Genetic analysis of hair cell regeneration in zebrafish

描述（由申请人提供）：机械感觉毛细胞损失是人类听力和平衡障碍的主要原因。虽然新的毛细胞不会在人类身上再生，但这一过程在其他动物身上很常见。此外，在一些动物中，毛细胞在其一生中不断产生，需要稳定地供应新的毛细胞前体。在这个R21应用中，我们提出了在斑马鱼侧线系统中识别自我更新前体的实验，并筛选改变前体功能的突变。侧线机械感觉毛细胞与内耳具有许多相同的特性，但由于它们位于体表，因此易于观察和操作。这些实验利用了斑马鱼系统的优势，包括它们的快速发育，已建立的遗传学和先进的基因组学。我们提出了两个目标：鉴定改变毛细胞再生的突变，作为揭示这一过程的分子调控的第一步；鉴定成体侧线内的毛细胞前体，并确定它们是否具有干细胞的自我更新特性。本次探索性研究旨在建立斑马鱼侧线毛细胞再生的模型，开发遗传资源，为研究提供参考。机械感觉毛细胞的损失是人类听力和平衡障碍的主要原因，是不可逆转的。相反，其他动物的毛细胞可以再生。了解成功再生背后的调控机制将影响人类功能恢复的策略。

DESCRIPTION (provided by applicant): Mechanosensory hair cell loss is the leading cause of human hearing and balance disorders. While new hair cells do not regenerate in humans, this process is common in other animals. Moreover, in some animals there is constant production of hair cells throughout their life, requiring a steady supply of new hair cell precursors. In this R21 application, we propose experiments to identify self-renewing precursors within the zebrafish lateral line system, and screen for mutations that alter precursor function. Lateral line mechanosensory hair cells share many properties with the inner ear, but since they are located on the body surface, they are easily accessible to visualization and manipulation. These experiments take advantage of the zebrafish system, including their rapid development, established genetics and advancing genomics. We propose 2 aims: to identify mutations that alter hair cell regeneration as a first step to uncovering the molecular regulation of this process, and to identify hair cell precursors within the adult lateral line and determine whether they have the self-renewing properties of stem cells. The proposed exploratory research should establish the zebrafish lateral line as a model for hair cell regeneration, and develop genetic resources that will be useful to the research community. Mechanosensory hair cell loss in humans, the leading cause of hearing and balance disorders, is irreversible. In contrast, hair cells regenerate in other animals. Understanding the regulatory mechanisms behind successful regeneration will influence strategies towards recovery of function in humans.