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Sensory hair cells of the inner ear are the primary mechano-electrical transducers of hearing and balance.
There are only a few thousand of these per human ear and if they are badly damaged they cannot be regenerated.
Although no adult mammal has ever been found that can regenerate sensory hair cells, the inner ears of early post-natal mice do have a limited capacity for regeneration. In contrast, the ears of all nonmammalian vertebrates (fish, amphibians, reptiles and birds) posess a robust abilty to regenerate hair cells after injury.
The progenitor cells for this regenerative program are the supporting cells that surround the hair cells within the inner ear. The HRP consortium has been exploring both of these systems (postnatal mice and regenerating bird inner ears) in a series of large-scale studies, with the aim of understanding what gets switched on or off in the mouse ear and how we might reactivate the regenerative process. We have very detailed datasets on all of the protein-coding genes that are used during these processes. In the current proposal we intend to explore an entirely different set of regulatory molecules called microRNAs (miRs). These short RNAs regulate very large-scale developmental processes and potentially hundreds of protein-coding genes. They are particularly attractive candidates for therapeutic manipulation, since altered expression of just a few miRNAs can have wide-ranging effects upon how cells make decisions about how to develop.
They have not been explored before in the mouse postnatal hair cells and supporting cells, or in the regenerating chick auditory system. We shall carefully collect pure populations of the relevant cells and derive (by Next Generation DNA Sequencing) a comprehensive catalogue of the miRs that are present during these decisive developmental processes. We shall computationally analyze these to identify possible candidates for future miR-based manipulations in the mammalian ear.




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