Roles of the Synapse in Hair-Cell Pathology

项目摘要 噪声暴露对耳蜗内毛细胞与听觉神经元突触联系的损伤 神经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，导致分离的听觉神经的缓慢退化。然而，最近的研究也支持了 哺乳动物耳蜗具有在噪声后进行毛细胞突触修复的内在能力 损害明确创伤性噪声后突触修复的细胞机制是研究神经元损伤的关键一步。 确定治疗靶点，以促进毛细胞突触接触的修复并防止听觉丧失， 神经 本研究的总体目标是了解毛细胞形态和功能的分子基础 器官修复和恢复后，噪音引起的损害。目前我们对毛细胞 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。本项目将通过以下方式规避这些问题： 研究机械诱导的斑马鱼侧线毛细胞突触丢失和随后的修复， 一种由神经支配的毛细胞簇组成的机械感觉器官。斑马鱼侧线毛细胞 在分子和细胞水平上与哺乳动物毛细胞相当，包括共同的 创伤性过度刺激后毛细胞突触丧失和去神经支配。然而侧线毛细胞迅速 并在刺激引起的损伤后数小时内明确修复失去的突触连接。目标1 我们的建议将测试毛细胞活动支配突触修复的假设，而Aim 2将定义 炎症对突触恢复和神经再支配的贡献。我们每个目标的结果将提供 关于毛细胞突触连接如何在创伤性过度刺激后恢复的信息， 确定促进噪声暴露耳蜗内源性修复的策略， 听觉神经退化和听力损失。

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.