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）：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非常重要。众所周知，OHC 生理学受到源自内侧橄榄耳蜗 (MOC) 通路的传出信号的调节 (Guinan, 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。人们认为膜电位的这种变化可以调节耳蜗放大器。其他与钙相关的事件和蛋白质磷酸化可能是细胞骨架和 OHC 运动蛋白 prestin 发生变化的基础。还涉及对静纤毛中的机电转导（MET）的影响。据推测，这些变化的缓慢方面对于在高声级下保护 OHC 很重要。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，我们使用各种经过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。使用具有改变的细胞骨架、缺失或无功能的 prestin、钙结合蛋白缺陷以及 MET 各个方面的功能障碍的小鼠，将使我们能够表征与 MOC 激活相关的 OHC 调节的快速和慢速方面相关的细胞成分。途径。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，可以了解在快速和慢速时间尺度上 OHC 功能变化所需的机制。公共健康相关性：美国有超过 3000 万有听力问题的人，其中绝大多数存在外毛细胞 (OHC) 功能缺陷。耳蜗内的这些感觉受体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会导致重大的处理困难，因此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。