Understanding Noise-Induced Delayed Primary Degeneration of the Auditory Nerve

了解噪声引起的听觉神经迟发性原发性变性

• 批准号: 8385567
• 负责人: Konstantina M Stankovic
• 金额: $ 23.5万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385567
• 关键词: Acoustic Nerve; Acoustic Trauma; Acoustics; Acute; Address; Advisory Committees; Aminoglycosides; Apoptotic; Auditory; Award; Brain-Derived Neurotrophic Factor; CREB1 gene; Candidate Disease Gene; Cell Death; Cells; Cessation of life; Diagnosis; Down-Regulation; Ear; Environment; Event; Exposure to; Extracellular Signal Regulated Kinases; Foundations; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Hair Cells; Health; Hearing; Hearing Aids; Hour; Immunohistochemistry; In Situ Hybridization; Injury; Inner Hair Cells; Investigation; JUN gene; Left; MAPK8 gene; Medical; Mentors; Modeling; Molecular; Molecular Biology; Molecular Target; NGFR Protein; Nature; Nerve; Nerve Degeneration; Nerve Growth Factor Receptors; Neurons; Neuropathy; Neurosciences; Neurotrophin 3; Noise; Noise-Induced Hearing Loss; Organ of Corti; Otolaryngology; Outcome; Pain; Pathway Analysis; Pathway interactions; Performance; Phosphorylation; Physicians; Presbycusis; Research; Research Training; Role; Sampling; Scientist; Sensorineural Hearing Loss; Sensory; Sequence Analysis; Signal Transduction; Stereocilium; Supporting Cell; Surveys; Synapses; Systems Biology; Testing; Therapeutic Intervention; Time; Training Programs; Transcript; Up-Regulation; Western Blotting; Work; brain-derived neurotrophic factor precursor; career; career development; cell type; clinically significant; deafness; deep sequencing; design; genome-wide; interest; light microscopy; mouse model; neuron loss; neurotrophic factor; new technology; novel; novel diagnostics; novel therapeutics; prevent; public health relevance; relating to nervous system; research study; skills; spiral ganglion; transcription factor; upstream kinase

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.

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，并且损伤听力的暴露不一定是痛苦的。长期以来，毛细胞的损失或损伤一直被认为是噪声引起的听力损失的主要原因，而听神经的退化仅作为次要事件发生。然而，最近，它已被证明，声学过度暴露造成中度，但完全可逆的，阈值升高离开耳蜗感觉细胞完好无损，但引起急性损失的毛细胞上的神经末梢和延迟的听神经变性。这种原发性听神经病表明，噪声引起的耳朵损伤比传统的阈值测试所揭示的要广泛得多。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，其上游发起人，是不同的原发性和继发性听神经病。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（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索其机制，该技术可以比传统的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。这些研究将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：该提案描述了一个培训计划，以发展康斯坦丁娜斯坦科维奇成为一个独立的医生科学家在耳鼻喉科。职业发展活动包括培训和研究，以获得在以健康为导向的科学调查中可持续职业所需的必要技能。一个指导小组和一个由在声创伤、神经科学、分子生物学、遗传学和系统生物学领域备受推崇的科学家组成的咨询委员会将指导候选人向自主性过渡。该奖项将为候选人实现其长期职业目标提供基础，即开发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，目前尚不存在治愈性治疗方法。本提案针对噪声引起的原发性听神经病，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（特别是噪声环境中的听力问题）的主要原因，对于这种疾病，不存在医学治疗，助听器的放大作用很小。通过揭示这种原发性神经退行性病变在“暂时性”噪声引起的阈值偏移后的机制，拟议的研究应该为未来设计优化的治疗方法奠定基础，以防止这种退行性病变及其对听力表现的相关影响。