Drug-induced Protection from Acoustic Trauma

药物引起的声损伤保护

• 批准号: 8248198
• 负责人: JOE C ADAMS
• 金额: $ 19.63万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248198
• 关键词: Accounting; Acoustic Trauma; Affect; Animals; Antioxidants; Biological Assay; Cells; Cellular Stress; Cellular Stress Response; Cochlea; Defense Mechanisms; Disease; Documentation; Drug Combinations; Drug usage; Ear; Ear Diseases; Fiber; Future; Genes; Genetically Engineered Mouse; Goals; Knowledge; Labyrinth; Learning; Molecular; Mus; Noise; Noise-Induced Hearing Loss; Nuclear; Pattern; Pharmaceutical Preparations; Population; Prevention; Protective Agents; Public Health; Radial; Regimen; Reporting; Resveratrol; Stress; Testing; Thioctic Acid; Time; Tissues; Trauma; Work; base; biological adaptation to stress; cell type; compare effectiveness; dosage; drug efficacy; ebselen; ganglion cell; hearing impairment; otoacoustic emission; prevent; prospective; protective effect; public health relevance; pyrrolidine dithiocarbamate; research study; response; spiral ganglion; therapeutic target; transcription factor

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.

描述（由申请人提供）：噪声性听力损失是一个严重的公共卫生问题。预防和治疗噪声引起的耳损伤是可能的，某些药物，但我们的了解，在其行动所涉及的机制仍然是初步的。已经发现各种各样的药物可以保护实验动物免受听力损失，但是对于已经发现有效的不同药物的功效，没有统一的框架来制定理论解释。该项目确定了一个潜在的主基因，其活性控制和协调大量参与细胞应激反应的其他基因的活性。该基因被称为Nrf2。关于Nrf2激活在其他组织中的作用的研究已经将其确定为用于治疗多种疾病的治疗靶点，并且有充分的理由相信它对于治疗耳部疾病也应该是重要的。现在已知的是，已经发现诱导保护耳朵免受声学创伤的不同药物也被发现激活其他组织中的Nrf2。这项提案的目的是测试耳朵中的Nrf2激活是否是保护免受声学创伤所必需的，这是由一类保护性药物抗氧化剂提供的。初步实验表明，已知在其他组织中激活Nrf2的四种不同抗氧化剂的施用能够激活内耳细胞中的Nrf2，每种药物都显示出不同细胞群的激活。通过对核定位的Nrf2进行免疫染色来测定Nrf2的活化。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引起的听力损失有关。这将通过使用经过基因工程改造而缺乏Nrf2基因的小鼠进行测试。如果缺陷小鼠不能显示遗传正常小鼠所显示的药物诱导的对声损伤的保护，这将意味着Nrf2激活对于给定药物提供的保护是必不可少的。记录哪些耳蜗细胞显示药物诱导的Nrf2激活对于保护免受声损伤是必不可少的，这将拓宽我们关于有助于对声损伤的脆弱性和保护免受声损伤的细胞和分子机制的知识范围。了解哪些耳蜗细胞显示Nrf2激活将允许施用激活不同细胞群的药物组合，以确定是否可以由此获得更有效的保护免受声损伤。这将代表一种合理的方法来优化治疗，以减少或防止声损伤。将拟议的工作扩展到包括其他类别的Nrf2激活药物，将确定Nrf2可以在多大程度上为保护耳朵免受不同药物的损伤提供统一的解释。结果可能有应用程序的治疗和预防声创伤，以及其他耳科疾病。 噪声性听力损失是一个严重的公共卫生问题。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声损伤，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声引起的听力损失。