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：
9911048
负责人：
Samantha Rincon Sabatino
金额：
$ 4.5万
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 2023-01-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9911048
关键词：
Acoustic Trauma Acute Address Adverse effects American Animals Anti-inflammatory Antioxidants Apoptosis Apoptotic Attenuated Auditory Auditory Brainstem Responses 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 Genes Genetic Transcription Hair Cells Hearing Hour Immune response Immunohistochemistry Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Labyrinth Location Maps Mediating Military Personnel Modeling Molecular Monitor 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 base clinically relevant design disability efficacy testing excitotoxicity hazard hearing impairment hearing preservation hearing threshold immunohistochemical markers innovation insight macrophage member natural hypothermia neuroprotection normal hearing novel novel strategies otoprotectant pre-clinical preclinical study preservation protective effect recruit rectal relating to nervous system repaired response to injury ribbon synapse 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.

项目概要由于暴露于强烈或重复的噪音而引起的噪音性听力损失（NIHL）会导致敏感神经受损耳蜗内的结构损伤已成为几乎困扰着人们的主要职业和娱乐危害之一。 4000万美国人也面临着严重的NIHL问题，总体上造成了沉重的经济负担。尽管已经提出了许多治疗方法来减轻 NIHL 的影响。尽管临床前研究取得了令人鼓舞的结果，但目前尚无 FDA 批准的轻度治疗性低温疗法。（30-33°C）主要作为针对各种类型神经创伤的神经保护策略进行研究，因为我们的目标是了解其介导对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。评估局部低温治疗在减轻声学治疗后耳蜗损伤方面的益处在这项提案中，我们寻求设计一种用于诱导局部轻度创伤的新型非侵入性设备。 NIHL 后的低温治疗并评估长期功能性听力和耳蜗神经基质的保存。初步结果表明，NIHL 后可向内耳提供受控和局部治疗性低温与正常体温对照相比，低温治疗动物的听力阈值变化显着降低此外，我们还观察到低温治疗可降低耳蜗突触病理学。体温过低的保护机制，我们将确定受调节的分子途径和基因网络 NIHL 后的温度对相关啮齿动物模型中通路的详细描述将为未来提供帮助。根据初步结果，我们的主要机制是确定其他协同耳保护目标的机会。重点将放在半胱天冬酶依赖性细胞凋亡途径和活化巨噬细胞的炎症反应上从长远来看，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手术引起的听力损失。