Novel Approaches for Prevention and Treatment of Noise Induced Hearing loss

预防和治疗噪声性听力损失的新方法

• 批准号: 8277598
• 负责人: Debashree Mukherjea
• 金额: $ 14.55万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277598
• 关键词: Acoustic Trauma; Affect; Age; American; Anesthesia procedures; Animals; Area; Auditory Brainstem Responses; Candidate Disease Gene; Cations; Cell Death; Chronic; Cisplatin; Clinic; Cluster Analysis; Cochlea; Communicable Diseases; Communication; Communication impairment; Control Groups; Data; Developed Countries; Dose; Drops; Drug Delivery Systems; Drug Formulations; Ear; Effectiveness; Employment; Environmental air flow; Exposure to; Future; Gene Expression; Gene Expression Profile; Gene Targeting; Generations; Genes; Goals; High-Frequency Hearing Loss; Human; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Institutes; Intramuscular; Isomerism; Laboratories; Labyrinth; Leisure Activities; Local anesthesia; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Molecular; Molecular Profiling; NADPH Oxidase; Noise; Noise-Induced Hearing Loss; Organ of Corti; Outcome; Outpatients; Pathway interactions; Pharmaceutical Preparations; Prevention; Procedures; Protein Isoforms; Quality of life; Rattus; Reaction Time; Reactive Oxygen Species; Regulation; Reporting; Research; Role; Route; Scanning; Scanning Electron Microscopy; Signal Pathway; Silicones; Snowmobile; Social Interaction; Source; Stress; Techniques; Time; Transcript; Trauma; Tube; Tumor Necrosis Factor-alpha; Tympanic membrane; United States; Validation; Vanilloid; Western Blotting; Workplace; age group; alternative treatment; analog; base; cyclooxygenase 2; deafness; effective therapy; efficacy testing; genetic linkage analysis; hearing impairment; human NOS2A protein; immunocytochemistry; intraperitoneal; middle ear; novel; novel strategies; prevent; receptor; response; sound; subcutaneous; transplatin

DESCRIPTION (provided by applicant): Noise induced hearing loss (NIHL) is a significant problem in the United States, affecting ~15 percent of individuals from all age groups. These individuals are exposed to loud noise in their workplace or during leisure activities. A recent report by the National Institute of Deafness and Communicative Disorder indicated that 30 million Americans are exposed to hazardous levels of noise regularly. Chronic noise exposure leads to irreversible damage to inner ear structures and hearing loss. There are no known treatments available for NIHL, suggesting that it is imperative to develop effective treatment options. Recent data from our laboratory, indicate increased reactive oxygen species (ROS) generation and increased inflammatory mediators in the cochlea after noise trauma. Thus we hypothesize that NIHL is initiated by the generation of ROS in the cochlea which promote coclear inflammation, leading to damage and death of cells in the inner ear. Mediators of this inflammatory response include the cochlear specific NADPH oxidase, NOX3 (a primary source of ROS generation) and transient receptor potential V1 (TRPV1), a nonspecific cation channel, which is induced by ROS and participates in the cochlear inflammation. Thus, ROS serve as common mediator of cochlear inflammation in response to noise trauma. As such, targeting NOX3 and/or TRPV1 for inhibition would constitute treatment options for NIHL. We have identified a novel agent, transplatin, which ameliorates NIHL by inhibiting TRPV1, NOX3 and inflammatory mediators. The overall goal of this project is to examine the role of ROS mediated inflammation in NIHL and to determine if inhibition of these pro- inflammatory mediators by transplatin provides otoprotection. Specific aim 1 (sub-aim 1A) will determine the effective doses of transplatin providing protection and examine the time-window for this drug to be effective prophylactically and as a rescue agent after noise trauma. Sub-aim 1B will determine whether administration of transplatin following noise exposure would provide otoprotection. The efficacy of both trans-tympanic and intraperitoneal routes of administration will be assessed by auditory brainstem responses (ABRs) and scanning electron microscopy (SEM). Specific aim 2 will assess the molecular basis of transplatin otoprotection. Specifically, sub-aim 2A will determine the gene expression profile of the cochlea after noise and/or transplatin, compared to control, using whole transcript microarrays. Target gene/miRNA validation will be performed by quantitative PCR and Western blotting. Sub-aim 2B will focus on cochlear pro-inflammatory gene pathways identified by microarray of the cochlea after noise trauma. Overall, this study will provide comprehensive data regarding gene expression profile of the cochlea in NIHL and provide a more complete picture of the efficacy and mechanism of action of transplatin against NIHL. This information could highlight potentially new signaling pathways mediating NIHL and provide novel drug treatment targets. A successful outcome of this approach in the animal studies is expected to have direct translational application for the treatment of NIHL in human. PUBLIC HEALTH RELEVANCE: Noise induced hearing loss (NIHL) is a significant problem in industrialized countries. In the United States, it is estimated that 30 million people are exposed to high noise levels on a daily basis. Loss of hearing prevents effective communication and decreases social interaction and the quality of life of affected individuals. Since there are currently no treatments available for NIHL, research aimed at developing novel treatments is essential. This study will assess the effectiveness of transplatin (an inactive analog of cisplatin, which has been shown to be effective against drug-induced hearing loss and in preliminary studies of NIHL. We will test the efficacy of transplatin as a prophylatctic and as a rescue agent to treat NIHL in a rat model.

