Sensorineural hearing loss is caused by the death of hair cells in the organ of Corti, and once lost, cochlear hair cells in humans and other mammals do not regenerate. In contrast, non-mammalian vertebrates can functionally recover from deafening injury by mobilizing supporting cells to divide and differentiate to replace lost hair cells. Over the last 10 years, the consensus from many studies is that supporting cells in the embryonic and neonatal organ of Corti retain a limited capacity to divide and differentiate into hair cells under certain conditions, but that this ability declines precipitously prior to the onse of hearing. One facet of such an age-dependent decline in regenerative potential is the function of the transcription factor Atoh1. Ectopic expression of Atoh1 in embryonic or neonatal cochlear tissue can transform supporting cells or adjacent non-sensory into hair cells - but this ability appears to be severely diminished after the onset of hearing in mice. The goal of this proposal is to understand why the ability of Atoh1 to drive cochlear hair cell regeneration declines with age. Although there are many possible mechanisms for this age-dependent decline, we will test just two in the current proposal. First, we hypothesize that at least some of the transcriptional target of Atoh1 become epigenetically modified in supporting cells with age, rendering them unavailable for transcription. Our second hypothesis, which is not mutually exclusive with the first, is that Atoh1 requires transcriptional co-factors that are not present in the mature cochlea Studies from Drosophila and our preliminary data have identified the zinc finger transcription factor Gfi1 as a good candidate to potentiate the activity of Atoh1 during hair cell formation.
The most common form of hearing loss is caused by the death of hair cells in the cochlea. Many animals such as birds, frogs and fish, are capable of regenerating their hair cells, and recent work has shown that young mammals are capable of a limited amount of regeneration. However, this ability disappears in mammals by the time they are old enough to hear, and in our proposal, we will test two different hypotheses as to why mature mammals are unable to regenerate their sensory hair cells.
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