Pharmacology of Rescue from Acoustic Trauma

描述(由申请人提供)：对治疗听觉创伤的承诺来自申请人最近的发现，即损伤后有一段短暂的时期，此时内耳本身可能能够限制或自我修复大部分损伤。这一抢救过程可使永久性听力损失减少约40db，暴露于束缚应激(释放糖皮质激素)和使用合成糖皮质激素(如地塞米松)可诱发听力损失。当在受伤几天后触发时，从听觉创伤中进行救援是最有效的。申请者已经确定了一种皮质类固醇反应转录因子PLZF(早幼粒细胞白血病锌指蛋白)，这是从听觉创伤中进行救援所必需的。在束缚应激和皮质类固醇注射后，PLZF升高，PLZF缺陷的突变小鼠没有表现出从听觉创伤中获救。PLZF缺陷小鼠不能诱导保护，这为发现在动物中正常产生保护或修复听损伤的潜在机制提供了机会，并提供了一条最终开发药理疗法供人类使用的途径。目的是检测PLZF激活对耳蜗内白细胞侵袭和激活的影响，并评估这些影响对声损伤的影响。其具体目的是：1)确定PLZF激活对声损伤的救治作用；2)评估PLZF激活对听损伤后白细胞进入和巨噬细胞激活状态的影响；3)确定控制救援反应的细胞信号。目前，皮质类固醇是治疗急性听力损失的为数不多的有效疗法之一，其作用机制(S)尚不清楚。虽然已经在耳朵中分析了许多有希望的类固醇激活的潜在靶点，但尚未确定其作用的令人信服的机制。一种药物反应转录因子的发现可以诱导创伤后耳朵的修复，这为开发预防终身衰弱听力损失的药物疗法提供了一个独特的机会。人们可以设想在创伤后向内电针提供一种药物，可以预防或严重减少与创伤相关的永久性听力损失。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转录因子，对于条件反射介导的声损伤保护至关重要，也为识别保护和修复耳蜗的特定分子机制提供了一个直接的机会。

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.