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.

外毛细胞与噪声性听力损失 项目总结 听力损失是影响全球数百万人的最常见的感官缺陷之一。像这样的侮辱 噪声、年龄和耳毒性药物在听力器官中引起应激，导致耳蜗损伤，包括耳聋 外毛细胞和内毛细胞都有突触。我们目前的听力测量不能 以可靠地检测到低水平的耳蜗性损伤。最重要的是，在此之前，不可能识别出耳蜗压力 不可逆转的组织损伤和听力损失已经发生。因此，迫切需要 建立一种检测早期耳蜗应力和损伤的有效方法。 哺乳动物的听力需要外耳细胞对声音进行机械放大才能产生高灵敏度和锐利的声音 频率选择性。毛囊也是耳蜗中最脆弱的成分，并且非常敏感。 并经常受到不同攻击的损害，这些攻击导致体内钙超载和活性氧物种(ROS)超载 毛囊虫。因此，OHC的蛋白质可能是一个很好的选择，以揭示生物标记物，以检测早期耳蜗应激。 OHC携带一种独特的细胞质钙结合蛋白，即肿瘤调节蛋白(OCM)，其含量异常高。 集中精神。从其他外周系统获得的最新数据表明，OCM可以分泌到 细胞外空间，促进周围神经再生。基于已发布的信息和我们的 初步数据，我们建议调查OCM是否可以作为细胞内应力传感器 OCES，一个耳蜗应激的细胞外血清学生物标记物，和一个储存在 毛囊虫。为了解决我们的假设，我们将在体外确定应激刺激是否会触发OCM的分泌 系统(目标I)。然后，我们将在袭击后不同时间测量血液中分泌的OCM， 通过听力测量和耳蜗和血液的解剖组织学分析。我们打算确定 不同病因引起的耳蜗病、听力损失与血流中分泌型OCM的相关性研究 应激性刺激(AIM II)。最后，螺旋神经节神经元(SGN)原代培养和OCM转基因小鼠 模型将被用来测试OCM促进SGN轴突再生和存活的能力(AIM III)。我们的项目 探索OHC的一种新功能，该功能与其在扩增中的已知作用无关，通过靶向关键的 听力器官所特有的分子。因此，所获得的关于OCM作为待命应激的知识 指示器和保护器可能会显著改变目前对OHC在耳蜗可持续性中的作用的看法。是这样的 一种新的机制对于开发检测、预防和治疗听力损失的治疗策略至关重要。