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Roles of the Synapse in Hair-Cell Pathology

突触在毛细胞病理学中的作用

基本信息

批准号：
10801270
负责人：
Lavinia Sheets
金额：
$ 50.58万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-17 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10801270
关键词：
AMPA Receptors Acoustic Nerve Address Afferent Neurons Aging Automobile Driving Biological Assay Biological Models Calcium Cell physiology Cochlea Data Development Ear Exocytosis Exposure to Fishes Functional Imaging Funding Glutamate Receptor Glutamates Goals Hair Cells Hearing Hour Human Image Immunofluorescence Immunologic Impairment Inflammation Inflammatory Response Injury Innate Immune System Inner Hair Cells Knock-out Loudness Macrophage Maintenance Mammals Membrane Potentials Metabolic stress Mitochondria Modeling Molecular Morphology N-Methyl-D-Aspartate Receptors N-Methylaspartate Nerve Degeneration Noise Organ Pathology Permeability Phagocytes Pharmacology Play Recovery Recovery of Function Research Role Sensory Receptors Signal Pathway Site Stimulus Study models Synapses Synaptic Vesicles Testing Time Trauma Visualization Work Zebrafish cholinergic defined contribution excitotoxicity gain of function genetic manipulation glutamatergic signaling hearing impairment injured lateral line mechanotransduction mitochondrial metabolism nerve repair nerve supply noise exposure organ repair pharmacologic postsynaptic presynaptic prevent recruit reinnervation repaired ribbon synapse synaptic inhibition synaptogenesis therapeutic target

项目摘要

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.

项目概要噪音暴露会损害耳蜗内毛细胞和支配听觉的突触连接神经。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丧失可能与永久性的，导致分离的听觉神经缓慢退化。然而最近的研究也支持哺乳动物耳蜗具有在噪声后修复毛细胞突触的内在能力损害。定义创伤性噪音后突触修复的细胞机制是迈向这一目标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。该提案的总体目标是了解毛细胞形态和功能的分子基础噪声引起的损伤后的器官修复和恢复。目前我们对毛细胞如何运作的理解存在差距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促进哺乳动物模型系统中的突触修复。该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—— 由受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，包括共享的机制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丢失的突触连接。目标 1 的我们的提案将检验毛细胞活动控制突触修复的假设，而目标 2 将定义炎症对突触恢复和神经支配的贡献。我们每个目标的结果将提供有关毛细胞突触连接如何在创伤性过度刺激后恢复的信息将有所帮助确定促进噪声暴露耳蜗内源性修复的策略，从而防止后续听觉神经退化和听力丧失。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mechanical overstimulation causes acute injury and synapse loss followed by fast recovery in lateral-line neuromasts of larval zebrafish.

DOI：
10.7554/elife.69264
发表时间：
2021-10-19
期刊：
eLife
影响因子：
7.7
作者：
Holmgren M;Ravicz ME;Hancock KE;Strelkova O;Kallogjeri D;Indzhykulian AA;Warchol ME;Sheets L
通讯作者：
Sheets L

Lateral line ablation by ototoxic compounds results in distinct rheotaxis profiles in larval zebrafish.