Drug-induced Protection from Acoustic Trauma

描述(申请人提供)：噪声性听力损失是一个严重的公共卫生问题。使用某些药物可以预防和治疗噪音引起的耳朵损伤，但我们对其作用机制的了解仍处于初级阶段。已发现多种药物在实验动物中提供听力损失保护，但没有统一的框架来对已被发现有效的不同药物的疗效进行理论解释。该项目确定了一个预期的主控基因，该主控基因的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。关于Nrf2在其他组织中的激活作用的研究已经确定它是治疗各种疾病的治疗靶点，有充分的理由相信它也应该对耳朵疾病的治疗很重要。现在已经知道，已经发现的能够防止耳朵声损伤的不同药物也被发现在其他组织中激活Nrf2。这项提案的目标是测试耳朵中Nrf2的激活是否对于由一类保护性药物-抗氧化剂提供的听觉创伤保护是必要的。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，每种药物都显示出激活了一组独特的细胞。Nrf2的活化通过核定位的Nrf2的免疫染色来检测。拟议的实验将确定所选药物激活内耳细胞中的Nrf2是否与保护耳朵免受噪声暴露造成的听力损失有关。这将通过使用缺乏Nrf2基因的基因工程小鼠进行测试。如果缺陷小鼠未能表现出遗传正常小鼠所表现出的药物诱导的抗声损伤保护作用，这将意味着Nrf2的激活对于特定药物提供的保护是必不可少的。有关耳蜗细胞显示药物诱导的Nrf2激活对声损伤保护至关重要的文献将拓宽我们关于导致声损伤易感性和保护的细胞和分子机制的知识范围。了解哪些耳蜗细胞显示Nrf2激活，将允许给药激活不同细胞群的药物组合，以确定是否因此可以获得更有效的保护，以防声音创伤。这将是一种合理的方法来优化治疗，以减少或防止声音创伤。将拟议的工作扩展到包括其他类别的Nrf2激活药物将决定Nrf2在多大程度上能够为保护耳朵免受不同药物的侮辱提供统一的解释。这一结果可能会应用于治疗和预防听觉创伤以及其他耳科疾病。 与公共健康相关：噪声引起的听力损失是一个主要的公共健康问题。该项目将研究组织防御机制，以更好地了解如何保护耳朵免受噪音损害，以及如何优化未来的治疗方法，以更好地预防和最大限度地减少噪音导致的听力损失。

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.