Enhancing Atoh1 function in hair cell regeneration

项目总结 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，就是耳蜗 人类和其他哺乳动物的毛细胞不会再生。相比之下，非哺乳类脊椎动物可以 动员支持细胞分裂分化置换功能恢复耳聋损伤 失去了毛细胞。在过去的10年里，来自许多研究的共识是，支持细胞在 Corti的胚胎和新生器官保留了有限的分裂和分化为毛细胞的能力 在某些情况下，但这种能力在听力开始之前急剧下降。 这种与年龄相关的再生潜力下降的一个方面是转录因子的功能 Atoh1.Atoh1在胚胎或新生儿耳蜗组织中的异位表达可将支持细胞转化为 邻近的非感觉细胞转化为毛细胞-但这种能力在发病后似乎严重减弱 老鼠的听力。我们已经证明，额外的毛细胞转录因子，如Gfi1和Pou4f3，可以 增强Atoh1在老年动物中产生毛细胞样细胞的能力，但目前尚不清楚它们之间的关系 就像真正的毛细胞一样，在慢性耳聋的耳朵中重新编程是否可行， 以及额外的干预措施是否能改善我们观察到的适度复苏。这项建议旨在 评估转录因子重新编程在成熟、耳聋的耳蜗中的可行性。我们还将 将这些耳蜗再生策略应用于成熟的椭圆形，我们和其他人已经证明它有一个 再生能力比耳蜗强，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.