Studies in cochlear hair cell transduction

耳蜗毛细胞转导研究

• 批准号: 8721389
• 负责人: Mary Ann Cheatham
• 金额: $ 47.91万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721389
• 关键词: Acetylcholine; Acoustic Nerve; Amplifiers; Animals; Auditory; Basilar Membrane; Binding; Biochemical; Biological Assay; Calcium; Calcium-Binding Proteins; Calmodulin; Cell physiology; Cells; Clinical; Cochlea; Complement; Cytoskeleton; Defect; Dendrites; Development; Disease; Efferent Neurons; Event; Excision; Exhibits; Feedback; Foundations; Frequencies; Generations; Grant; Hair; Hair Cells; Hearing; In Vitro; Individual; Knock-out; Knockout Mice; Learning; Length; Location; Measurement; Measures; Mechanics; Medial; Mediating; Membrane; Membrane Potentials; Modification; Molecular; Molecular Analysis; Motor; Mus; Mutant Strains Mice; Nerve Fibers; Neurobiology; Noise; Outcome; Outer Hair Cells; Pathway interactions; Pattern; Peripheral; Phosphorylation; Potassium; Process; Property; Proteins; Public Health; Receptor Cell; Receptor Signaling; Reflex action; Research Support; Sensory Receptors; Signal Transduction; Stereocilium; Time; Work; abstracting; base; cell motility; cellular transduction; design; electrical potential; improved; mouse model; oncomodulin; rat Pres protein; receptor; research study; response; signal processing; sound; tectorial membrane

Abstract The purpose of this proposal is to further our understanding of outer hair cell (OHC) function. Since these sensory receptor cells are required for normal sensitivity and frequency selectivity, it is important to define the protein networks involved in establishing these essential features of peripheral signal processing. It is known that OHC physiology is modulated by efferent signals originating in the medial olivocochlear (MOC) pathway (Guinan, 1996). In response to the release of acetycholine (ACh), intracellular calcium increases and the subsequent outflow of potassium hyperpolarizes the cell. This change in membrane potential is thought to adjust the cochlear amplifier. Additional calcium-associated events and protein phosphorylation are likely to underlie changes in the cytoskeleton and in prestin, the OHC's motor protein. An influence on mechanoelectrical transduction (MET) in the stereocilia is also implicated. Speculation suggests that slow aspects of these changes are important for protecting OHCs at high sound levels. The fast changes, however, are thought to improve hearing in noise. Although studied for well over 50 years (Rasmussen, 1946; Galambos, 1956), the mechanisms underlying these changes are largely hypothetical. We are, therefore using various genetically altered mice to define the protein networks comprising this mechanical feedback loop. The use of mice with altered cytoskeleton, missing or nonfunctional prestin, defects in calcium-binding proteins and malfunction in various aspects of MET, will allow us to characterize cellular components associated with both fast and slow aspects of OHC modulation associated with activation of the MOC pathway. By combining measurements of basilar membrane mechanics and cochlear potentials with in vitro OHC and molecular analysis, it is possible to learn which mechanisms are required for changes in OHC function on both fast and slow time scales.

摘要 本研究的目的是进一步了解外毛细胞（OHC）的功能。由于这些 感觉感受器细胞是正常的敏感性和频率选择性所必需的，重要的是要定义 蛋白质网络参与建立外周信号处理的这些基本特征。已知 OHC生理学受源自内侧橄榄耳蜗（MOC）通路的传出信号调节 （Guinan，1996年）。作为对乙酰胆碱（ACh）释放的反应，细胞内钙离子增加， 随后钾的流出使细胞超极化。膜电位的这种变化被认为是 调整耳蜗放大器。额外的钙相关事件和蛋白磷酸化很可能 是细胞骨架和普雷斯廷（OHC的运动蛋白）变化的基础。影响到 静纤毛中的机械电转导（MET）也涉及。据推测， 这些变化的各个方面对于在高声级下保护OHC是重要的。然而，快速的变化， 被认为可以改善噪音中的听力。虽然研究了50多年（拉斯穆森，1946年; Galambos，1956），这些变化背后的机制在很大程度上是假设。因此，我们使用 各种基因改变的小鼠来定义包含这种机械反馈回路的蛋白质网络。的 具有改变的细胞骨架、缺失或无功能的普雷斯廷、钙结合蛋白缺陷和 在MET的各个方面的故障，将使我们能够表征与两者相关的细胞成分 与MOC通路激活相关的OHC调节的快和慢方面。通过组合 用体外OHC和分子生物学方法测量基底膜力学和耳蜗电位 通过分析，可以了解OHC功能的快速和快速变化所需的机制， 缓慢的时间尺度