Roles of the Synapse in Hair-Cell Pathology

项目摘要 噪声暴露损害耳蜗内毛细胞与神经听觉之间的突触联系 太紧张了。来自哺乳动物模型和人类的数据表明，一些内毛细胞突触的丢失可能是 永久性的，导致分离的听神经缓慢退化。然而，最近的研究也支持 哺乳动物耳蜗具有噪声后毛细胞突触修复的内在能力 损坏。明确创伤噪声后突触修复的细胞机制是迈向 确定促进毛细胞突触修复和防止听力丧失的治疗靶点 太紧张了。 这项建议的总体目标是了解毛细胞形态和功能的分子基础。 噪声损伤后的器官修复和恢复。目前我们对毛细胞如何 创伤性噪音后的突触修复在很大程度上是由于我们无法定义细胞过程 在哺乳动物模型系统中促进突触修复。该项目将通过以下方式绕过这些问题 研究机制诱导斑马鱼侧线毛细胞突触丢失和随后的修复- 一种机械感觉器官，由成簇的神经支配的毛细胞组成。斑马鱼侧线毛细胞 在分子和细胞水平上可与哺乳动物毛细胞相媲美，包括一种共同的 创伤性过度刺激后毛细胞突触丢失和失神经。然而，侧线毛细胞迅速 并在刺激诱导的损伤后几个小时内毫不含糊地修复丢失的突触连接。目标1 我们的建议将检验毛细胞活动管理突触修复的假设，而目标2将定义 炎症在突触恢复和神经再支配中的作用。我们每个目标的结果都将提供 有关创伤性过度刺激后毛细胞突触连接如何恢复的信息将有所帮助 确定促进暴露在噪声中的耳蜗内源性修复的策略，从而防止随后的 听神经变性和听力损失。

Project Summary Noise exposure damages synaptic connections between cochlear inner hair cells and innervating auditory nerves. Data from mammalian models and humans indicate that loss of some inner hair cell synapses can be permanent, leading to the slow degeneration of detached auditory nerves. Yet recent research also supports that the mammalian cochlea possesses the intrinsic capacity for hair cell synaptic repair following noise damage. Defining the cellular mechanisms of synapse repair following traumatic noise is a critical step toward identifying therapeutic targets to promote repair of hair cell synaptic contacts and prevent loss of auditory nerves. The overall goal of this proposal is to understand the molecular basis of morphological and functional hair cell organ repair and recovery following noise-induced damage. Current gaps in our understanding of how hair cell synapses repair following traumatic noise are in large part due to our inability to define the cellular processes that promote synaptic repair in mammalian model systems. This project will circumvent these issues by investigating mechecaniclly induced hair-cell synapse loss and subsequent repair in the zebrafish lateral line— a mechanosensory organ which is made up of clusters of innervated hair cells. Zebrafish lateral-line hair cells are comparable to mammalian hair cells at the molecular and cellular level, including a shared mechanism of hair cell synapse loss and de-innervation following traumatic overstimulation. Yet lateral line hair cells rapidly and unambiguously repair lost synaptic connections within hours following stimulus-induced damage. Aim 1 of our proposal will test the hypothesis that hair cell activity governs synaptic repair, while Aim 2 will define the contribution of inflammation to synaptic recovery and reinnervation. The results of each of our Aims will provide information on how hair cell synaptic connections are restored following traumatic overstimulation and will help identify strategies to promote endogenous repair in noise exposed cochlea, thereby preventing subsequent auditory nerve degeneration and hearing loss.