DEVELOPMENT OF A DRUG THERAPY TO AMELIORATE PERMANENT HEARING LOSS

开发改善永久性听力损失的药物疗法

基本信息

批准号：
8797377
负责人：
Jianxin Bao
金额：
$ 38.01万
依托单位：
NORTHEAST OHIO MEDICAL UNIVERSITY
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：
2009-09-21 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8797377
关键词：
DEVELOPMENT DRUG THERAPY AMELIORATE PERMANENT

项目摘要

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.

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) 是继年龄相关性听力损失（老年性耳聋）之后第二种最常见的感音神经性听力缺陷形式。尽管已经找到了主要基于自由基途径的减少 NIHL 的有前途的方法，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途径阻碍了有效治疗的发展。在本提案中，我们通过询问针对多种信号通路的联合疗法是否可以有效预防 NIHL，从而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，可显着预防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既有预防作用又有治疗作用。 NIHL 也可以通过糖皮质激素信号通路的上调来预防。在该应用的 R21 阶段，我们将开发一种抗惊厥药和合成糖皮质激素的联合疗法，用于治疗一只 NIHL 病症的小鼠，这种疗法对于暂时性和永久性阈值变化都有显着的变化。在 R33 阶段，我们将扩展到另外两种 NIHL 小鼠模型，这些模型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疗法是否可以改善龙猫的永久性听力损失。我们的方法的创新点有两个：（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，具有丰富的药理学信息； (2)我们的联合治疗策略是干预多种信号传导途径，而不是仅仅关注经过充分研究的自由基途径。这种药理学方法还可能揭示对 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性质，因为我们不知道多种信号通路的干预是否会对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组合治疗中已经观察到协同效应。我们的研究不仅可能在 NIHL 领域产生巨大影响，而且可能在传播科学的其他领域产生巨大影响。例如，如果成功，可以探索类似的方法来治疗老年性耳聋和耳鸣。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。