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

项目摘要 噪声性听力损失(NIHL)是由于暴露在强烈或反复的噪声中而引起的，会对敏感的大脑造成损害 耳蜗内的结构。NIHL已成为困扰近几年的主要职业和娱乐危害之一 4000万美国人。NIHL也是我们军队的严重关切，总体上造成了沉重的经济负担 工人补偿和退伍军人伤残。尽管已经提出了许多治疗方法来缓解NIHL， 尽管在临床前研究中取得了可喜的结果，但仍没有FDA批准的治疗NIHL的方法。轻度治疗性低温 (30-33°C)作为一种针对各种神经创伤的神经保护策略已被广泛研究，因为 其调节创伤的各种损伤反应的能力，包括氧化应激、细胞凋亡和炎症。我们的目标是 评价局部亚低温治疗对减轻声学耳蜗病的疗效 啮齿动物模型中的创伤。在这项提议中，我们试图设计一种新的非侵入性设备，用于诱导局部轻度 治疗后低温NIHL，并评估长期功能听力和耳蜗神经基质的保存。我们的 初步结果表明，NIHL术后对内耳提供有控制和局部的治疗低温 与常温对照组相比，低温处理的动物显著降低了听力阈值漂移 动物。此外，我们还观察了治疗性低温对耳蜗神经突触病理的影响。要确定 低温下的保护机制，我们将确定受调控的分子通路和基因网络 根据NIHL后的温度。在相关啮齿动物模型中对这些途径的详细描述将提供未来 有机会确定更多的协同耳防目标。根据初步结果，我们的主要机制是 重点将放在caspase依赖的凋亡途径和激活的巨噬细胞的炎症反应上。 招募和表达。从长远来看，我们的目标是解决NIHL有限的治疗选择，可能是 扩大到各种耳科创伤，包括爆炸导致的听力损失或手术导致的听力损失。

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.