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：大声或扩展的噪声暴露会损害人工耳蜗毛细胞 导致与听觉神经纤维的突触连接丧失或发胶死亡。一 通过过度刺激毛细胞发生这种损害的机制，这导致了激增 在发胶突触时的Ca2+，毛细胞上的代谢应力以及过量释放 神经递质谷氨酸。该提议的总体目标是了解病理 由于噪声暴露过多而导致的传染元件突触的变化最终导致 噪声引起的伤害。我们的目标是1）测试发丝的假设 过度刺激触发突触 - 丝带损失，2）确定谷氨酸信号在 主电池病理学和声学过度暴露的修复，3）识别下游 谷氨酸蛋白受体介导的发型死亡的效应因子。 当前的差距在我们对发纤管突触过度刺激如何有助于头发的理解中 细胞损伤在很大程度上是由于我们无法遵循动态内的时间过程 暴露于噪声的毛细胞中的过程，分离谷氨酸诱导发型损伤 哺乳动物耳蜗中的神经末端与神经支配。这个项目将绕过这些 通过使用活细胞成像，组织特异性研究噪声诱导的发丝损伤来进行问题 斑马鱼侧线中的遗传消融和药物工具 - 机械学 器官由神经支配的毛细胞组成。斑马鱼侧线毛细胞是 与分子和细胞水平上的哺乳动物毛细胞相似，但在药物上是 并且在整个幼虫中可以光学访问。此功能允许直接环境 现场完整的准备中的操纵和表型观察，目前不是 在哺乳动物耳蜗中可行。我们每个目标的结果将揭示如何具体 发型元件突触的病理变化导致多种病理 过多的噪音暴露，从而进一步了解我们对 感官听力损失。