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.

概括该项目的长期目标是研究噪声引起的耳蜗的潜在机制突触病和隐性听力损失。噪音是听力损失的常见危险因素。最近的研究已经证明，即使是一次噪音过度暴露也会导致短暂的听力损失，即，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。特别是自发率低 (LSR) 听觉神经及其与内毛细胞的突触连接优先丢失。这暴露于噪音的动物和人类表现出正常的听力阈值和敏感性（即隐藏性听力损失）在早期阶段，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。噪音会刺激毛细胞和神经元过度激活并增加 K+ 流出，从而导致增加细胞外 K+ 浓度。众所周知，高细胞外 K+ 可诱导毒性导致损伤和中风后大脑中的第二次细胞死亡。我们假设噪声暴露后细胞外 K+ 过高也会导致 SG 突触和神经元耳蜗退化。我们之前发现耳蜗中的 ATP 嘌呤能 P2X 受体需要使 K+ 下沉重新进入细胞。最近的一项研究还表明，P2X2 受体对于 TTS 的发展是必需的。此外，我们发现P2X2突变可以增加对噪音的敏感性并导致听力损失。这些研究表明 P2X 受体可能在噪声引起的耳蜗突触病和隐性听力损失中起关键作用。在这个项目中，我们首先测试高细胞外K+是否会引起SG突触和神经元退化（具体目标 1，SA1）。然后，我们将识别和表征 P2X 受体表达 SG 神经元，包括 LSR 和 HSR（高自发率）纤维突触末梢，并测试 P2X 受体是否可以介导 SG 神经元中的 K+ 下沉。在SA3中，我们将测试是否 P2X受体缺乏可诱发和加剧耳蜗突触病和听力损失在噪音暴露和高 K+ 挑战之后。这些研究的完成将直接揭示噪声引起的耳蜗突触变性和隐性听力的分子机制损失。这些新颖的研究还将为针对噪声引起的听力开辟一条新的治疗途径损失和耳蜗突触病。