Understanding Noise-Induced Delayed Primary Degeneration of the Auditory Nerve

描述（由申请人提供）：噪声引起的听力损失是一个具有深远临床意义、日益严重和重大社会影响的问题，因为过度暴露的机会比比皆是，而损害听力的暴露不一定会带来痛苦。长期以来，毛细胞的损失或损伤一直被认为是噪音引起的听力损失的主要原因，而听觉神经的退化只是次要事件。然而，最近的研究表明，声音过度暴露会导致中度但完全可逆的阈值升高，使耳蜗感觉细胞完好无损，但会导致毛细胞上神经末梢的急性损失和听觉神经的延迟退化。这种原发性听觉神经病变表明，噪声引起的耳朵损伤比传统阈值测试所揭示的更为广泛。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子在原发性和继发性听神经病中是不同的。为了检验这一假设，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（目标 1），然后通过将候选分子方法（目标 2）与使用新技术（Solexa 深度测序目标 3）的全基因组定量调查相结合来探讨其机制，该技术可以比传统微阵列更可靠地检测罕见转录本和基因表达的微小变化。这些研究应有助于确定新的分子靶点，用于噪声性听力损失的诊断和治疗干预。候选人：该提案描述了一项将康斯坦蒂娜·斯坦科维奇培养为耳鼻喉科独立医师科学家的培训计划。职业发展活动包括培训和研究，以获得以健康为导向的科学研究可持续职业所需的必要技能。由声创伤、神经科学、分子生物学、遗传学和系统生物学领域备受尊敬的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权过渡。该奖项将为候选人实现其长期职业目标奠定基础，即开发针对感音神经性听力损失的新诊断和治疗方法——这是一个具有重大临床意义的问题，但目前尚不存在治愈性治疗方法。该提案解决了噪声引起的原发性听觉神经病变，这是一个潜在的非常常见的问题，并且可能是导致神经性老年性耳聋（尤其是在嘈杂环境中的听力问题）的主要原因，目前尚无药物治疗方法，并且使用助听器放大声音也无济于事。通过揭示“暂时”噪声引起的阈值偏移后这种原发性神经变性的机制，拟议的研究应该为未来设计优化疗法奠定基础，以防止这种变性及其对听力表现的相关影响。 公共健康相关性：该提案解决了噪声引起的原发性听觉神经病，这是一个潜在的非常常见的问题，并且可能是导致神经性老年性耳聋（尤其是在嘈杂环境中的听力问题）的主要原因，目前尚无药物治疗方法，并且使用助听器放大效果也无济于事。通过揭示暂时性后这种原发性神经变性的机制。噪声引起的阈值偏移，拟议的研究应该为未来设计优化疗法奠定基础，以防止这种退化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.