DEVELOPMENT OF A DRUG THERAPY TO AMELIORATE PERMANENT HEARING LOSS

描述（由申请人提供）：噪音是最常见的职业和环境危害。噪声性听力损失（NIHL）是仅次于老年性听力损失（老年性耳聋）的第二常见的感觉神经性听力损失形式。虽然已经确定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中涉及的一系列复杂的细胞和分子途径阻碍了有效治疗方法的发展。在本提案中，我们通过询问针对多种信号通路的联合治疗是否可以有效预防NIHL，将这一困难转化为优势。这项工作的直接目标是探索NIHL的治疗方向。长期目标是开发一种有效的药物组合，以显著防止永久性噪音引起的听力损失。我们最近发现阻断t型钙通道的抗癫痫药物对NIHL具有预防和治疗双重作用。NIHL也可以通过糖皮质激素信号通路的上调来预防。在该申请的R21期，我们将开发一种抗惊厥药和合成糖皮质激素联合治疗小鼠NIHL的方法，该方法在暂时性和永久性阈值变化方面都有显著变化。在R33阶段，我们将扩展到另外两个NIHL小鼠模型，它们与附近爆炸或制造噪音引起的人类状况相似。我们还将确定类似的联合治疗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，这些药物已经在动物身上进行了广泛的研究，具有丰富的药理信息；(2)我们的联合治疗策略是干预多种信号通路，而不是只关注已被充分研究的自由基通路。这种药理学方法也可能揭示对NIHL发展至关重要的新分子靶点。我们意识到这个项目的高风险，因为我们不知道干预多种信号通路是否会对NIHL产生协同效应。然而，在获得性免疫缺陷综合征和癌症的药物联合治疗中已经观察到协同效应。我们的研究不仅在NIHL领域，而且在通信科学的其他领域都有很大的影响。例如，如果成功，可以探索治疗老年性耳鸣的类似方法。总之，该提案将开发一种范式转换方法来测试针对NIHL的新型药物组合。

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.