ROLE OF MACROPHAGES IN NOISE-INDUCED COCHLEAR SYNAPTOPATHY AND NEUROPATHY

巨噬细胞在噪声引起的耳蜗突触病和神经病中的作用

基本信息

批准号：
9098921
负责人：
Tejbeer Kaur
金额：
$ 15.25万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9098921
关键词：
Acoustic Trauma Afferent Neurons Auditory Brain CX3CL1 gene CX3CR1 gene Cell Death Cells Cessation of life Cochlea Cochlear Implants Cochlear Nerve Cochlear implant procedure Complex Data Diphtheria Toxin Elements Exposure to Fractalkine Future Genetic Hair Cells Human Immune system Infiltration Inflammation Inflammatory Injection of therapeutic agent Injury Inner Ear Infection Inner Hair Cells Knowledge Labyrinth Lead Lesion Light Mediating Methods Molecular Molecular Target Monitor Morphology Mus Nerve Fibers Neurons Neuropathy Noise Noise-Induced Hearing Loss Pathology Pharmaceutical Preparations Play Prosthesis Recovery Recruitment Activity Role Sensorineural Hearing Loss Sensory Receptors Severities Signal Transduction Signaling Molecule Stimulus Supporting Cell Synapses Temporary Threshold Shift Testing Time Transgenic Mice Trauma afferent nerve base cell injury cellular targeting chemokine receptor diphtheria toxin receptor excitotoxicity fractalkine receptor ganglion cell hair cell regeneration hearing impairment interest killings macrophage migration monocyte neuronal survival normal aging novel public health relevance research study restoration sound spiral ganglion success therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Noise exposures that cause both permanent threshold shift (with accompanying hair cell loss) and temporary threshold shifts (no evident hair cell loss) also result in rapid and permanent loss of synaptic elements and cochlear nerve terminals. Such injury also leads to degeneration of spiral ganglion (SG) cell bodies, but this occurs over a period of months to years. Neuronal survival is a key determinant of the success of cochlear implants, so it is of great interest to understand the mechanisms that promote neuronal survival after cochlear insults. We have recently discovered that hair cell loss is sufficient to recruit macrophages into the spiral ganglion, and that disruption of signaling between macrophages and afferent neurons (by genetic deletion of fractalkine receptor CX3CR1), leads to reduced macrophage recruitment into the spiral ganglion, and also results in diminished survival of afferent neurons. Here we propose to investigate the role of fractalkine signaling after noise induced hearing loss. We hypothesize that: 1) fractalkine regulates macrophage recruitment into the noise-damaged cochlea, and 2) fractalkine promotes the survival of afferent synapses and neurons after noise injury. Aim 1 will examine the role of fractalkine signaling in neuropathy caused by permanent threshold shift. Specific experiments will assess the effects of genetic disruption of fractalkine signaling on macrophage infiltration, spiral ganglion cell pathology, and auditory function over short (weeks) and long (months) survival periods. Aim 2 will test the hypothesis that macrophages also serve a critical role after noise exposure that causes temporary threshold shift (TTS). We will characterize any migration of macrophages towards inner hair cell-afferent nerve fiber synapse, and determine whether disruption of fractalkine signaling can influence the severity of, or recovery from, noise-induced cochlear synaptopathy and neuropathy. For both aims, we will monitor changes in cochlear function via ABRs, and cochleae will be collected for histological analysis of macrophages, hair cells and afferent neurons, as well as inner hair cell- cochlear nerve terminal synapse number and morphology.

描述（由适用提供）：引起永久阈值移动（参与毛细胞损失）和临时阈值移位（无证据毛细胞丢失）的噪声暴露也导致突触元素的快速和永久性丧失。这种损伤还导致螺旋神经节（SG）细胞体变性，但这发生在几个月到几年的时间内。神经元的生存是对人工耳蜗成功的关键确定剂，因此了解促进耳蜗损伤后神经元存活的机制非常有趣。 We have recently discovered that hair cell loss is sufficient to recruit macrophages into the spiral ganglion, and that disruption of signaling between macrophages and afferent neurons (by genetic deletion of fractalkine receptor CX3CR1), leads to reduced macrophage recruitment into the spiral ganglion, and also results in diminished survival of afferent Neurons.在这里，我们建议研究噪声引起的听力丧失后分子信号传导的作用。我们假设：1）分面调节巨噬细胞募集到噪声损害的耳蜗中，2）分子碱促进噪声损伤后传入突触和神经元的存活。 AIM 1将检查分子信号传导在永久阈值转移引起的神经病中的作用。具体的实验将评估分子信号传导遗传破坏对巨噬细胞浸润，螺旋神经节病理学以及在短（几周）和长（几个月）存活期内功能的影响。 AIM 2将检验以下假设：巨噬细胞在噪声暴露后也起着至关重要的作用，从而导致暂时的阈值移位（TTS）。我们将表征巨噬细胞向内部毛细胞症状神经纤维突触的任何迁移，并确定分子信号传导的破坏是否会影响噪声引起的耳蜗突触病和神经病的严重程度或恢复。对于这两个目标，我们都将通过ABR监测人工耳蜗功能的变化，并将收集耳蜗，以进行巨噬细胞，毛细胞和传入神经元的组织学分析，以及内部毛细胞 - 耳蜗神经终末突触数和形态。