Pharmacology of Rescue from Acoustic Trauma

描述（由申请人提供）：治疗声损伤的希望来自申请人最近的发现，即在损伤后的短暂时间内，内耳本身可能能够限制或自我修复大部分损伤。这种挽救过程可以使永久性听力损失降低约40 dB，并且可以通过暴露于束缚应激（释放糖皮质激素）和给予合成糖皮质激素（例如地塞米松）来诱发。从声损伤中抢救是最有效的，当受伤后几天触发。申请人已经鉴定了皮质类固醇响应性转录因子PLZF（早幼粒细胞白血病锌指蛋白），其是产生从声创伤的拯救所必需的。PLZF升高后约束应激和皮质类固醇管理，PLZF缺陷的突变小鼠不显示救援声创伤。PLZF缺陷小鼠不能诱导保护提供了一个机会，以发现潜在的机制，通过该机制在动物中正常产生声损伤的保护或修复，并提供了一种途径，通过该途径可以开发最终用于人类的药理学疗法。目的是检查PLZF激活白细胞侵入和激活耳蜗的影响，并评估这些影响对声损伤的后果。具体目标是：1）确定通过PLZF激活可以挽救哪些声损伤效应; 2）评估PLZF激活对声损伤后耳蜗白细胞进入和巨噬细胞激活状态的影响;以及3）确定控制挽救反应的细胞信号。目前，皮质类固醇是治疗急性听力损失的少数几种有效方法之一，其作用机制尚不清楚。虽然许多有前途的类固醇激活的潜在目标已被分析在耳朵，没有令人信服的机制尚未确定其行动。发现一种可以诱导创伤后耳朵修复的药物反应性转录因子，为开发药物治疗以预防终身衰弱性听力损失提供了独特的机会。可以设想在外伤性损伤后向内耳提供一种药物，其可以预防或严重减少与外伤相关的永久性听力损失的量。几天的治疗时间窗增加了治疗的实用性。识别一个单一的，皮质类固醇反应性转录因子，是必不可少的诱导条件介导的保护声创伤也提供了一个简单的机会，以确定特定的分子机制，保护和修复耳蜗。

DESCRIPTION (provided by applicant): Promise for a treatment for acoustic trauma comes from the recent discovery by the applicants that there is a brief period following the injury when the inner ear itself may be capable of limiting or of self-repairing much of the damage. This rescue process can provide ~40dB reduction in permanent hearing loss and can be evoked by exposure to restraint stress (which releases glucocorticoids) and by administration of synthetic glucocorticoids (e.g. dexamethasone). Rescue from acoustic trauma is most effective when triggered days after the injury. The applicants have identified a corticosteroid-responsive transcription factor, PLZF (promyelocytic leukemia zinc finger protein), which is necessary to generate rescue from acoustic trauma. PLZF is elevated following restraint stress and corticosteroid administration, and mutant mice deficient in PLZF do not show rescue from acoustic trauma. The inability of PLZF-deficient mice to induce protection provides an opportunity to discover the underlying mechanism through which protection or repair of acoustic trauma is generated normally in the animal, and provides a pathway by which pharmacological therapies can be developed ultimately for human use. The aims are to examine the influence of PLZF activation of leukocyte invasion and activation in the cochlea and to evaluate the consequences of those influences on acoustic trauma. The specific aims are to: 1) determine which effect of acoustic trauma can be rescued via PLZF activation; 2) evaluate the effects of PLZF activation on cochlear leukocyte entry and macrophage activation state following acoustic trauma; and 3) determine the cell signals controlling the rescue response. Corticosteroids are, at present, one of the few available treatments for acute loss of hearing, and their mechanism(s) of action are not understood. While many promising potential targets of steroid activation have been analyzed in the ear, no compelling mechanism has yet been identified for its action. The discovery of a drug-responsive transcription factor that can induce repair of the ear following trauma provides a unique opportunity to develop pharmaceutical therapies to prevent life-long debilitating hearing loss. One can envision providing a drug after traumatic injury to the inner ea that could prevent or seriously reduce the amount of permanent hearing loss associated with the trauma. The therapeutic time window of a few days increases practicality of the therapy. The identification of a single, corticosteroid-responsive transcription factor that is essential to indce conditioning-mediated protection from acoustic trauma also offers a straightforward opportunity to identify specific molecular mechanisms that protect and repair the cochlea.