Epigenetic mechanisms underlying the failure of hair cell regeneration in mammals

项目摘要/摘要： 感觉性毛细胞再生并不是在成熟的哺乳动物器官Corti中自发发生的， 使听力损失成为永久性的。这项提案的目标是找出导致 毛细胞再生失败，以及刺激内耳存活种群再生的方法 聋人体内的支持细胞。我们的主要假设是再生需要重新- 参与发育基因网络以引导支持细胞走向毛细胞的命运，以及在 出生后，内耳成熟，表观遗传障碍出现，阻止这些基因网络的重新激活。 目标是开发克服这些表观遗传障碍的方法，并建立新的细胞命运 科尔蒂器官内的再生潜能。 实验上，围产期小鼠保留了直接支持细胞转分化为 毛细胞一样的命运，但这种能力在出生后的第一周就会迅速丧失。这种与年龄相关的变化 再生潜力提供了一个窗口，通过它来研究从许可到 在正常成熟的Corti器官中，这种形式的再生是不允许的状态。这件事的工作 建议阐明转分化在围产期支持中的表观遗传控制机制(S) 细胞(Aim1)，并确定与成熟相关的机制的表观遗传/染色质结构的变化 内耳的支持细胞。(目标2)。我们假设这些变化是导致 再生。最后，研究成人支持细胞染色质的表观遗传结构。 耳聋小鼠(目标3)。我们假设，操纵表观遗传状态是 未来的再生医学是修复失去的毛细胞的方法。

Project Summary/Abstract: Sensory hair cell regeneration does not occur spontaneously in the mature mammalian organ of Corti, making hearing loss permanent. The goal of this proposal is to identify the causes and mechanisms behind the failure of hair cell regeneration, as well as ways to stimulate regeneration in surviving populations of inner ear supporting cells in deafened individuals. Our primary hypothesis is that regeneration requires the re- engagement of developmental gene networks to guide supporting cells to a hair cell fate, and that during postnatal inner ear maturation, epigenetic barriers arise that block the re-activation of these gene networks. The goal is to develop methods to overcome these epigenetic barriers, and to establish new cell fates with regenerative potential within the organ of Corti. Experimentally, perinatal mice retain a latent capacity for direct supporting cell transdifferentiation to a hair cell-like fate, but this capacity is rapidly lost in the first weeks after birth. This age-dependent change in regenerative potential provides a window through which to investigate the transition from a permissive to a non-permissive state for this form of regeneration in the normally maturing organ of Corti. The work of this proposal is to elucidate the mechanism(s) of epigenetic control of transdifferentiation in perinatal supporting cells (Aim1) and to identify the machinery of maturation-related changes in epigenetic/chromatin structure in supporting cells of the inner ear. (Aim 2). We hypothesize that these changes are responsible for the failure of regeneration. Finally, to investigate the epigenetic structure of adult supporting cell chromatin in normal and deafened mice (Aim 3). We hypothesize that manipulation of the epigenetic state is an important approach for future regenerative medicine approaches to restoring lost hair cells.