Proteome Biology of Noise Induced Hearing Loss

噪声引起的听力损失的蛋白质组生物学

• 批准号: 9037646
• 负责人: Jeffrey Nicholas Savas
• 金额: $ 24.9万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9037646
• 关键词: Acoustic Stimulation; Adult; American; Animals; Antibodies; Apoptosis; Atlases; Auditory system; Biochemical; Bioinformatics; Biology; Categories; Cell Death; Cells; Characteristics; Cochlea; Cochlear Nerve; Communication; Data; Data Set; Databases; Defect; Development; Economics; Ensure; Environmental Health; Epilepsy; Etiology; Event; Exposure to; FDA approved; Fractionation; Genetic Transcription; Glycerol; Goals; Hair; Hair Cells; Hearing; Heredity; Huntington Disease; Immunohistochemistry; Individual; Injury; Investigation; Knockout Mice; Label; Labyrinth; Life; Mass Spectrum Analysis; Measurement; Measures; Mentors; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Sieve Chromatography; Multiple Sclerosis; Mus; N-terminal; NMDA receptor antagonist; National Institute on Deafness and Other Communication Disorders; Necrosis; Noise; Noise-Induced Hearing Loss; Occupational Health; Occupational Noise; Organ of Corti; Parkinson Disease; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Pilot Projects; Prevention; Protein Analysis; Proteins; Proteome; Proteomics; Quality of life; Reactive Oxygen Species; Reporter; Reporting; Research; Risk; Role; Sedimentation process; Sensory; Shotguns; Spinal cord injury; Stroke; Structure; Supporting Cell; Surveys; Synapses; System; Temporary Threshold Shift; Testing; Therapeutic; Thinking; Time; Tissues; Western Blotting; Work; base; comparative; disability; economic cost; falls; hearing impairment; in vivo; mutant; novel; prevent; protein complex; protein expression; protein protein interaction; research study; tool

PROJECT SUMMARY Hearing impairment is one of the most common sensory disabilities, 250 million people worldwide have moderate to severe hearing loss (38), and significantly reduces quality of life due to the central role of verbal communication. On an economic scale, the total negative impact of hearing loss is greater than that of multiple sclerosis, spinal cord injury, stroke, epilepsy, Parkinson's and Huntington's disease combined and effects 4 times as many people (68). The most common causative factor among the defined hearing loss etiologies is excessive noise, and millions of people are exposed to dangerously loud noise at work. We hope that our research findings will aid in the reduction of noise-induced hearing loss by identifying significant proteins and pathways responsible for hearing loss. Specifically, we have developed a quantitative proteomic analysis platform to probe the effect of excess noise on the cochlear proteome. Our preliminary data shows this approach can accurately measure thousands of proteins from a single mouse and has already revealed proteins significantly perturbed after noise exposure. We have also made progress isolating the organ of Corti to ensure the accurate measurement of low abundant but potentially altered proteins in hair and adjacent support cells, and in cochlear nerve synapses. More specifically, we will quantitatively analyze inner ear extracts from mice exposed to multiple levels of noise. Through these comparative exposures, we will differentiate proteins with characteristics that are impacted by excess noise. The candidates from these proteomic experiments will be explored with bioinformatic tools and validated by traditional antibody based approaches. Next we will develop biochemical methods to ensure the accurate measurement of rare low abundance proteins. We will also test if protein–protein interactions are disrupted without significant changes in expression levels. Finally we will use bioactive molecules known to protect from NIHL and repeat the proteomic analysis to investigate the mechanisms by which these drugs are effective. In particular, we think that a comprehensive understanding of the inner ear proteome will accelerate the greater research field of hearing injury. In summary, we propose here to identify and investigate molecular defects in NIHL by applying quantitative proteomic tools that can simultaneously and sensitively investigate thousands of proteins in a single analysis. We believe this proposal represents the first ever application of quantitative proteomics to the investigation of NIHL and may hold the required analytical strength to kick start the development towards effective therapeutics to eventually treat and prevent NIHL.

项目摘要 听力障碍是最常见的感觉障碍之一， 全世界有中度至重度听力损失（38），并显着降低生活质量 因为语言交流的核心作用。在经济规模上， 听力损失的影响大于多发性硬化症，脊髓损伤，中风， 癫痫、帕金森和亨廷顿舞蹈病的发病率是其他疾病的4倍 （68）。在已定义的听力损失病因中，最常见的致病因素是过度 噪音，数以百万计的人在工作中暴露在危险的噪音中。我们希望我们的 研究结果将有助于减少噪音引起的听力损失， 导致听力损失的蛋白质和途径。具体来说，我们开发了一个 定量蛋白质组学分析平台，以探测过量噪声对耳蜗的影响 蛋白质组我们的初步数据显示，这种方法可以准确地测量数千个 从一只老鼠的蛋白质，并已经揭示了蛋白质显着扰动后， 噪声暴露我们还在分离Corti器官方面取得了进展，以确保准确的 测量毛发和邻近支持细胞中低丰度但可能改变的蛋白质， 和耳蜗神经突触。更具体地说，我们将定量分析内耳 从暴露于多种噪声水平的小鼠中提取。通过这些比较曝光， 我们将区分具有受过量噪声影响的特征的蛋白质。 这些蛋白质组学实验的候选者将用生物信息学方法进行探索。 工具，并通过传统的基于抗体的方法进行验证。下一步我们将开发生物化学 方法，以确保稀有低丰度蛋白质的准确测量。我们还将测试 如果蛋白质-蛋白质相互作用被破坏而表达水平没有显著变化。 最后，我们将使用已知的生物活性分子来保护NIHL，并重复蛋白质组学分析。 分析研究这些药物有效的机制。我们尤其 我认为，对内耳蛋白质组的全面了解将加速更大的 听力损伤的研究领域。总之，我们建议在这里确定和调查 通过应用定量蛋白质组学工具， 在一次分析中灵敏地研究数千种蛋白质。我们认为这项提议 代表了定量蛋白质组学在NIHL研究中的首次应用， 可以保持所需的分析能力，以启动有效的发展， 最终治疗和预防NIHL。