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Studies in cochlear hair cell transduction

耳蜗毛细胞转导研究

基本信息

批准号：
8236321
负责人：
Mary Ann Cheatham
金额：
$ 49.87万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
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/8236321
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 Receptor Cell Receptor Signaling Reflex action Research Support Sensory Receptors Signal Transduction Stereocilium Time Work 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

项目摘要

DESCRIPTION (provided by applicant): 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 acetylcholine (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. PUBLIC HEALTH RELEVANCE: Of the well over 30 million people in the US with auditory problems, the vast majority have defects in outer hair cell (OHC) function. These sensory receptor cells within the cochlea are required for normal sensitivity and frequency selectivity. Because their loss or malfunction results in major processing difficulties, our work on both normal and genetically altered OHCs is required in order to improve clinical outcomes.

描述（由申请人提供）：本提案的目的是进一步了解外毛细胞（OHC）的功能。由于这些感觉受体细胞是正常的敏感性和频率选择性所必需的，因此定义参与建立外周信号处理的这些基本特征的蛋白质网络是很重要的。已知OHC生理学由源自内侧橄榄耳蜗（MOC）通路的传出信号调节（Guinan，1996）。响应于乙酰胆碱（ACh）的释放，细胞内钙增加，随后钾的流出使细胞超极化。这种膜电位的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可能是细胞骨架和普雷斯廷（OHC的运动蛋白）变化的基础。还涉及静纤毛中的机械电转导（MET）的影响。推测表明，这些变化的缓慢方面对于在高声级下保护OHC很重要。然而，这种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（Rasmussen，1946; Galambos，1956），这些变化的机制基本上是假设的。因此，我们正在使用各种基因改变的小鼠来定义包括这种机械反馈回路的蛋白质网络。使用细胞骨架改变、普雷斯廷缺失或无功能、钙结合蛋白缺陷和MET各方面功能障碍的小鼠，将使我们能够表征与MOC途径激活相关的OHC调节的快和慢方面相关的细胞组分。通过将基底膜力学和耳蜗电位的测量与体外OHC和分子分析相结合，可以了解OHC功能在快速和慢速时间尺度上变化所需的机制。公共卫生相关性：在美国超过3000万有听觉问题的人中，绝大多数都有外毛细胞（OHC）功能缺陷。耳蜗内的这些感觉感受器细胞是正常敏感性和频率选择性所必需的。由于它们的丢失或故障导致主要的处理困难，我们需要对正常和基因改变的OHC进行研究，以改善临床结果。