The Role of Vesicular Zinc in Noise-induced Cochlear Degeneration and Hearing Loss

囊泡锌在噪声引起的耳蜗变性和听力损失中的作用

• 批准号: 10472027
• 负责人: Brandon Bizup
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2023-09-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472027
• 关键词: 3-Dimensional; Acoustics; Affect; Auditory Brainstem Responses; Basilar Membrane; Cell Death; Cells; Chelating Agents; Clinical; Cochlea; Cochlear Nerve; Cognitive; Data; Dendrites; Disease; Event; Excision; Exhibits; Exposure to; Genetic; Hair Cells; Health; Hearing problem; Histologic; Hyperacusis; Immunofluorescence Microscopy; Knock-out; Knockout Mice; Knowledge; Lead; Loudness; Messenger RNA; Methods; Molecular; Mus; Natural regeneration; Nerve Degeneration; Nerve Fibers; Nervous System Trauma; Nervous system structure; Noise; Noise-Induced Hearing Loss; Optic Nerve Injuries; Permeability; Physiological; Predisposition; Presynaptic Terminals; Protein Analysis; Proteins; Protocols documentation; RNA analysis; Recovery; Regenerative capacity; Retina; Role; SLC30A3 gene; Signal Transduction; Structure; Synapses; Synaptic Transmission; Synaptic Vesicles; Testing; Time; Tinnitus; Western Blotting; Width; Wild Type Mouse; Zinc; base; chelation; experimental study; extracellular; functional outcomes; ganglion cell; hearing impairment; improved; injured; insight; new therapeutic target; noise exposure; novel; otoacoustic emission; preservation; prevent; protective effect; protein expression; psychologic; ratiometric; repaired; resilience; ribbon synapse; sensor; social; sound; spiral ganglion; zinc-binding protein

Project Summary/Abstract Exposure to loud noise causes degeneration in the cochlea involving hair cell death and ribbon synapse loss, resulting in permanent deficits that can be hidden or overt. The exact mechanisms by which noise-induced hearing loss occurs are not clear, and there is a need to identify the critical events that result in permanent cochlear degeneration. Vesicular zinc is important in the nervous system in fine-tuning synaptic transmission and sound processing, but in cases of nervous system injury, such as in the retina, vesicular zinc exacerbates neurodegeneration and hinders regeneration. Our preliminary audiometric and histological data indicate that removal of vesicular zinc via genetic deletion of ZnT3, the vesicular zinc transporter loading zinc in presynaptic terminals, results in resilience to- and improved recovery from noise-induced hearing loss, both in terms of structure and function. Furthermore, both cochlear and systemic chelation of zinc result in resilience to noise- induced hearing loss. Moreover, ZnT3 protein expression increases immediately following noise exposure, consistent with a role for vesicular zinc dysregulation in noise-induced hearing loss. This proposal aims to test the hypothesis that noise-induced dysregulation of zinc signaling contributes to noise-induced hearing loss by promoting degeneration and limiting regeneration in the cochlea. Using a combination of cochlear physiological recordings, histological analysis, and quantitative protein and RNA analysis, this proposal will examine the effects of vesicular zinc following harmful noise exposure. Results from this proposal will help to elucidate the mechanisms of degeneration within the cochlea that lead to temporary and permanent hearing impairments after noise-induced hearing loss. These data may provide novel therapeutic targets for treatment of noise-induced hearing loss and related disorders, such as tinnitus and hyperacusis, and further our understanding of cochlear vulnerability to noise.

项目总结/摘要 暴露在巨大的噪音中会导致耳蜗退化，包括毛细胞死亡和带状突触丧失， 导致可能是隐藏或公开的永久性缺陷。噪声引起的 听力损失的发生并不清楚，有必要确定导致永久性听力损失的关键事件。 耳蜗变性囊泡锌在神经系统微调突触传递中是重要的 和声音处理，但在神经系统损伤的情况下，如在视网膜中，泡状锌加剧 神经变性并阻碍再生。我们初步的听力测试和组织学数据表明， 通过遗传缺失ZnT 3去除囊泡锌，ZnT 3是突触前膜中装载锌的囊泡锌转运蛋白。 终端，结果弹性-和改善恢复从噪音引起的听力损失，无论是在方面 结构和功能。此外，耳蜗和全身的锌螯合作用都导致对噪音的恢复力- 听力损失此外，ZnT 3蛋白表达在噪声暴露后立即增加， 与囊泡锌调节异常在噪声性听力损失中的作用一致。该提案旨在测试 噪声诱导的锌信号失调通过以下方式导致噪声诱导的听力损失的假说 促进耳蜗的退化和限制再生。结合耳蜗生理学 记录，组织学分析，定量蛋白质和RNA分析，这项建议将审查 有害噪声暴露后囊泡锌的影响。这项建议的结果将有助于阐明 耳蜗内的退化机制，导致暂时性和永久性听力障碍， 噪音引起的听力损失这些数据可能为治疗噪声诱导的 听力损失和相关疾病，如耳鸣和听觉过敏，并进一步了解耳蜗 易受噪音影响。