Understanding Noise-Induced Delayed Primary Degeneration of the Auditory Nerve

描述(申请人提供)：噪声引起的听力损失是一个具有深刻临床意义、日益严重的问题和重大的社会影响，因为过度暴露的机会比比皆是，而暴露于损害听力的机会并不一定是痛苦的。长期以来，毛细胞的丢失或损伤一直被认为是噪音导致听力损失的主要原因，听神经退化只是次要事件。然而，最近的研究表明，引起中度但完全可逆的阈值升高的声学过度暴露使耳蜗感觉细胞保持完好，但会导致毛细胞上神经末梢的急性丢失和听神经的延迟退化。这种原发的听神经病表明，噪声对耳朵的损害比传统的阈值测试所揭示的要广泛得多。确定这一新现象的分子机制是我们关注的重点。我们的工作假设是，在原发性和继发性听神经病中，细胞死亡级联及其上游启动子是不同的。为了验证这一假设，我们建议，首先，更好地描述原发神经病变(目标1)的时间进程和性质，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索其机制，该新技术可以比传统微阵列更可靠地检测罕见的转录本和基因表达的微小变化。这些研究应该有助于确定新的分子靶点，用于诊断和治疗噪声性听力损失。候选人：该提案描述了一项培训计划，将Konstantina Stankovic培养成耳鼻喉科的独立内科科学家。职业发展活动包括培训和研究，以获得在面向健康的科学调查方面实现可持续职业生涯所必需的必要技能。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过渡到自主能力。这一奖项将为候选人实现她的长期职业目标奠定基础，即开发治疗感音神经性耳聋的新诊断和治疗方法--这是一个具有重大临床意义的问题，目前尚不存在根治方法。这项建议旨在解决噪声诱发的原发听神经病，这是一种潜在的非常常见的问题，可能是神经性老年性耳聋(特别是在嘈杂环境中的听力问题)的主要诱因，目前尚无治疗方法，使用助听器放大也没有什么帮助。通过揭示噪声引起的暂时性阈值漂移后这种初级神经变性的机制，拟议的研究应该为未来设计优化的治疗方法奠定基础，以防止这种退化及其对听力表现的相关影响。 与公共卫生相关：这项提案针对的是噪声诱发的原发听神经病，这是一个潜在的非常常见的问题，可能是神经性老年性耳聋(特别是在嘈杂环境中的听力问题)的主要诱因，目前还没有治疗方法，使用助听器放大也没有什么帮助。通过揭示这种初级神经退行性变的机制。对于噪声引起的阈值漂移，拟议的研究应该为未来设计优化的治疗方法奠定基础，以防止这种退化及其对听力性能的相关影响。

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.