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

• 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
• 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

 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（由申请人提供）：噪声暴露导致永久性阈值偏移（伴随毛细胞损失）和暂时性阈值偏移（无明显毛细胞损失），也导致突触元件和耳蜗神经末梢的快速和永久性损失。这种损伤也会导致螺旋神经节（SG）细胞体的退化，但这会发生数月至数年的时间。神经元存活是人工耳蜗植入成功的关键因素，因此了解耳蜗损伤后促进神经元存活的机制具有重要意义。我们最近发现，毛细胞损失足以将巨噬细胞募集到螺旋神经节中，并且巨噬细胞和传入神经元之间的信号传导的破坏（通过fractalkine受体CX 3CR 1的遗传缺失）导致巨噬细胞募集到螺旋神经节中的减少，并且还导致传入神经元的存活减少。在这里，我们建议调查fractalkine信号的作用后，噪声引起的听力损失。我们假设：1）fractalkine调节巨噬细胞募集到噪声损伤的耳蜗中，以及2）fractalkine促进噪声损伤后传入突触和神经元的存活。目的1将研究fractalkine信号在永久性阈值偏移引起的神经病变中的作用。具体实验将评估Fractalkine信号传导的遗传破坏对巨噬细胞浸润、螺旋神经节细胞病理学和短期（数周）和长期（数月）生存期内听觉功能的影响。目的2将测试巨噬细胞在噪声暴露后也起关键作用的假设，导致暂时性阈值偏移（TTS）。我们将表征巨噬细胞向内毛细胞-传入神经纤维突触的任何迁移，并确定fractalkine信号传导的中断是否会影响噪声诱导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，我们将通过ABR监测耳蜗功能的变化，并将收集耳蜗用于巨噬细胞、毛细胞和传入神经元的组织学分析，以及内毛细胞-耳蜗神经末梢突触的数量和形态。