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：过大或过长的噪音暴露通常会损害耳蜗毛细胞 导致与听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，导致毛细胞激增 毛细胞突触上的钙离子，毛细胞上的代谢压力，以及毛细胞过度释放 神经递质谷氨酸。这项提案的总体目标是了解病理性 过度噪音暴露引起的毛细胞突触的变化最终导致 噪音造成的损害。我们的目标是1)检验毛细胞 过度刺激触发突触带丢失，2)确定谷氨酸信号在 毛细胞病理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因子。 目前我们对毛细胞突触过度刺激如何影响头发的理解存在差距- 细胞损伤在很大程度上是因为我们无法跟踪细胞内动态变化的时间进程 噪声暴露毛细胞的过程及谷氨酸对毛细胞损伤的分离 与哺乳动物耳蜗神经末梢的神经末梢相比较。该项目将绕过这些 使用活细胞成像研究噪声引起的毛细胞损伤的问题，组织特异性 斑马鱼侧线的基因消融和药理工具--机械感觉 由一簇簇受神经支配的毛细胞组成的器官。斑马鱼的侧线毛细胞是 在分子和细胞水平上与哺乳动物毛细胞相似，但在药理上是 并在整个幼虫内可光学接触到。此功能允许直接在环境中 在活的、完整的制剂中进行操纵和表型观察，目前还没有 在哺乳动物的耳蜗里是可行的。我们每一个目标的结果都将揭示出我们有多具体 毛细胞突触的病理变化导致多种病理变化 过量接触噪音，从而加深我们对 感觉神经性听力损失。