Competence of support cells to form hair cells in the mammalian inner ear

摘要/摘要 在人类中，内耳毛细胞的丧失会导致听力和平衡障碍，因为这些细胞会 而不是再生。相比之下，在非哺乳类脊椎动物中，如鸟类和鱼类，受损的听觉毛细胞 从周围的支持细胞非常有效地再生。支持细胞长出毛发的能力 通过转分化的细胞首先是由Corwin在两栖动物的侧线上展示的，直接 使用延时成像进行观察，但更多的间接方法也发现了类似的过程发生在鸟类身上 基底乳头。这些结果共同表明，人的内耳毛细胞再生问题 哺乳动物可以概括为两个基本问题：(1)是什么导致支持细胞增殖的丧失 损伤后的细胞和(2)是什么限制了支持细胞向新毛细胞的转分化？在这 资助申请我们的目标是研究限制前庭系统再生的因素是什么 哺乳动物。我们将使用各种转基因菌株来激活可能导致毛细胞刺激的通路 再生。我们将具体地将我们的研究引向克里斯塔(位于大脑底部的感觉区域 三个半规管)，检测头部在三个有序平面上的旋转。随着人口老龄化，人口趋于平衡 紊乱变得更加普遍，而这个器官对保持凝视特别重要。脊骨 到目前为止在分子水平上还没有得到充分的研究，我们最近开发了一种培养方法和 正在使用先进的分子技术来阐明克里斯塔支持细胞能力的变化 产生毛细胞。

Summary/Abstract In humans, loss of the hair cells in the inner ear leads to hearing and balance impairment, since these cells do not regenerate. By contrast, in non-mammalian vertebrates, like birds and fish, damaged auditory hair cells are regenerated very efficiently from the surrounding supporting cells. The ability of support cells to give rise to hair cells through transdifferentiation was first demonstrated by Corwin in the amphibian lateral line, by direct observation using time-lapse imaging, but more indirect methods also found a similar process to occur in bird basilar papilla. These results together suggest that the problem of hair cell regeneration in the inner ear of the mammal can be summarized in two fundamental questions: (1) What causes the loss in proliferation of support cells following damage and (2) what limits the transdifferentiation of the support cells to new hair cells? In this grant application we aim to study what are the factors that limit regeneration in the vestibular system of the mammal. We will use various transgenic strains to activate pathways that may lead to stimulation of hair cell regeneration. We will specifically direct our studies towards the crista (the sensory regions at the base of the three semicircular canals) that detect head rotation in the three ordinal planes. As the population ages balance disorders become more prevalent and this organ is particularly important for maintaining gaze. The cristae have been understudied at the molecular level to date and we have recently developed a culture method and are using advanced molecular techniques to elucidate changes in the competence of crista support cells to generate hair cells.