Maximizing Hearing Recovery from Peri-Synaptic Damage

最大限度地提高突触周围损伤的听力恢复能力

• 批准号: 10348676
• 负责人: Hongzhe Li
• 金额: --
• 依托单位: VA LOMA LINDA HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10348676
• 关键词: Acoustic Nerve; Acoustics; Adrenal Cortex Hormones; Affect; Aftercare; Aminoglycoside Antibiotics; Aminoglycosides; Animal Model; Animals; Antibiotics; Antineoplastic Agents; Auditory; Auditory Brainstem Responses; Auditory Threshold; Auditory system; Bacterial Infections; Benchmarking; Body Weight; CBA/CaJ Mouse; Cell physiology; Cessation of life; Cisplatin; Cochlea; Data; Disease; Dose; Effectiveness; Electrophysiology (science); Elements; Environment; Exposure to; Frequencies; Gentamicins; Goals; Hair Cells; Health; Hearing; Human; Inflammation; Injections; Inner Hair Cells; Investigation; Knockout Mice; Labyrinth; Life; Loudness; Measures; Methylprednisolone; Microscopy; Military Personnel; Modeling; Modification; Molecular; Morphology; Mouse Strains; Mus; Mutant Strains Mice; Nerve Degeneration; Nerve Fibers; Nervous System Trauma; Nervous system structure; Neurons; Noise; Noise-Induced Hearing Loss; Outcome; Outcome Study; Outer Hair Cells; Pathologic; Performance; Personal Communication; Pharmaceutical Preparations; Play; Population; Principal Investigator; Process; Protocols documentation; Publishing; Quality of life; Recovery; Rehabilitation therapy; Research Proposals; Resistance; Risk; Role; Sensory Hair; Signal Transduction; Speech; Stress; Synapses; TRPV1 gene; Testing; Therapeutic; Time; Variant; Veterans; Veterans Health Administration; aminoglycoside-induced ototoxicity; antagonist; capsazepine; cell injury; cigarette smoke; cochlear synaptopathy; density; design; dosage; effective intervention; gentamicin A; hearing impairment; high risk; improved; injured; military service; mouse model; neurotrophic factor; noise exposure; otoacoustic emission; ototoxicity; prevent; programs; rehabilitation strategy; service member; sound; spiral ganglion; synaptic function; transmission process; wounded soldier

Principal Investigator: Hongzhe Li Program Summary Project Title: Maximizing hearing recovery from peri-synaptic damage Program Summary Ototoxicants such as aminoglycoside antibiotics, and anti-neoplastic cisplatin, cause cytoplasmic stress within the sensory hair cells and the spiral ganglion neurons, affecting synaptic functionalities and signal transmission towards the central auditory system. We hypothesize that ototoxic cochlear synaptic damage that to some extent resembles noise-induced synaptopathy, accounts for the observation that after various ototoxic insults, within particular dosing range, without effective intervention, the auditory functions deteriorate permanently, despite of minimal or no hair cell loss. Thus, in the present project, we will investigate the similarity and discrepancy of synaptic damage due to noise or aminoglycosides and decipher the cause of synaptopathy at cellular and molecular levels. The proposed project is designed to investigate the aminoglycoside treatment conditions, which result in classic synaptopathy, and to search for optimal therapeutic temporal windows and candidate agents to intervene with degeneration process. In this manner, study findings will permit maximal hearing recovery after either noise over-stimulation or exposure to ototoxic insults. The specific aims of this project are to: First, determine the optimal aminoglycoside dosage that produces maximal ototoxic synaptopathy without functional hair cell damage in CBA/CaJ mice. An established 14-day gentamicin protocol will be used, with various dosing strategy. Electrophysiological and acoustical measures, including auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs), will be used to assess post-synaptic (ABR) and pre-synaptic (DPOAE) outer hair cell function, respectively. Second, using the optimal gentamicin dosing, we will characterize the dynamic synaptic modification in ototoxic synaptopathy. Here, we will conduct morphological investigation to visualize the synaptic variation and the survival of spiral ganglion neurons at multiple time points after the initiation of gentamicin treatment. Third, we will determine the effects of cochlear inflammation on synaptic damage, using genetically modified mouse models including Darc and TrpV1 knockout mice. Both strains of mice present certain degree of resistance to noise-induced hearing loss. Last, we will test potential audiologic rehabilitation strategies for synaptopathy, focusing on inflammation suppressive corticosteroids. This is the major rehabilitation component of the project, we will perform intratympanic injection of several therapeutics in the models of ototoxic and noise-induced synaptopathy. Auditory function will be assessed by ABR and DPOAE at several post-treatment time points, and synaptic element examined by immunolabeling and microscopy. Cochlear synaptopathy plays an essential role in auditory damage, likely affecting the supra- threshold auditory functions. These functions are critical for frequency selectivity and temporal processing, both important for speech understanding and listening in the noise environment. This creates an extreme adverse situation in military settings when effective interpersonal communication means life-or-death, and greatly affects the life quality of Veterans. This research proposal is ultimately to improve the effectiveness of rehabilitation from synaptic damage in the inner ear.

