Hair cell development in the mouse embryo

描述（由申请人提供）：据估计，每千名儿童中就有一名患有严重的听力和/或平衡障碍。这些先天性疾病的很大一部分源于感觉神经性，要么发生在内耳的感觉毛细胞内，要么发生在毛细胞信号所指向的大脑区域内。大约有12种毛细胞基因已被确定引起听觉和前庭功能缺陷。尽管最近在听力损失的遗传学方面取得了这些进展，但在了解先天性听力和平衡功能障碍的病理生理学方面却进展甚微。理解这些产前疾病的一个明显的先决条件是了解毛细胞在正常状态下如何发育。为了实现这一目标，本文提出的研究旨在通过检查产前小鼠毛细胞的正常生理来促进对毛细胞发育的理解。该项目有两个主要目标。第一个目的是表征前庭毛细胞电压敏感电导的产前获取。第二个目的是表征发育中的毛细胞的机械转导和适应的获得。这两个目标都将通过全细胞、密封技术来记录完整感觉上皮的胚胎毛细胞（胚胎第13天至出生）。机械转导将通过用硬探针或射流使毛束偏转而引起。一项平行的分子研究将把离子通道亚基和适应相关蛋白的产前表达模式与生理数据联系起来。最终，我们的目标是了解毛细胞如何以及何时开始发挥毛细胞的功能。这项工作也有望为促进毛细胞再生的项目提供一个可作为参考的发育时间表。

DESCRIPTION (provided by applicant): It has been estimated that one out of every thousand children is born with significant hearing and/or balance impairment. A substantial portion of these congenital disorders are sensorineural in origin, arising either within the sensory hair cells of the inner ear or within the brain regions to which the hair-cell signals project. Approximately 12 hair-cell genes have been identified that cause auditory and vestibular deficits. Despite these recent advances in the genetics of hearing loss, there has been little progress toward understanding the pathophysiology of congenital hearing and balance dysfunction. An obvious prerequisite to understanding these prenatal disorders is knowledge of how hair cells develop in the normal state. Toward that goal, the studies proposed here aim to advance an understanding of hair-cell development by examining the normal physiology of hair cells from prenatal mice. The project has two main objectives. The first aim is to characterize the prenatal acquisition of voltage sensitive conductances in vestibular hair cells. The second aim is to characterize the acquisition of mechanotransduction and adaptation in developing hair cells. Both of these aims will be addressed using the whole-cell, tight-seal technique to record from embryonic hair cells of the intact sensory epithelium (embryonic day 13 to birth). Mechanotransduction will be evoked by deflecting the hair bundles with either a stiff probe or a jet of fluid. A parallel molecular investigation will correlate the prenatal expression patterns of ion channel subunits and adaptation-associated proteins with the physiologic data. Ultimately, the objective is to understand how and when hair cells begin to function as hair cells. It is also expected that this work will provide a developmental timeline that may serve as reference for projects aimed at promoting hair cell regeneration.