Studies in cochlear hair cell transduction

耳蜗毛细胞转导研究

• 批准号: 8336849
• 负责人: Mary Ann Cheatham
• 金额: $ 57.19万
• 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/8336849
• 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; computerized data processing; design; electrical potential; improved; mouse model; oncomodulin; rat Pres protein; receptor; research study; response; 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.

抽象的 该提案的目的是进一步了解外毛细胞（OHC）功能。由于这些 感觉受体细胞是正常灵敏度和频率选择性所必需的，因此定义 蛋白质网络参与建立外周信号处理的这些基本特征。我们都知道 OHC 生理机能受到源自内侧橄榄耳蜗 (MOC) 通路的传出信号的调节 （桂南，1996）。响应乙酰胆碱 (ACh) 的释放，细胞内钙增加， 随后钾的流出使细胞超极化。膜电位的这种变化被认为 调整耳蜗放大器。其他钙相关事件和蛋白质磷酸化可能会 是细胞骨架和 OHC 运动蛋白 prestin 变化的基础。影响 静纤毛中的机电转导（MET）也与此有关。推测表明缓慢 这些变化的各个方面对于保护高声级的 OHC 非常重要。然而，快速的变化， 被认为可以改善噪音中的听力。尽管研究了 50 多年（Rasmussen，1946； Galambos，1956），这些变化背后的机制很大程度上是假设的。因此，我们正在使用 各种基因改造的小鼠来定义包含这种机械反馈回路的蛋白质网络。这 使用细胞骨架改变、prestin缺失或无功能、钙结合蛋白缺陷和 MET 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 途径激活相关的 OHC 调节的快慢方面。通过结合 使用体外 OHC 和分子测量基底膜力学和耳蜗电位 通过分析，可以了解 OHC 功能快速和快速变化所需的机制 缓慢的时间尺度。