首席研究员：李宏哲 项目概要 项目名称：最大限度地提高突触周围损伤的听力恢复能力 计划概要 耳毒性药物，如氨基糖苷类抗生素和抗肿瘤顺铂，会导致细胞质 感觉毛细胞和螺旋神经节神经元内的压力，影响突触功能和 信号传输至中枢听觉系统。我们假设耳毒性耳蜗突触 在某种程度上类似于噪声引起的突触病的损伤，解释了以下观察结果： 各种耳毒性损伤后，在特定剂量范围内，如果没有有效干预，听觉 尽管毛细胞损失很少或没有损失，但功能会永久恶化。因此，在本项目中， 我们将研究噪声或氨基糖苷类药物引起的突触损伤的相似性和差异 并在细胞和分子水平上破译突触病的原因。 拟议项目旨在研究氨基糖苷类治疗条件，其中 导致经典的突触病，并寻找最佳的治疗时间窗口和候选者 干预退化过程的药物。通过这种方式，研究结果将允许最大程度的听力 噪音过度刺激或暴露于耳毒性损伤后的恢复。本次活动的具体目标 项目是： 首先，确定产生最大耳毒性突触病的最佳氨基糖苷剂量 CBA/CaJ 小鼠中没有功能性毛细胞损伤。已制定的 14 天庆大霉素方案将 使用不同的剂量策略。电生理学和声学测量，包括听觉 脑干反应（ABR）和失真产物耳声发射（DPOAE），将用于 分别评估突触后 (ABR) 和突触前 (DPOAE) 外毛细胞功能。 其次，使用最佳庆大霉素剂量，我们将表征动态突触修饰 在耳毒性突触病中。在这里，我们将进行形态学研究以可视化突触 启动后多个时间点螺旋神经节神经元的变化和存活 庆大霉素治疗。 第三，我们将利用基因确定耳蜗炎症对突触损伤的影响 改良小鼠模型，包括 Darc 和 TrpV1 敲除小鼠。两种品系的小鼠均表现出某些 对噪声引起的听力损失的抵抗程度。 最后，我们将测试突触病的潜在听力康复策略，重点是 抑制炎症的皮质类固醇。这是该项目的主要康复部分，我们 将在耳毒性和噪音诱发模型中进行多种治疗药物的鼓室内注射 突触病。 ABR 和 DPOAE 将在治疗后的几个时间评估听觉功能 通过免疫标记和显微镜检查检查点和突触元件。 耳蜗突触病在听觉损伤中起着重要作用，可能影响上耳 阈听觉功能。这些功能对于频率选择性和时间选择性至关重要 处理，对于噪声环境中的语音理解和听力都很重要。这 当有效的人际沟通时，会在军事环境中造成极其不利的情况 意味着生死攸关，极大地影响退伍军人的生活质量。该研究计划最终 提高内耳突触损伤康复的效果。