Drug-induced Protection from Acoustic Trauma

描述（申请人提供）：噪音性听力损失是一个严重的公共卫生问题。某些药物可以预防和治疗噪音引起的耳部损伤，但我们对其作用机制的理解仍处于初级阶段。各种各样的药物已经被发现可以保护实验动物免受听力损失，但是对于已经被发现有效的不同药物的功效，还没有统一的框架来制定一个理论解释。该项目确定了一个潜在的主基因，其活性控制和协调参与细胞应激反应的大量其他基因的活性。这种基因被称为Nrf2。对Nrf2在其他组织中的激活作用的研究已经将其确定为治疗多种疾病的治疗靶点，并且有充分的理由相信它对治疗耳部疾病也很重要。现在已经知道，已经发现的不同的药物可以诱导保护耳朵免受听觉创伤，也可以激活其他组织中的Nrf2。这项提议的目的是测试Nrf2在耳朵中的激活是否对一类保护药物抗氧化剂提供的声损伤的保护是必要的。初步实验表明，服用四种已知能激活其他组织中Nrf2的不同抗氧化剂，也能激活内耳细胞中的Nrf2，每种药物都显示出对不同细胞群的激活。通过核定位Nrf2的免疫染色检测Nrf2的活化。拟议的实验将确定所选药物是否激活内耳细胞中的Nrf2与保护耳朵免受噪音暴露导致的听力损失有关。这将通过对缺乏Nrf2基因的转基因小鼠进行测试。如果有缺陷的小鼠不能像基因正常的小鼠那样表现出药物诱导的对声损伤的保护作用，这将意味着Nrf2的激活对于给定药物提供的保护作用是必不可少的。耳蜗细胞显示药物诱导的Nrf2激活对保护耳蜗免受声损伤至关重要的文献记录将扩大我们对声损伤易感性和保护耳蜗的细胞和分子机制的认识范围。了解哪些耳蜗细胞表现出Nrf2激活，将允许使用药物组合来激活不同的细胞群，以确定是否可以因此获得更有效的声损伤保护。这将代表一种合理的方法来优化治疗，以减少或防止听觉创伤。将这项工作扩展到其他种类的Nrf2激活药物，将决定Nrf2在多大程度上可以为保护耳朵免受不同药物的伤害提供统一的解释。该结果可能应用于治疗和预防听觉创伤，以及其他耳科疾病。

DESCRIPTION (provided by applicant): Noise-induced hearing loss is a serious public health problem. Prevention and treatment of noise-induced ear damage is possible with certain drugs but our understanding of the mechanisms involved in their actions is still rudimentary. A wide variety of drugs have been found to provide protection from hearing loss in experimental animals but there is no unifying framework upon which to formulate a theoretical explanation for the efficacy of the disparate drugs that have been found to be effective. This project identifies a prospective master gene, the activity of which controls and coordinates the activity of a large number of other genes that are involved in cellular stress responses. The gene is called Nrf2. Work on effects of Nrf2 activation in other tissues have identified it as a therapeutic target for treatment of a wide variety of disorders and there are good reasons to believe that it should also be important for treatment of disorders of the ear. It is now known that disparate drugs that have been found to induce protection from acoustic trauma of the ear have also been found activate Nrf2 in other tissues. The goal of this proposal to test whether Nrf2 activation in the ear is necessary for the protection from acoustic trauma that is provided by one class of protective drugs, antioxidants. Preliminary experiments show that administration of four different antioxidants that are known to activate Nrf2 in other tissues are capable of activating Nrf2 in inner ear cells, with each drug showing activation of a distinctive population of cells. Activation of Nrf2 is assayed by immunostaining for nuclear localized Nrf2. The proposed experiments will ascertain whether activation of Nrf2 in inner ear cells by the chosen drugs is associated with protection of the ear from hearing loss due to noise exposures. This will be tested by the use of mice that are genetically engineered to lack the Nrf2 gene. If the deficient mice fail to show drug induced protection from acoustic trauma that is shown by genetically normal mice, it will mean that Nrf2 activation is essential for the protection afforded by a given drug. Documentation of which cochlear cells show drug- induced Nrf2 activation that is essential for protection from acoustic trauma will broaden the scope of our knowledge concerning the cellular and molecular mechanisms that contribute to vulnerability to and protection from acoustic trauma. Knowledge of which cochlear cells show Nrf2 activation will permit administration of combinations of drugs that activate different cell populations to determine if more efficacious protection from acoustic trauma can thereby be obtained. This will represent a rational approach to optimizing treatments to reduce or prevent acoustic trauma. Extension of the proposed work to include other classes of Nrf2 activating drugs will determine the extent to which Nrf2 can provide a unifying explanation for protection of the ear from insults by disparate drugs. The results may have applications for the treatment and prevention of acoustic trauma, as well as other otologic disorders. PUBLIC HEALTH RELEVANCE: Noise-induced hearing loss is a major public health problem. This project will study tissue defense mechanisms to better understand how the ear can be protected from noise damage and how future treatments can be optimized to better prevent and minimize noise-induced hearing loss.