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.