Outer hair cells and noise-induced hearing loss

外毛细胞和噪音引起的听力损失

• 批准号: 10862034
• 负责人: Jing Zheng
• 金额: $ 40.79万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10862034
• 关键词: Ablation; Acoustic Nerve; Address; Adult; Affect; Affinity; Age; Amplifiers; Anatomy; Axon; Biochemical; Biological Markers; Blood; Blood Circulation; Brain; Buffers; Calcium; Calcium Binding; Calcium-Binding Proteins; Calmodulin; Cell Line; Cell physiology; Characteristics; Cisplatin; Cochlea; Cysteine; Cytoplasm; Data; Defect; Dimerization; Dissociation; Disulfides; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Evaluation; Exposure to; Extracellular Space; Frequencies; Genes; Goals; Grant; Half-Life; Hearing; Hearing Tests; Histologic; Image; Immunofluorescence Immunologic; In Vitro; Inflammation; Inner Hair Cells; Ionophores; Knowledge; Labyrinth; Macrophage; Measures; Mechanics; Mediating; Methods; Molecular Conformation; Motion; Mus; Natural regeneration; Nerve Regeneration; Neurites; Neurons; Noise; Noise-Induced Hearing Loss; Organ; Organ Culture Techniques; Organ of Corti; Outer Hair Cells; Oxidation-Reduction; Pathway interactions; Peripheral; Peripheral Nerves; Persons; Pharmaceutical Preparations; Plasma; Play; Primary Cell Cultures; Property; Protein Secretion; Proteins; Publishing; Reaction; Reactive Oxygen Species; Role; Sensorineural Hearing Loss; Sensory; Serology; Serum; Signal Transduction; Source; Spectrophotometry; Stimulus; Stress; Sulfhydryl Compounds; Synapses; System; Testing; Therapeutic; Tissues; Transgenic Mice; Zymosan; assault; detection method; detector; extracellular; hearing impairment; hearing measurement; mouse model; neurotrophic factor; neutrophil; noise exposure; novel; oncomodulin; ototoxicity; peripheral nerve regeneration; permanent hearing loss; prevent; prevent hearing loss; rat Pres protein; response; sensor; sound; spiral ganglion; systemic inflammatory response

Title: Outer hair cells and noise-induced hearing loss PROJECT SUMMARY Hearing loss is one of the most common sensory defects affecting millions of people globally. Insults such as noise, age and ototoxic drugs induce stress in hearing organs that leads to cochlear damage including loss of both outer hair cells (OHCs) and inner hair cell (IHC) synapses. Our current hearing measurements are unable to reliably detect low level cochlear damage. Most importantly, it is impossible to identify cochlear stress before irreversible tissue damage and hearing loss have already occurred. Thus, there is thus an urgent need for developing an effective method for detecting early cochlear stress and damage. Mammalian hearing requires mechanical amplification of sound by OHCs to produce high sensitivity and sharp frequency selectivity. OHCs are also the most vulnerable components in the cochlea, and are extremely sensitive to and often damaged from different assaults that cause overloaded Ca2+ and reactive oxygen species (ROS) in OHCs. Thus, OHC’s proteins may be a good choice for uncovering biomarkers to detect early cochlear stress. OHCs carry a unique cytoplasmic calcium-binding protein, oncomodulin (Ocm), at an exceptionally high concentration. Recent data obtained from other peripheral systems suggest that Ocm can be secreted into extracellular space and promote peripheral neural regeneration. Based on the published information and our preliminary data, we propose to investigate whether Ocm could function as an intracellular stress-sensor for OHCs, an extracellular serological biomarker for cochlear stress, and a standby ‘neurotrophic factor’ stored in OHCs. To address our hypothesis, we will determine whether stressful stimuli triggers Ocm secretion in in vitro systems (Aim I). Then, we will measure secreted Ocm in the bloodstream at different times after assaults, along with hearing measurements and anatomic histological analyses of the cochlea and blood. We intend to determine a correlation between cochlear damage, hearing loss, and secreted Ocm in the bloodstream due to different stressful stimuli (Aim II). Finally, spiral ganglion neuron (SGN) primary cell cultures and Ocm transgenic mouse models will be used to test Ocm's ability to promote SGNs' neurite regeneration and survival (Aim III). Our project explores a novel function of OHCs unrelated to their commonly known role in amplification by targeting a critical molecule unique to hearing organs. Therefore, the obtained knowledge regarding Ocm as a standby stress indicator and protector may significantly change the current view of OHCs’ role in cochlear sustainability. Such a novel mechanism is critical for developing therapeutic strategies to detect, prevent, and treat hearing loss.

标题：外毛细胞和噪音引起的听力损失 项目概要 听力损失是影响全球数百万人的最常见的感觉缺陷之一，例如侮辱。 噪音、年龄和耳毒性药物会对听觉器官造成压力，从而导致耳蜗损伤，包括丧失听力。 我们目前无法测量外毛细胞 (OHC) 和内毛细胞 (IHC) 突触。 可靠地检测低水平的耳蜗损伤 最重要的是，之前不可能识别耳蜗应力。 不可逆的组织损伤和听力损失已经发生，因此迫切需要治疗。 开发一种有效的方法来检测早期耳蜗应力和损伤。 哺乳动物的听力需要 OHC 对声音进行机械放大，以产生高灵敏度和锐利的声音 OHC 也是耳蜗中最脆弱的组成部分，并且极其敏感。 经常受到不同攻击的损害，这些攻击会导致体内 Ca2+ 和活性氧 (ROS) 超载 因此，OHC 的蛋白质可能是发现早期耳蜗应激的生物标志物的不错选择。 OHC 携带独特的细胞质钙结合蛋白，癌调节蛋白 (Ocm)，具有极高的 最近从其他外周系统获得的数据表明，Ocm 可以分泌到 根据已发表的信息和我们的研究，细胞外空间并促进周围神经再生。 初步数据显示，我们建议研究 Ocm 是否可以作为细胞内压力传感器 OHC，一种耳蜗应激的细胞外血清学生物标志物，以及储存在中的备用“神经营养因子” 为了验证我们的假设，我们将确定压力刺激是否会在体外触发 Ocm 分泌。 然后，我们将在攻击后的不同时间测量血液中分泌的 Ocm。 我们打算通过听力测量和耳蜗和血液的解剖组织学分析来确定。 由于不同的原因，耳蜗损伤、听力损失和血流中分泌的 Ocm 之间存在相关性 最后，螺旋神经节神经元 (SGN) 原代细胞培养物和 Ocm 转基因小鼠。 模型将用于测试 Ocm 促进 SGN 神经突再生和存活的能力（目标 III）。 通过靶向关键的靶标，探索了 OHC 的一种新功能，与其众所周知的放大作用无关 因此，获得了关于 Ocm 作为备用应力的知识。 指示器和保护器可能会显着改变目前对 OHC 在耳蜗可持续性中的作用的看法。 一种新的机制对于制定检测、预防和治疗听力损失的治疗策略至关重要。