权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

ATP-purinergic mechanisms underlying noise-induced cochlear synaptopathy and hearing loss

噪声引起的耳蜗突触病和听力损失的 ATP 嘌呤能机制

基本信息

批准号：
10756250
负责人：
Hong-Bo Zhao
金额：
$ 32.51万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-22 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10756250
关键词：
ATP purinergic mechanisms underlying noise

项目摘要

SUMMARY The long-term goal of this project is to investigate mechanisms underlying noise-induced cochlear synaptopathy and hidden hearing loss. Noise is a common risk factor for hearing loss. Recent studies have demonstrated that even a single episode of noise overexposure induces transient hearing loss, i.e., temporal threshold shift (TTS), noise-exposed animals could have no hair cell loss but have extensive spiral ganglion neuron (SG) and synapse degeneration. In particular, low spontaneous rate (LSR) auditory nerves and their synaptic connections with inner hair cells are preferentially lost. The noise-exposed animals and humans demonstrate normal hearing threshold and sensitivity (i.e., hidden hearing loss) in the early stage but will eventually exhibit other hearing disorders and hearing loss. Currently, the underlying mechanism for such cochlear synaptopathy remains unclear. Noise stimulates hair cell and neuron over-activation and increases K+ efflux that leads to increasing extracellular K+ concentration. It is well-established that high extracellular K+ can induce toxicity leading to second cell death in the brain following injury and stroke. We hypothesize that high, excess extracellular K+ following noise exposure can also cause SG synapse and neuron degeneration in the cochlea. We previously found that ATP purinergic P2X receptors in the cochlea are required for sinking K+ to re-enter into cells. A recent study also demonstrated that P2X2 receptors are necessary for the development of TTS. In addition, we found that P2X2 mutation can increase susceptibility to noise and induce hearing loss. These studies indicate that P2X receptors may have a critical role in noise-induced cochlear synaptopathy and hidden hearing loss. In this project, we will first test whether high extracellular K+ can cause SG synapse and neuron degeneration (Specific Aim 1, SA1). Then, we will identify and characterize P2X receptor expression in SG neurons, including LSR and HSR (high spontaneous rate) fiber synaptic endings, and test whether P2X receptors can mediate K+-sinking in the SG neurons. In SA3, we will test whether deficiency of P2X receptors can induce and exacerbate cochlear synaptopathy and hearing loss following noise exposure and high-K+ challenge. Completion of these studies will directly reveal the molecular mechanism underlying noise-induced cochlear synaptic degeneration and hidden hearing loss. These novel studies will also open a new therapeutic avenue for targeting noise-induced hearing loss and cochlear synaptopathy.

总结本项目的长期目标是研究噪声诱导耳蜗损害的机制。突触病和隐性听力损失。噪声是听力损失的常见危险因素。最近的研究已经证明即使是一次噪声过度暴露也会引起短暂的听力损失，也就是说，时间阈值偏移（TTS），暴露于噪声的动物可能没有毛细胞损失，但有广泛的螺旋神经节神经元（SG）和突触变性。特别是，低自发率 (LSR)听觉神经及其与内毛细胞的突触连接优先丢失。的暴露于噪声的动物和人表现出正常的听力阈值和灵敏度（即，隐藏性听力损失），但最终会表现出其他听力障碍和听力损失目前，这种耳蜗突触病的潜在机制仍不清楚。噪声刺激毛细胞和神经元过度激活，增加K+流出，导致增加细胞外K+浓度。众所周知，高细胞外K+可以诱导导致脑损伤和中风后第二细胞死亡的毒性。我们假设噪声暴露后细胞外高浓度K+也可引起SG突触和神经元耳蜗退化我们以前发现耳蜗中的ATP嘌呤能P2 X受体是吸收K+重新进入细胞所必需的。最近的一项研究还表明，P2 X2 受体对于TTS的发展是必需的。此外，我们发现P2 X2突变可以增加对噪音敏感性并导致听力损失。这些研究表明，P2 X受体可能在噪声诱发的耳蜗突触病和隐性听力损失中起关键作用。在这项目中，我们将首先测试高细胞外K+是否会导致SG突触和神经元变性（特异性目的1，SA 1）。然后，我们将识别和表征P2 X受体表达在SG神经元中，包括LSR和HSR（高自发率）纤维突触末梢，并且测试 P2 X受体是否能介导SG神经元的K+-下沉。在SA 3中，我们将测试是否 P2 X受体缺乏可诱发和加重耳蜗突触病和听力损失噪音暴露和高钾离子挑战后。这些研究的完成将直接揭示噪声诱发耳蜗突触变性和隐性听力的分子机制损失这些新的研究也将为针对噪声引起的听力开辟新的治疗途径丧失和耳蜗突触病。