Intracochlear Electrochemical Gradients

耳蜗内电化学梯度

• 批准号: 9336287
• 负责人: WILLIAM E BROWNELL
• 金额: $ 49.43万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336287
• 关键词: Acetylcholine; Adult; Aging; Amplifiers; Animals; Behavior; Biomedical Engineering; Biophysics; Cavia; Cell Shape; Cell Signaling Process; Cell membrane; Cells; Charge; Chemicals; Chloride Ion; Chlorides; Chlorpromazine; Cholesterol; Cochlea; Data; Development; Endolymph; Environment; Exhibits; Failure; Frequencies; Genes; Goals; Hair Cells; Health; Hearing; Individual; Interphase Cell; Labyrinth; Lateral; Length; Liquid substance; Location; Measures; Mechanics; Membrane; Membrane Lipids; Membrane Potentials; Membrane Proteins; Modeling; Molecular; Motor; Movement; Neurosciences; Neurotransmitters; Organ; Outer Hair Cells; Output; Passive Ion Transport; Performance; Pharmaceutical Preparations; Phase; Physics; Physiological; Production; Property; Receptor Cell; Rest; Role; Salicylic Acids; Structure; System; Techniques; Therapeutic Intervention; base; deafness; density; design; electrical potential; electrical property; hearing impairment; improved; in vivo; male; model development; patch clamp; pressure; public health relevance; rat Pres protein; receptor; response; sex; sound; theories; voltage; voltage clamp

DESCRIPTION (provided by applicant): There are differences in electrical potential and chemical composition between the fluids of the inner ear and the insides of its cells. These electrochemical gradients are the battery providing power to a membrane-based motor essential for hearing. Systematic differences in the strength of the battery predict gradients in motor function within the inner ear. Recent findings have confirmed that the functional density decreases on going from high to low frequency regions of the inner ear and suggest gradients in motor function along the length of individual outer hair cells. We will investigate both the organ and cellular level gradients to achieve our goal of characterizing the mechanisms that maintain motor function and cochlear amplification at optimal performance. The membrane protein prestin is an integral part of the motor and its presence results in currents that are out of phase with the AC voltage that evokes them. Membrane voltage changes have similar effects on prestin-associated currents and outer hair cell length changes. The voltage of maximum gain for both the currents and length changes should be maintained close to the in vivo resting potential to assure that outer hair cell receptor potentials generate maximal electromechanical forces. A variety of external manipulations modify the voltage of maximum gain of both functions. Some modifiers act on the membrane directly; these include changes in holding potential, tension, and cholesterol as well as a variety of membrane reactive drugs such as salicylate and chlorpromazine. Changes of chloride ion concentration and the neurotransmitter acetylcholine also modify motor performance. Aim 1 will determine whether there is a tonotopic gradient in the voltage of maximum gain by recording from cells isolated from all cochlear turns. Aim 2 will measure the gradients in prestin-function along the length of individual outer hair cells and determine the contribution of the non-homogeneous motor distribution to the fine structure of whole cell currents. An aspiration pipette will mechanically deform the membrane at different locations along the lateral wall and the resulting charge movement will be measured with a whole-cell patch pipette. Aim 3 will examine interactions between modifiers and compare the data to predictions of a systems based model of the outer hair cell. Aims 1&2 will reveal how the outer hair cell membrane potential is established under physiologic conditions and clarify the differences in prestin function between the high and low frequency regions of the inner ear. Data from all three aims will be used to clarify the role of prestin's transporter properties in the motr mechanism. Cell biophysics, neuroscience, chemical physics, and bioengineering approaches will be used. The studies will contribute to improved therapeutic interventions for the hearing impaired particularly loss resulting from decreased output or failure of the cochlear battery. The impact, if any, of maturation and sex on prestin-function will also be identified.

描述（由申请人提供）：内耳及其细胞内部流体之间的电势和化学组成存在差异。这些电化学梯度是为基于膜的电动机提供电力的电池。电池强度的系统差异可以预测内耳内部运动功能的梯度。最近的发现证实，功能密度从内耳的高频区域到低频区域降低，并暗示沿单个外毛细胞长度的运动功能梯度。我们将研究器官和细胞水平梯度，以实现表征在最佳性能下保持运动功能和人工耳蜗的机制的目标。膜蛋白prestin是电动机不可或缺的一部分，其存在会导致电流不相同 用交流电压唤起它们。膜电压变化对Prestin相关电流和外毛细胞长度的变化具有相似的影响。电流和长度变化的最大增益电压应保持在体内静止的潜力附近，以确保外毛细胞受体电位会产生最大的机电力。各种外部操作修改了这两个功能的最大增益的电压。一些修饰符直接在膜上起作用。这些包括持有潜力，张力和胆固醇的变化以及多种膜反应性药物，例如水杨酸盐和氯丙嗪。氯离子浓度和神经递质乙酰胆碱的变化也改变了运动性能。 AIM 1将通过从所有耳蜗旋转的细胞中记录最大增益的电压来确定最大增益电压是否存在吨位梯度。 AIM 2将测量沿单个外毛细胞长度的Prestin功能中的梯度，并确定非均匀运动分布对整个细胞电流的细胞结构的贡献。抽吸移液管将在沿侧壁的不同位置机械变形膜，并使用全细胞贴片移液管来测量所得的电荷运动。 AIM 3将检查修饰符之间的相互作用，并将数据与基于系统外毛细胞模型的预测进行比较。 AIMS 1和2将揭示如何在生理条件下建立外毛细胞膜电位，并阐明内耳高频和低频区域之间的Prestin功能差异。来自所有三个目标的数据将用于阐明Prestin转运蛋白特性在MOTR机制中的作用。将使用细胞生物物理学，神经科学，化学物理学和生物工程方法。这些研究将有助于改善听力的治疗干预措施，这特别是由于耳蜗电池的产出或故障导致的损失尤其受损。还将确定对Prestin功能的成熟和性别的影响（如果有的话）。