Understanding Noise-Induced Delayed Primary Degeneration of the Auditory Nerve

描述（由申请人提供）：噪音引起的听力损失是一个具有深刻临床意义、日益严重和重大社会影响的问题，因为过度暴露的机会很多，并且损害听力的暴露不一定是痛苦的。毛细胞的丢失或损伤一直被认为是噪音性听力损失的主要原因，听神经的退化只是次要事件。然而，最近有研究表明，过度暴露引起中度但完全可逆的阈值升高，耳蜗感觉细胞完好无损，但引起毛细胞神经末梢的急性丧失和听神经的延迟变性。这种原发性听神经病变表明，噪音引起的耳部损伤比常规阈值测试所显示的要广泛得多。确定这种新现象的分子机制是我们的重点。我们的工作假设是细胞死亡级联及其上游启动者在原发性和继发性听神经病变中是不同的。为了验证这一假设，我们建议，首先，更好地表征原发性神经病变的时间过程和性质（Aim 1），然后通过结合候选分子方法（Aim 2）和使用新技术（Solexa深度测序Aim 3）的全基因组定量调查来探索其机制，该方法可以比传统的微阵列更可靠地检测罕见转录本和基因表达的微小变化。这些研究将有助于发现新的分子靶点来诊断和治疗噪声性听力损失。候选人：该提案描述了一个培训计划，将康斯坦蒂娜·斯坦科维奇培养成一名独立的耳鼻喉科医生。职业发展活动包括培训和研究，以获得从事面向健康的科学调查的可持续职业所需的必要技能。一个由声创伤、神经科学、分子生物学、遗传学和系统生物学领域的知名科学家组成的指导团队和咨询委员会将指导候选人向自主过渡。该奖项将为候选人实现她的长期职业目标提供基础，为感音神经性听力损失开发新的诊断和治疗方法-这是一个具有重大临床意义的问题，目前尚无治愈性治疗方法。这一建议解决了噪声引起的原发性听神经病变，这是一个潜在的非常常见的问题，并且可能是神经老年性耳聋的主要原因（特别是在嘈杂环境中的听力问题），医学治疗不存在，助听器的放大作用很小。通过揭示“暂时”噪声引起的阈值移位后原发性神经变性的机制，本研究将为未来设计优化治疗方法奠定基础，以防止这种变性及其对听力表现的相关影响。

DESCRIPTION (provided by applicant): Noise-induced hearing loss is a problem of profound clinical significance, growing magnitude, and major societal impact, because opportunities for overexposure abound, and exposures that damage hearing are not necessarily painful. Loss of, or damage to, hair cells has long been considered the primary cause of noise-induced hearing loss, with degeneration of the auditory nerve occurring only as a secondary event. Recently, however, it has been shown that acoustic overexposures causing moderate, but completely reversible, threshold elevation leave cochlear sensory cells intact, but cause acute loss of nerve terminals on hair cells and delayed degeneration of the auditory nerve. This primary auditory neuropathy suggests that noise-induced damage to the ear is considerably more widespread than is revealed by conventional threshold testing. Identifying molecular mechanisms of this novel phenomenon is our focus. Our working hypothesis is that the cell death cascade, and its upstream initiators, are different in primary and secondary auditory neuropathy. To test this hypothesis we propose, first, to better characterize the time course and nature of the primary neuropathy (Aim 1), and then to probe its mechanisms by combining a candidate-molecule approach (Aim 2) with a genome-wide quantitative survey using a new technology (Solexa deep sequencing Aim 3), which can detect rare transcripts and small changes in gene expression more reliably than conventional microarrays. These studies should help identify new molecular targets for diagnosis and therapeutic intervention for noise-induced hearing loss. CANDIDATE: The proposal describes a training program to develop Konstantina Stankovic to an independent physician scientist in otolaryngology. Career development activities include training and research to acquire the requisite skills necessary for a sustainable career in health-oriented scientific investigation. A mentoring team and an advisory committee of highly regarded scientists in the fields of acoustic trauma, neuroscience, molecular biology, genetics, and systems biology will guide the candidate in her transition to autonomy. This award will provide a foundation for the candidate to achieve her long-term career goal of developing new diagnostics and therapeutics for sensorineural hearing loss - a problem of major clinical significance for which curative treatments do not yet exist. This proposal addresses noise-induced primary auditory neuropathy, a potentially very common problem, and likely a major contributor to neural presbycusis (especially the problems with hearing in noisy environments) for which medical therapies do not exist, and amplification with hearing aids is of little help. By uncovering mechanisms of this primary neurodegeneration after "temporary" noise-induced threshold shift, the proposed studies should lay groundwork for future design of optimized therapies to prevent this degeneration and its associated impact on hearing performance. PUBLIC HEALTH RELEVANCE: This proposal addresses noise-induced primary auditory neuropathy, a potentially very common problem, and likely a major contributor to neural presbycusis (especially the problems with hearing in noisy environments) for which medical therapies do not exist, and amplification with hearing aids is of little help. By uncovering mechanisms of this primary neurodegeneration after .temporary. noise-induced threshold shift, the proposed studies should lay groundwork for future design of optimized therapies to prevent this degeneration and its associated impact on hearing performance.