IONIC CHANNELS OF HAIR CELLS

毛细胞的离子通道

• 批准号: 2125437
• 负责人: ALBERT JAMES HUDSPETH
• 金额: $ 25.66万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2125437
• 关键词: Rana; alternatives to animals in research; biological signal transduction; calcium channel; calcium flux; cochlea; confocal scanning microscopy; ear hair cell; electrical conductance; environmental adaptation; hearing; labyrinthine membrane; mechanical pressure; mechanoreceptors; myosins; neurotransmitter metabolism; nucleotide analog; otocyst /otolith; psychoacoustics; sensorineural hearing loss; sound frequency; voltage /patch clamp; voltage gated channel

Nearly thirty million people in the United States suffer from impaired hearing or balance. The majority of these individuals experience "sensorineural" deficits, which largely ensue from the derangement or death of the ear's sensory receptors, the hair cells. The proposed experiments are meant to provide a better understanding of the normal transduction process by which hair cells capture mechanical stimuli - sounds in the cochlea, and accelerations in the vestibular apparatus - and transform them into electrical responses that can be interpreted by the brain. The long-term goal of the studies is to recognize how hearing and balance are impaired by genetic abnormalities, infections, ototoxic drugs, traumatic sounds, and ageing, and thus to develop rational strategies for the prevention or amelioration of hearing and balance problems. The experiments proposed in this application deal with five principal issues. Each hair cell possesses an adaptation mechanism that constantly sets its sensitive hair bundle in an optimal position to respond to mechanical stimulation. It has been proposed that adaptation involves the activity of a molecular motor, perhaps a member of the myosin family. The first proposed studies are meant to determine precisely the forces produced by the putative motor during adaptation. A second, related set of experiments will explore the sensitivity of the motor to nucleotide analogues that are expected to interfere with the activity of myosin-like molecules. A third topic to be explored is the contribution of hair bundles to the mechanical properties of the receptor organs in which they reside. The studies planned in this context should indicate whether hair bundles could influence the basilar membrane's motion in the cochlea and the movement of otolithic membranes and cupulae in the vestibular labyrinth. Under in vitro conditions, a hair bundle can display rapid, twitching motions triggered by mechanical inputs. These transients are the fourth subject of investigation: how do they arise, what is their timecourse and dependence upon stimulation, and are they energetic enough to contribute to amplification of stimuli in the ear? In addition to responding to mechanical inputs, hair cells have two other important roles in information processing: they effect tuning by selecting inputs at frequencies of greatest behavioral relevance, and they synaptically transmit signals to afferent nerve fibers. The final topic of the proposed research deals with the ion channels key to both processes, voltage-activated Ca2+ channels on a hair cell's basolateral surface. An effort will be made to determine whether clusters of these channels occur at the sites of transmitter release. The results will clarify how Ca2+ entry mediates transmitter release, and aid in our understanding of frequency tuning by electrical resonance.

美国近三千万人患有残疾 听力或平衡。 这些人中的大多数都经历过 “感觉神经性”缺陷，主要是由于精神错乱或 耳朵的感觉受体（毛细胞）死亡。 拟议的 实验的目的是为了更好地理解正常情况 毛细胞捕获机械刺激的转导过程 - 耳蜗中的声音和前庭装置中的加速度 - 并将它们转化为可以解释的电响应 大脑。 研究的长期目标是了解听力如何 和平衡因遗传异常、感染、耳毒性而受损 药物、创伤性声音和衰老，从而培养理性 预防或改善听力和平衡的策略 问题。 本申请中提出的实验涉及五个主要问题 问题。 每个毛细胞都具有适应机制，不断地 将其敏感的发束设置在最佳位置以响应 机械刺激。 有人提出，适应涉及 分子马达的活​​动，可能是肌球蛋白家族的成员。 第一项提议的研究旨在精确确定力 由假定的电机在适应过程中产生。 第二组相关的 实验将探索电机对核苷酸的敏感性 预计会干扰肌球蛋白样活性的类似物 分子。 第三个要探讨的话题是头发的贡献 束与它们所在的受体器官的机械特性有关 居住。 在这方面计划的研究应该表明头发是否 束可以影响耳蜗中基底膜的运动 前庭耳石膜和耳罩的运动 迷宫。 在体外条件下，发束可以表现出快速、 由机械输入触发的抽搐运动。 这些瞬变是 第四个研究主题：它们是如何产生的，它们是什么 时间进程和对刺激的依赖性，以及他们是否足够精力充沛 有助于放大耳朵的刺激？ 除了响应机械输入外，毛细胞还有另外两个功能 在信息处理中的重要作用：它们通过以下方式影响调整 以行为相关性最大的频率选择输入，以及 它们将突触信号传递至传入神经纤维。 决赛 拟议研究的主题涉及对两者都至关重要的离子通道 毛细胞基底外侧上的电压激活 Ca2+ 通道 表面。 将努力确定这些集群是否 通道发生在发射器释放的位置。 结果将 阐明 Ca2+ 进入如何介导递质释放，并帮助我们 了解通过电谐振进行频率调谐。