DEVELOPMENT OF A DRUG THERAPY TO AMELIORATE PERMANENT HEARING LOSS

描述(申请人提供)：噪音是最常见的职业危害和环境危害。噪声性听力损失(NIHL)是仅次于老年性听力损失(老年性耳聋)的第二种最常见的感觉神经性听力障碍。虽然已经发现了主要基于自由基途径的减少NIHL的有希望的方法，但目前还没有有效的药物来预防NIHL。NIHL涉及的一系列复杂的细胞和分子通路阻碍了有效治疗方法的发展。在这项提案中，我们将这一困难转化为优势，询问是否可以通过针对多个信号通路的联合疗法有效地预防NIHL。这项工作的近期目标是探索NIHL的治疗方向。长期目标是开发一种有效的药物组合，显着防止永久性噪音导致的听力损失。我们最近发现，阻断T型钙通道的抗癫痫药物对NIHL既有预防作用，又有治疗作用。糖皮质激素信号通路的上调也可以预防NIHL。在这项应用的R21阶段，我们将开发一种在一种小鼠NIHL条件下使用抗惊厥药物和合成糖皮质激素的联合疗法，这种疗法对暂时性和永久性阈值漂移都有巨大的变化。在R33阶段，我们将扩展到另外两个类似于附近爆炸或制造噪音造成的人类环境的NIHL小鼠模型。我们还将确定类似的联合疗法是否可以改善龙猫的永久性听力损失。我们方法的创新方面有两个方面：(1)我们将专注于FDA批准的药物，这些药物已经在具有丰富药理信息的动物身上进行了广泛的研究；(2)我们的联合治疗的策略是干预多个信号通路，而不仅仅是关注研究充分的自由基途径。这种药理学方法也可能揭示对NIHL的发展至关重要的新的分子靶点。我们知道这个项目的高风险性质，因为我们不知道干预多个信号通路是否会对NIHL产生协同作用。然而，在获得性免疫缺陷综合征和癌症的药物联合治疗中观察到了协同效应。我们的研究不仅可能对NIHL领域产生重大影响，而且还可能对传播学的其他领域产生重大影响。例如，如果成功，可以探索一种类似的方法来治疗老年性耳聋和耳鸣。总而言之，这项提议将开发一种范式转换的方法来测试针对NIHL的新型药物组合。 公共卫生相关性：该提案中的工作与开发噪声引起的永久性听力损失的药物干预措施非常相关。美国有3000多万人经常暴露在危险水平的噪音中。这项提议将发现预防NIHL的新药物组合，如果成功，将为未来预防永久性NIHL的临床试验提供足够的动物数据。

DESCRIPTION (provided by applicant): Noise is the most common occupational and environmental hazard. Noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit, after age-related hearing loss (presbycusis). Although promising approaches have been identified for reducing NIHL that are mainly based on the free radical pathway, currently there are no effective medications to prevent NIHL. Development of an efficacious treatment has been hampered by the complex array of cellular and molecular pathways involved in NIHL. In this proposal, we have turned this difficulty into an advantage by asking whether NIHL can be effectively prevented by a combination therapy targeting multiple signaling pathways. The immediate goal of this work is to explore this therapeutic direction for NIHL. The long-term goal is to develop an effective drug combination that dramatically prevents permanent noise-induced hearing loss. We have recently found that antiepileptic drugs blocking T-type calcium channels have both prophylactic and therapeutic effects for NIHL. NIHL can also be prevented by an up-regulation of glucocorticoid signaling pathways. In the R21 phase of this application, we will develop a combination therapy with anticonvulsants and synthetic glucocorticoids in one mouse NIHL condition, which has dramatic changes for both temporary and permanent threshold shifts. In the R33 phase, we will expand to two other NIHL mouse models that are similar to human conditions caused by a nearby explosion or manufacturing noise. We will also determine if the similar combination therapy can ameliorate permanent hearing loss in chinchillas. The innovative aspects of our approach are two-fold: (1) we will focus on FDA-approved drugs, which have already been extensively studied in animals with abundant pharmacological information; (2) the strategy of our combination therapy is to intervene in multiple signaling pathways instead of focusing only on the well-studied free radical pathway. This pharmacological approach may also reveal novel molecular targets critical to the development of NIHL. We are aware of the high-risk nature of this project because we do not know whether intervention in multiple signaling pathways will have a synergistic effect against NIHL. However, synergistic effects have been observed in drug combination treatments for acquired immunodeficiency syndrome and cancers. Our study can potentially have a high impact not only in the field of NIHL but also in other areas of communication science. For example, if successful, a similar approach can be explored for the treatment of presbycusis and tinnitus. In summary, this proposal will develop a paradigm-shifting approach to test novel drug combinations against NIHL. PUBLIC HEALTH RELEVANCE: The work in this proposal is very relevant to the development of pharmacologic interventions for noise-induced permanent hearing loss. More than 30 million people in the USA are exposed to hazardous levels of noise on a regular basis. This proposal will discover new drug combinations to prevent NIHL, and if successful, provide sufficient animal data for future clinical trials to prevent permanent NIHL.