Protein sorting in the maturation of inner ear cells

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SummaryOur ability to hear a vast range of sounds relies on thousands of specialised sensory receptors inside the auditory part of the ear. These "hair cells" are also found in balance organs within the inner ear, where they allow us to sense movements of our head and appreciate the effects of gravity. Errors in the development of these cells are associated with hearing loss and balance deficits found in a number of diseases, and progressive loss of hair cells most likely contributes to the majority of cases of age-related hearing loss and falls in the elderly.Hair cells bear a mechanically sensitive apparatus, known as the "hair bundle", and this delicate structure must be placed in the right place and in the correct orientation to be most sensitive to the microscopic fluid movements provided by sound and head movements. This process is instructed by numerous interacting genes, and variations in these genes can cause forms of inherited hearing loss and balance problems that contribute to complex syndromes. It is not currently understood how the essential building blocks and signalling molecules that are involved in building the bundle are directed to be in the right place in hair cells, at the right time.This project has several goals. We wish to determine how the complexity of hair bundle shape and orientation is regulated at a molecular level during normal development, and how this regulation is affected under conditions during certain diseases of the nervous system. We aim to find out how essential proteins are delivered to specific regions of a hair cell. We want to know if this protein sorting pathway contributes to ongoing replacement of hair cells and repair after damage to the inner ear. Finally, we want to know if a molecular regulator of hair bundle shape during embryonic development can subsequently play quite distinct roles in support of the functionally mature inner ear. Our studies would provide a detailed analysis of mechanisms contributing to the normal development of the inner ear, explain how these mechanisms are affected by genetic disease, and how they may be harnessed in the future in order to repair the inner ear following damage or during old age, by replacing lost hair cells or by prolonging their lifespan. These mechanisms are likely to be important in other regions of the nervous system, and so our results will be of wider importance, and may contribute to future treatments of neural disorders.