Efficacy and Mechanisms of Mild Therapeutic Hypothermia for Hearing Preservation from NIHL

NIHL 轻度低温治疗对听力保护的疗效和机制

• 批准号: 10321892
• 负责人: Samantha Rincon Sabatino
• 金额: $ 4.16万
• 依托单位: UNIVERSITY OF MIAMI CORAL GABLES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-09 至 2022-11-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321892
• 关键词: Acoustic Trauma; Acute; Address; Adverse effects; American; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Apoptotic; Attenuated; Auditory Brainstem Responses; Auditory Threshold; Autopsy; Biological Process; CASP3 gene; Caspase; Cells; Cochlea; Cochlear Nerve; Control Animal; Data; Devices; Economic Burden; Elements; Engineering; Environment; Evaluation; Exposure to; FDA approved; Functional disorder; Future; Genetic Transcription; Hair Cells; Hearing; Hearing problem; Hour; Immune response; Immunohistochemistry; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Labyrinth; Location; Maps; Mediating; Military Personnel; Modeling; Molecular; Morphology; N-Methylaspartate; Nervous System Trauma; Neurons; Noise; Noise-Induced Hearing Loss; Occupational; Operative Surgical Procedures; Outcome; Oxidative Stress; Pathway Analysis; Pathway interactions; Pre-Clinical Model; Process; Protocols documentation; Quantitative Reverse Transcriptase PCR; Rattus; Residual state; Resources; Rodent Model; Safety; Sensorineural Hearing Loss; Structure; Swelling; Synapses; System; Temperature; Temporary Threshold Shift; Testing; Therapeutic; Time; Trauma; Treatment Efficacy; United States; Validation; Veterans; Workers' Compensation; antagonist; auditory threshold shift; base; clinically relevant; design; disability; efficacy evaluation; efficacy testing; excitotoxicity; gene network; hazard; hearing impairment; hearing preservation; immunohistochemical markers; innovation; insight; macrophage; natural hypothermia; neuroprotection; noise exposure; normal hearing; novel; novel strategies; otoprotectant; pre-clinical; preclinical study; preservation; protective effect; recruit; rectal; relating to nervous system; remote monitoring; repaired; reparative process; response to injury; ribbon synapse; service member; sound; spiral ganglion; transcription factor; transcriptome; transcriptome sequencing

Project Summary Noise-induced hearing loss (NIHL) caused by exposure to intense or repeated noise results in damage to the sensitive structures within the cochlea. NIHL has become one of the leading occupational and recreational hazards afflicting nearly 40 million Americans. NIHL is also a serious concern for our military, and overall results in a high economic burden due to worker compensation and veteran disability. Although many treatments have been proposed to mitigate NIHL with promising results in preclinical studies, there are still no FDA-approved treatments for NIHL. Mild therapeutic hypothermia (30-33 °C) has been extensively studied as a neuroprotective strategy against various types of neurological traumas because of its ability to mediate various injury responses to trauma including oxidative stress, apoptosis, and inflammation. We aim to assess the therapeutic benefit of localized therapeutic hypothermia in mitigation of cochlear injury following acoustic trauma in a rodent model. In this proposal, we seek to engineer a novel non-invasive device used to induce localized mild therapeutic hypothermia post-NIHL and assess long-term functional hearing and cochlear neural substrate preservation. Our preliminary results suggest that controlled and localized therapeutic hypothermia provided to the inner ear post-NIHL significantly lowers hearing threshold shifts in hypothermia-treated animals when compared to normothermic control animals. Furthermore, we observe reduced cochlear synaptopathology with therapeutic hypothermia. To determine protective mechanisms underlying hypothermia, we will identify molecular pathways and gene networks that are regulated by temperature post-NIHL. A detailed characterization of the pathways in a relevant rodent model will provide future opportunities to identify additional synergistic otoprotective targets. Based on preliminary results, our primary mechanistic emphases will be on caspase-dependent apoptotic pathways and inflammatory responses with activated macrophage recruitment and expression. In the long-term, we aim to address the limited therapeutic options for NIHL that may be extended to various otological traumas, including blast-induced hearing loss or surgically-induced hearing loss.

项目摘要 噪声性听力损失（NIHL）是由于暴露于强烈或重复的噪声中导致的， 耳蜗内的结构。NIHL已成为主要的职业和娱乐危害之一， 四千万美国人。NIHL对我们的军队来说也是一个严重的问题，总体上造成了很高的经济负担， 工人赔偿和退伍军人伤残尽管已经提出了许多治疗方法来减轻NIHL， 尽管在临床前研究中取得了令人鼓舞的结果，但仍然没有FDA批准的NIHL治疗方法。亚低温治疗 （30-33 °C）作为针对各种类型的神经创伤的神经保护策略已被广泛研究， 其介导对创伤的各种损伤反应的能力，包括氧化应激、凋亡和炎症。我们的目标 评估局部治疗性低温在减轻声学损伤后耳蜗损伤中的治疗益处， 在啮齿动物模型中的创伤。在这项提案中，我们试图设计一种新的非侵入性设备，用于诱导局部轻度 NIHL后治疗性低温，并评估长期功能性听力和耳蜗神经基质保存。我们 初步结果表明，控制和局部治疗低温提供给内耳后NIHL 与正常体温对照组相比， 动物此外，我们观察到减少耳蜗突触病理与治疗低温。以确定 保护机制的基础低温，我们将确定分子途径和基因网络， 通过NIHL后的温度。在相关的啮齿动物模型中详细描述的途径将提供未来 机会，以确定额外的协同耳保护目标。根据初步结果，我们的主要机制 重点将放在半胱天冬酶依赖的凋亡途径和活化的巨噬细胞的炎症反应 招募和表达。从长远来看，我们的目标是解决NIHL的有限治疗选择， 扩展到各种耳科创伤，包括爆炸引起的听力损失或爆炸引起的听力损失。