Pharmacology of Rescue from Acoustic Trauma

声损伤救援的药理学

• 批准号: 8994727
• 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/8994727
• 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; Health; Human; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Labyrinth; Leukocytes; Life; Macrophage Activation; Mechanics; Mediating; Molecular; Mus; Mutant Strains Mice; Nerve Degeneration; Pathway interactions; Peroxides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Process; Proteins; Role; Signal Transduction; Stereocilium; Steroids; Stimulus; Superoxides; Testing; Therapeutic; Time; Tissues; Trauma; Traumatic injury; Work; Wound Healing; ZNF145 gene; assault; collagenase; conditioning; cytokine; hearing impairment; leukocyte activation; macrophage; novel strategies; prevent; protective effect; protein activation; 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）：对声学创伤进行治疗的承诺来自申请人最近发现的，即受伤后短暂的一段时间，内耳本身可能能够限制或自我修复大部分损害。这种救援过程可以减少永久性听力损失的〜40dB，并且可以通过暴露于约束应力（释放糖皮质激素）和通过合成糖皮质激素（例如，去塞米松）来诱发。受伤几天后触发时，从声学创伤中救出最有效。申请人已经确定了皮质类固醇反应性转录因子PLZF（Promyelocytic Leukemia锌指蛋白），这对于从声学创伤中产生救援是必不可少的。在约束应激和皮质类固醇给药后，PLZF升高，而缺乏PLZF的突变小鼠不会从声学创伤中救出。 PLZF缺陷型小鼠无法诱导保护提供了一个机会，可以发现一种基本机制，通过该机制在动物中正常产生声学创伤的保护或修复，并提供了一种可以最终开发出用于人类使用的药理治疗的途径。目的是检查白细胞侵袭和耳蜗激活PLZF激活的影响，并评估这些影响对声学创伤的后果。具体目的是：1）确定可以通过PLZF激活挽救声学创伤的哪些作用； 2）评估PLZF激活对声学创伤后耳蜗白细胞进入和巨噬细胞激活状态的影响； 3）确定控制救援响应的细胞信号。目前，皮质类固醇是急性听力丧失的少数可用治疗方法之一，其作用机制尚不清楚。尽管已经在耳朵中分析了许多有前途的类固醇激活的潜在潜在靶标，但尚未确定其作用的引人注目的机制。创伤后可能诱导耳朵修复的药物响应转录因子的发现为开发药物疗法提供了独特的机会，以防止终身衰弱的听力损失。可以设想在内部EA发生创伤后提供药物，以防止或严重减少与创伤相关的永久性听力损失量。几天的治疗时间窗口增加了治疗的实用性。鉴定单个皮质类固醇反应性转录因子，这对于构成调节介导的原始创伤的保护至关重要，这也提供了一个直接的机会，可以识别保护和修复耳蜗的特定分子机制。