Enhancing Atoh1 function in hair cell regeneration

项目摘要 感音神经性听力损失是由Corti器官中的毛细胞死亡引起的，一旦失去，耳蜗 人类和其他哺乳动物的毛细胞不能再生。相反，非哺乳类脊椎动物可以 通过动员支持细胞进行分裂和分化， 失去了毛细胞在过去的10年里，许多研究的共识是， 胚胎和新生儿Corti器官保留有限的分裂和分化成毛细胞的能力， 在某些情况下，这种能力，但这种能力急剧下降之前的听力发作。 这种年龄依赖性再生潜力下降的一个方面是转录因子的功能 Atoh1. Atoh 1在胚胎或新生儿耳蜗组织中的异位表达可以转化支持细胞或 邻近的非感觉细胞进入毛细胞-但这种能力似乎在发病后严重减弱。 老鼠的听力我们已经表明，额外的毛细胞转录因子，如Gfi 1和Pou 4f 3， 增强Atoh 1在老年动物中产生毛细胞样细胞的能力，但尚不清楚这些细胞与 类似于真正的毛细胞，重新编程在长期受损的耳朵中是否可行， 以及额外的干预是否可以改善我们观察到的适度再生。这项建议旨在 评估转录因子重编程在成熟的、退化的耳蜗中的可行性。我们还将 将这些耳蜗再生策略应用于成熟的椭圆囊，我们和其他人已经证明， 比耳蜗更大的再生能力，对转录因子的反应也更好 重新编程

PROJECT SUMMARY 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 onset 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 cells into hair cells - but this ability appears to be severely diminished after the onset of hearing in mice. We have shown that additional hair cell transcription factors, such as Gfi1 and Pou4f3, can enhance the ability of Atoh1 to generate hair cell-like cells in older animals, but it is not clear how closely these resemble bona fide hair cells, whether reprogramming is feasible in ears that have been chronically deafened, and whether additional interventions can improve the modest regeneration we observe. This proposal seeks to evaluate the feasibility of transcription factor reprogramming in the mature, deafened cochlea. We will also apply these cochlear regenerative strategies to the mature utricle, which we and others have shown to have a greater capacity for regeneration than the cochlea, and also a better response to transcription factor reprogramming.