipulations of Caprin-1 and other stress granule components to test whether such interventions can improve hair cell survival during cochlear stress.