Novel Approaches for Prevention and Treatment of Noise Induced Hearing loss

描述(申请人提供)：噪声性听力损失(NIHL)在美国是一个严重的问题，所有年龄段的人中约有15%受到影响。这些人在工作场所或休闲活动中暴露在巨大的噪音中。美国国家耳聋和沟通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。慢性噪声暴露会对内耳结构造成不可逆转的损害，并导致听力损失。目前尚无已知的治疗NIHL的方法，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，噪声创伤后耳蜗内活性氧物种(ROS)的产生增加，炎性介质增加。因此，我们假设NIHL是由耳蜗内ROS的产生引发的，ROS促进了耳蜗炎症，导致内耳细胞的损伤和死亡。这种炎症反应的介质包括耳蜗特异性NADPH氧化酶、NOX3(ROS产生的主要来源)和瞬时受体电位V1(TRPV1)，TRPV1是由ROS诱导的参与耳蜗炎症的非特异性阳离子通道。因此，ROS是噪声创伤后耳蜗炎性反应的常见介质。因此，针对NOX3和/或TRPV1的抑制将构成NIHL的治疗选择。我们已经确定了一种新的药物，Transplatin，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研究ROS介导的炎症在NIHL中的作用，并确定转铂对这些促炎介质的抑制是否提供了耳保护。具体目标1(次级目标1A)将确定提供保护的顺铂的有效剂量，并审查该药物预防和作为噪声创伤后的救援剂有效的时间窗口。次级目标1B将确定在噪声暴露后给予转铂是否会提供耳保护。将通过听性脑干反应(ABR)和扫描电子显微镜(SEM)评估经鼓室和腹膜内给药的疗效。具体目标2将评估转铂耳道保护的分子基础。具体地说，子目标2A将使用整个转录本微阵列，与对照相比，确定噪声和/或转铂后耳蜗组织的基因表达谱。目的基因/miRNA验证将通过定量聚合酶链式反应和Western blotting进行。次目标2B将重点放在噪音创伤后耳蜗微阵列识别的耳蜗促炎基因通路上。总体而言，这项研究将提供有关NIHL耳蜗组织基因表达谱的全面数据，并提供更完整的图景，了解Transplatin治疗NIHL的疗效和作用机制。这些信息可以突出潜在的新的信号通路，介导NIHL，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有望直接应用于人类NIHL的治疗。 公共卫生相关性：噪声引起的听力损失(NIHL)在工业化国家是一个严重的问题。在美国，据估计，每天有3000万人暴露在高噪音水平下。听力丧失阻碍了有效的沟通，并降低了社会互动和受影响个人的生活质量。由于目前还没有治疗NIHL的方法，旨在开发新的治疗方法的研究是必不可少的。这项研究将评估Transplatin(顺铂的一种非活性类似物，已被证明对药物引起的听力损失和NIHL的初步研究有效)的有效性。我们将在大鼠模型上测试反铂作为预防和救援药物治疗NIHL的效果。

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.