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，损伤后有一段短暂的时期，内耳本身可能能够限制或自我修复大部分损伤，从而有望治疗声损伤。这种救援过程可以使永久性听力损失减少约 40dB，并且可以通过暴露于束缚压力（释放糖皮质激素）和施用合成糖皮质激素（例如地塞米松）来引起。声损伤的救援在受伤几天后触发是最有效的。申请人已经鉴定出一种皮质类固醇反应性转录因子PLZF（早幼粒细胞白血病锌指蛋白），它对于声损伤的救援是必需的。 PLZF 在束缚应激和皮质类固醇给药后升高，并且缺乏 PLZF 的突变小鼠没有表现出声损伤的挽救作用。 PLZF缺陷小鼠无法诱导保护，这为发现动物中正常产生声损伤的保护或修复的潜在机制提供了机会，并提供了最终开发用于人类的药物治疗的途径。目的是检查 PLZF 激活对白细胞侵袭和耳蜗激活的影响，并评估这些影响对声损伤的后果。具体目标是： 1) 确定哪些声损伤的影响可以通过 PLZF 激活来挽救； 2）评估声损伤后PLZF激活对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损失的少数可用治疗方法之一，其作用机制尚不清楚。虽然已经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。药物反应性转录因子的发现可以诱导创伤后耳朵的修复，这为开发药物疗法以预防终生衰弱性听力损失提供了独特的机会。人们可以设想在内耳遭受外伤后提供一种药物，可以预防或严重减少与外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。识别单个皮质类固醇反应性转录因子对于诱导条件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直接的机会。