描述（由申请人提供）：噪声引起的听力损失 (NIHL) 在美国是一个严重问题，影响着所有年龄段约 15% 的人。这些人在工作场所或休闲活动中暴露在巨大的噪音中。美国国家耳聋和交流障碍研究所最近的一份报告表明，3000 万美国人经常暴露在危险水平的噪音中。慢性噪音暴露会导致内耳结构不可逆转的损伤和听力损失。目前尚无已知的 NIHL 治疗方法，这表明开发有效的治疗方案势在必行。我们实验室的最新数据表明，噪音创伤后耳蜗中活性氧 (ROS) 的产生增加，炎症介质增加。因此，我们假设 NIHL 是由耳蜗中 ROS 的产生引发的，ROS 会促进耳蜗炎症，导致内耳细胞损伤和死亡。这种炎症反应的介质包括耳蜗特异性 NADPH 氧化酶、NOX3（ROS 生成的主要来源）和瞬时受体电位 V1 (TRPV1)，这是一种非特异性阳离子通道，由 ROS 诱导并参与耳蜗炎症。因此，ROS 是响应噪音创伤的耳蜗炎症的常见介质。因此，针对 NOX3 和/或 TRPV1 进行抑制将构成 NIHL 的治疗选择。我们发现了一种新型药物——转铂，它通过抑制 TRPV1、NOX3 和炎症介质来改善 NIHL。该项目的总体目标是检查 NIHL 中 ROS 介导的炎症的作用，并确定转铂抑制这些促炎介质是否能提供耳保护作用。具体目标 1（子目标 1A）将确定转铂提供保护的有效剂量，并检查该药物有效预防和作为噪音创伤后救援剂的时间窗口。子目标 1B 将确定噪声暴露后给予转铂是否会提供耳保护。经鼓室和腹膜内给药途径的功效将通过听觉脑干反应（ABR）和扫描电子显微镜（SEM）进行评估。具体目标 2 将评估转铂耳保护的分子基础。具体而言，子目标2A将使用全转录物微阵列确定与对照相比，噪声和/或转铂后耳蜗的基因表达谱。靶基因/miRNA 验证将通过定量PCR 和Western blotting 进行。子目标 2B 将重点关注噪音创伤后通过耳蜗微阵列识别的耳蜗促炎基因通路。总体而言，本研究将提供有关 NIHL 耳蜗基因表达谱的全面数据，并更全面地了解转铂对抗 NIHL 的功效和作用机制。这些信息可以突出介导 NIHL 的潜在新信号通路，并提供新的药物治疗靶点。这种方法在动物研究中的成功结果预计将直接应用于人类 NIHL 的治疗。 公共卫生相关性：噪声引起的听力损失 (NIHL) 是工业化国家的一个重大问题。在美国，估计有 3000 万人每天暴露在高噪音环境中。听力损失会阻碍有效的沟通，并降低受影响个体的社交互动和生活质量。由于目前尚无针对 NIHL 的治疗方法，因此旨在开发新治疗方法的研究至关重要。本研究将评估转铂（顺铂的无活性类似物，已被证明可有效对抗药物引起的听力损失以及 NIHL 的初步研究）的有效性。我们将在大鼠模型中测试转铂作为预防剂和救援剂治疗 NIHL 的功效。