Pharmacology of Rescue from Acoustic Trauma

声损伤救援的药理学

• 批准号: 8483632
• 负责人: WILLIAM F SEWELL
• 金额: $ 34.85万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8483632
• 关键词: Acoustic Trauma; Acoustics; Acute; Adrenal Cortex Hormones; Animals; Attenuated; Blood Circulation; Cochlea; Cochlear Nerve; Dexamethasone; Ear; Enzymes; Exposure to; Genes; Glucocorticoids; Goals; Hair Cells; Human; Inflammatory; Inflammatory Response; Injury; Labyrinth; Leukocytes; Life; Macrophage Activation; Mechanics; Mediating; Molecular; Mus; Mutant Strains Mice; Nerve Degeneration; Pathway interactions; Peroxides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Process; Role; Signal Transduction; Stereocilium; Steroids; Stimulus; Superoxides; Testing; Therapeutic; Time; Tissues; Trauma; Work; Wound Healing; assault; collagenase; conditioning; cytokine; hearing impairment; human ZNF145 protein; leukocyte activation; macrophage; novel strategies; prevent; protective effect; protein activation; public health relevance; receptor; repaired; response; restraint stress; sound; transcription factor

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.

描述（由申请人提供）：申请人最近发现，在损伤后的短时间内，内耳本身可能有能力限制或自我修复大部分损伤，因此有希望治疗听觉创伤。这种恢复过程可使永久性听力损失降低约40dB，并可通过暴露于约束应激（释放糖皮质激素）和使用合成糖皮质激素（如地塞米松）引起。在损伤几天后触发声创伤的抢救是最有效的。申请人已经确定了一种皮质类固醇应答转录因子PLZF（早幼粒细胞白血病锌指蛋白），这是产生声损伤抢救所必需的。PLZF在约束应激和皮质类固醇治疗后升高，PLZF缺乏的突变小鼠不能从声损伤中恢复。plzf缺陷小鼠无法诱导保护，这为发现动物正常产生声创伤保护或修复的潜在机制提供了机会，并为最终开发用于人类的药物治疗提供了途径。目的是研究PLZF激活对耳蜗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。具体目的是：1)确定哪些声损伤效应可以通过激活PLZF来抢救；2)评价PLZF激活对听损伤后耳蜗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丧失的少数几种有效方法之一，其作用机制尚不清楚。虽然在耳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。一种药物反应性转录因子的发现可以诱导耳部创伤后的修复，为开发药物治疗提供了一个独特的机会，以防止终身听力损失。人们可以设想，在内耳外伤后提供一种药物，可以预防或严重减少与创伤相关的永久性听力损失。几天的治疗时间窗口增加了治疗的实用性。单个皮质类固醇应答转录因子的鉴定对于诱导调节介导的声损伤保护至关重要，也为鉴定保护和修复耳蜗的特定分子机制提供了一个直接的机会。