Roles of the Synapse in Hair-Cell Pathology

突触在毛细胞病理学中的作用

• 批准号: 10187542
• 负责人: Lavinia Sheets
• 金额: $ 32.41万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-17 至 2023-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187542
• 关键词: AMPA Receptors; Ablation; Acoustic Nerve; Acoustic Trauma; Acoustics; Address; Apoptosis; Apoptotic; Biosensor; Cell Death; Clustered Regularly Interspaced Short Palindromic Repeats; Cochlea; DAP kinase; Data; Development; Fishes; Genetic; Glutamate Receptor; Glutamates; Goals; Hair Cells; Image; Impairment; Kainic Acid Receptors; Larva; Loudness; Mediating; Metabolic; Metabolic stress; Mitochondria; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve; Neurites; Nicotinamide adenine dinucleotide; Noise; Optics; Organ; Pathologic; Pathology; Pharmacology; Phenotype; Play; Preparation; Process; Production; Receptor Activation; Regenerative capacity; Reporting; Research; Role; Sensorineural Hearing Loss; Sensory Hair; Stimulus; Structure; Synapses; Synaptic Cleft; Testing; Time; Tissues; Work; Zebrafish; cell injury; defined contribution; excitotoxicity; fiber cell; genome editing; glutamatergic signaling; hearing restoration; in vivo imaging; kainate; lateral line; live cell imaging; neurotransmitter release; optogenetics; presynaptic; receptor; regenerative; repaired; response; ribbon synapse; stem; synaptogenesis; targeted treatment; tool

Project Summary: Loud or extended noise exposure damages cochlear hair cells often resulting in either loss of synaptic connections with auditory nerve fibers or hair-cell death. One mechanism for this damage occurs through overstimulation of hair cells, which leads to a surge of Ca2+ at hair-cell synapses, metabolic stress on the hair cell, and excessive release of the neurotransmitter glutamate. The overall goal of this proposal is to understand how pathological changes at the hair-cell synapse stemming from excessive noise exposure ultimately contribute to noise-induced damage. Our objectives are to 1) test the hypothesis that hair-cell overstimulation triggers synaptic-ribbon loss, 2) determine the role of glutamate signaling in hair-cell pathology and repair of acoustic overexposure, and 3) identify the downstream effectors of glutamate-receptor mediated hair-cell death. Current gaps in our understanding of how hair-cell synapse overstimulation contributes to hair- cell damage are in large part due our inability to follow the time course of dynamic intracellular processes in noise-exposed hair cells and to separate glutamate induced damage to hair-cells versus innervating nerve terminals in mammalian cochlea. This project will circumvent these issues by investigating noise-induced hair-cell damage using live-cell imaging, tissue-specific genetic ablation, and pharmacological tools in the zebrafish lateral line— a mechanosensory organ which is made up of clusters of innervated hair cells. Zebrafish lateral-line hair cells are similar to mammalian hair cells at the molecular and cellular level, but are pharmacologically and optically accessible within the whole larvae. This feature allows for direct environmental manipulation and phenotypic observations in a live, intact preparation, which is currently not feasible in the mammalian cochlea. The results of each of our objectives will reveal how specific pathological changes at hair-cell synapses contribute to multiple pathologies resulting from excess noise exposure, thereby furthering our understanding of the underlying causes of sensorineural hearing loss.

项目摘要：大声或长时间的噪音暴露通常会损害耳蜗毛细胞 导致与听觉神经纤维的突触连接丧失或毛细胞死亡。一 这种损伤的机制是通过过度刺激毛细胞而发生的，从而导致毛细胞激增 毛细胞突触处的 Ca2+、毛细胞的代谢应激以及过度释放 神经递质谷氨酸。该提案的总体目标是了解病理学如何 过度噪音暴露导致的毛细胞突触变化最终会导致 噪声引起的损坏。我们的目标是 1）检验毛细胞的假设 过度刺激会触发突触带丢失，2）确定谷氨酸信号传导在 毛细胞病理学和声学过度暴露的修复，以及 3) 识别下游 谷氨酸受体介导的毛细胞死亡的效应器。 目前我们对毛细胞突触过度刺激如何导致头发的理解存在差距 细胞损伤很大程度上是由于我们无法跟踪动态细胞内的时间进程 暴露于噪声的毛细胞中的过程并分离谷氨酸引起的毛细胞损伤 与哺乳动物耳蜗中支配神经末梢的比较。该项目将规避这些 通过使用活细胞成像、组织特异性研究噪声引起的毛细胞损伤来解决问题 斑马鱼侧线的基因消融和药理学工具——机械感觉 由神经支配的毛细胞簇组成的器官。斑马鱼侧线毛细胞是 在分子和细胞水平上与哺乳动物毛细胞相似，但在药理学上 并可在整个幼虫内进行光学检测。此功能允许直接环境 在活的、完整的制剂中进行操作和表型观察，目前还没有 在哺乳动物的耳蜗中是可行的。我们每个目标的结果将揭示具体的程度 毛细胞突触的病理变化导致多种病理 过度的噪音暴露，从而加深我们对噪音的根本原因的理解 感音神经性听力损失。