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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目摘要噪声引起的听力损失（NIHL）导致暴露于强烈或重复的噪声导致敏感的损害耳蜗内的结构。 NIHL几乎已成为领先的职业和休闲危害之一 4000万美国人。 NIHL对我们的军队也是一个严重的关注，总体上会导致高经济负担工人赔偿和退伍军人残疾。尽管已经提出了许多治疗方法来减轻NIHL 在临床前研究中，有希望的结果，对于NIHL仍然没有FDA批准的治疗方法。轻度治疗性体温过低（30-33°C）已被广泛研究为针对各种神经外伤的神经保护策略，因为它可以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体温过低对缓解耳蜗损伤的治疗益处啮齿动物模型中的创伤。在此提案中，我们试图设计一种用于诱导局部中部的新型非侵入性装置 NIHL和评估长期功能听力和人工耳蜗神经底物保存的治疗性体温过低。我们的初步结果表明，在NIHL后提供给内耳的受控和局部治疗性体温过低与正常热对照相比，低温治疗动物的听力阈值偏移大大降低动物。此外，我们观察到治疗性低温的人工耳蜗突触病理学降低。确定低温下的保护机制，我们将确定受调节的分子途径和基因网络按温度纳入NIHL。相关啮齿动物模型中途径的详细表征将提供未来识别其他协同保护靶标的机会。基于初步结果，我们的主要机制重点将放在caspase依赖性凋亡途径和激活巨噬细胞的炎症反应上招募和表达。从长远来看，我们旨在解决可能是NIHL的有限治疗选择扩展到各种耳动性创伤，包括爆炸引起的听力丧失或外科手术引起的听力损失。