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

基本信息

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
项目类别：
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

项目摘要

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的临床意义，日益增长和重大社会影响的问题，因为过度暴露的机会越来越多，并且损害听力的暴露不一定会痛苦。长期以来，毛细胞的损失或损害一直被认为是噪声引起的听力丧失的主要原因，听觉神经的退化仅作为次要事件。然而，最近，已经表明，声学过度曝光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端的急性丧失和听觉神经的延迟变性。这种原发性听觉神经病表明，与常规阈值测试所揭示的相比，噪声引起的耳朵损伤要广泛得多。识别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发起人在原发性和继发性神经病中不同。为了检验这一假设，我们首先提出，以更好地表征主要神经病变的时间过程和性质（目标1），然后通过将候选候选分子方法（AIM 2）与基因组全基因组的定量调查相结合，使用新技术（Solexa Deep sequencing Aim 3）来探测其机制，可以检测稀有的稀有频率差异和较小的依赖性依赖于依次的依然变化。这些研究应有助于确定用于诊断和治疗干预噪声引起的听力损失的新分子靶标。候选人：该提案描述了一项培训计划，以开发Konstantina Stankovic为耳鼻喉科的独立医师科学家。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所必需的必要技能。在声学创伤，神经科学，分子生物学，遗传学和系统生物学领域，由备受推崇的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治。该奖项将为候选人提供基础，以实现她长期职业目标，以开发新的诊断和治疗方法，以实现感官性听力损失 - 这是尚不存在治疗性治疗的主要临床意义的问题。该提案解决了噪声引起的原发性听觉神经病，这是一个可能非常常见的问题，并且可能是导致神经疗法不存在的神经长期造成的主要贡献者（尤其是在嘈杂环境中听力的问题），并且对听力辅助的扩增几乎没有帮助。通过在“临时”噪声引起的阈值转移之后发现这种主要神经变性的机制，拟议的研究应为未来设计优化疗法的设计奠定基础，以防止这种退化及其对听力表现的相关影响。