Investigating the mechanism of fast adaptation in auditory hair bundles.

研究听觉毛束的快速适应机制。

• 批准号: 8784538
• 负责人: JULIEN AZIMZADEH
• 金额: $ 4.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-25 至 2018-04-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784538
• 关键词: 19 year old; Acoustic Nerve; Adult; Affinity; American; Amplifiers; Auditory; Auditory system; Binding; Calcium; Calcium ion; Calmodulin; Cells; Child; Detection; Development; Diffusion; Disease; Ear; Elements; Environment; Esthesia; Feedback; Flying body movement; Frequencies; Future; Genetic; Gentamicins; Glass; Grant; Hair; Hair Cells; Health; Hearing; Height; Insecta; Investigation; Labyrinth; Link; Mechanics; Modeling; Molecular; Motion; Myosin ATPase; Neuraxis; Noise; Organelles; Output; Pathology; Pharmaceutical Preparations; Positioning Attribute; Preparation; Probability; Process; Property; Proteins; Rana catesbeiana; Reporting; Role; Side; Signal Transduction; Stereocilium; Stimulus; Syncope; Testing; Theoretical model; Work; auditory stimulus; base; cell motility; detector; flexibility; hearing impairment; insight; internal control; meter; novel; novel strategies; novel therapeutic intervention; nucleotide analog; photolysis; potassium ion; pressure; public health relevance; receptor; research study; sound; therapeutic target

DESCRIPTION (provided by applicant): With 17% of American adults (36 million) reporting some degree of hearing loss and 14.9% of 6-19 year-old children displaying hearing loss of greater than 16 dB in at least one ear, auditory deficits constitute a significant health concern. These deficits can be genetic, noise-induced, or drug- induced, and often involve hair cells, our auditory detectors and amplifiers. Understanding the mechanisms underlying normal auditory sensation is thus essential to developing new therapeutic interventions for these deficits. This study proposes to elucidate the molecular basis of fast adaptation, one of the processes underlying sound detection by hair bundles, our mechanosensitive organelles. Fast adaptation is a rapid calcium-sensitive negative feedback mechanism that resets the hair bundle's operative range after stimulation. In this study, I propose a novel approach wherein hair bundles are permeabilized to allow direct control of the internal calcium concentration. The calcium concentration will be increased through photolysis of caged calcium compounds, granting me exquisite temporal and spatial control over it, with minimal diffusion-related delays. I will detec a hair bundle's calcium-dependent motion with a flexible glass probe attached to the hair bundle's side. This preparation will allow me to determine whether fast adaptation occurs through one of the several currently proposed theoretical models, and to construct a new model if not. I will then identify a molecular candidate for the mechanism of fast adaptation by studying its properties, such as calcium affinity, and modulating specific candidates known to be present in the mechanotransduction apparatus, such as myosin, calmodulin, and the transmembrane-channel-like proteins (TMC 1 and 2). Elucidating the mechanism of fast adaptation will be a significant development in our understanding of hearing, and will open the door for future investigations of fast adaptation's role in the active process.

描述（由申请人提供）：17% 的美国成年人（3600 万）报告有一定程度的听力损失，14.9% 的 6-19 岁儿童至少一只耳朵听力损失超过 16 dB，存在听觉缺陷构成重大健康问题。这些缺陷可能是遗传性的、噪音引起的或药物引起的，并且通常涉及毛细胞、我们的听觉探测器和放大器。因此，了解正常听觉的机制对于开发针对这些缺陷的新治疗干预措施至关重要。这项研究旨在阐明快速适应的分子基础，这是通过发束（我们的机械敏感细胞器）进行声音检测的过程之一。快速适应是一种快速的钙敏感负反馈机制，可在刺激后重置发束的操作范围。在这项研究中，我提出了一种新方法，其中对发束进行透化以允许直接控制内部钙浓度。钙浓度将通过笼中钙化合物的光解而增加，从而使我能够对其进行精确的时间和空间控制，并将与扩散相关的延迟最小化。我将使用连接到发束侧面的柔性玻璃探针来检测发束的钙依赖性运动。这种准备工作将使我能够确定当前提出的几个理论模型之一是否会发生快速适应，如果没有，则构建一个新模型。然后，我将通过研究其特性（例如钙亲和力）并调节已知存在于力转导装置中的特定候选分子（例如肌球蛋白、钙调蛋白和跨膜通道样蛋白）来确定快速适应机制的候选分子。 （TMC 1 和 2）。阐明快速适应机制将是我们对听力理解的重大发展，并将为未来研究快速适应在主动过程中的作用打开大门。