Enhancing Atoh1 function in hair cell regeneration

 描述（由申请人提供）：感觉神经性听力损失是由Corti器官中的毛细胞死亡引起的，一旦丢失，人类和其他哺乳动物的耳蜗毛细胞就不能再生。相比之下，非哺乳类脊椎动物可以通过动员支持细胞分裂和分化来取代失去的毛细胞，从而从震耳欲聋的损伤中恢复功能。在过去的10年里，许多研究的共识是，胚胎和新生儿Corti器官中的支持细胞在某些条件下保留了有限的分裂和分化为毛细胞的能力，但这种能力在听力出现之前急剧下降。这种年龄依赖性再生潜力下降的一个方面是转录因子Atoh 1的功能。Atoh 1在胚胎或新生儿耳蜗组织中的异位表达可以将支持细胞或邻近的非感觉细胞转化为毛细胞-但这种能力似乎在小鼠听力开始后严重减弱。该提案的目标是了解为什么Atoh 1驱动耳蜗毛细胞再生的能力随着年龄的增长而下降。虽然这种年龄依赖性下降有许多可能的机制，但我们将在当前的提案中测试两个。首先，我们假设Atoh 1的至少一些转录靶点随着年龄的增长在支持细胞中发生表观遗传修饰，使它们无法转录。我们的第二个假设，这是不相互排斥的第一个，是Atoh 1需要转录辅因子，不存在于成熟的耳蜗研究从果蝇和我们的初步数据已经确定了锌指转录因子Gfi 1作为一个很好的候选人，以加强活动Atoh 1在毛细胞形成。

 DESCRIPTION (provided by applicant): 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.