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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：
10093003
负责人：
Hong-Bo Zhao
金额：
$ 32.51万
依托单位：
UNIVERSITY OF KENTUCKY
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 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10093003
关键词：
Acoustic Nerve Address Animals Apoptosis Apoptotic Area Astrocytes Auditory Threshold Auditory system Brain CASP3 gene Cell Death Cells Cessation of life Cochlea Data Development Exhibits Fiber Gap Junctions Gene Family Generations Genetic Goals Hair Cells Hearing problem Homogeneously Staining Region Human Injury Inner Hair Cells Mediating Microscopy Molecular Mutation Nerve Degeneration Nerve Fibers Neurons Noise Noise-Induced Hearing Loss Optics P2X-receptor Pathway interactions Play Postsynaptic Membrane Predisposition Protein Isoforms Purinoceptor Research Resolution Risk Factors Role Stroke Synapses Techniques Technology Testing Therapeutic Intervention Toxic effect cochlear synaptopathy extracellular hearing impairment hidden hearing loss light microscopy normal hearing novel novel therapeutics public health relevance receptor receptor expression receptor function reconstruction spiral ganglion

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