Intracochlear Electrochemical Gradients

耳蜗内电化学梯度

• 批准号: 7525863
• 负责人: WILLIAM E BROWNELL
• 金额: $ 58.47万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7525863
• 关键词: Address; Affect; Anatomy; Anions; Binding; Bioinformatics; Biological; Biological Assay; Biomedical Engineering; Biophysics; Cavia; Cell membrane; Cell physiology; Cells; Charge; Chemicals; Chemistry; Chloride Ion; Chlorides; Cholesterol; Cochlea; Colon; Cytoplasm; Data; Dependence; Development; Disease; Docosahexaenoic Acids; Electric Capacitance; Embryo; Environment; Family; Family member; Frequencies; Genus Cola; Goals; Hair Cells; Hearing; Homeostasis; Human; Hydrophobicity; Individual; Ions; Kidney; Labyrinth; Lateral; Lead; Length; Lipids; Liquid substance; Lung; Maintenance; Measurement; Measures; Mechanics; Membrane; Membrane Proteins; Modeling; Molecular; Molecular and Cellular Biology; Motor; Movement; Mutation; Nanotechnology; Nature; Neurosciences; Numbers; Outer Hair Cells; Pancreas; Performance; Physics; Property; Quinine; Series; Site; Structure; Therapeutic Intervention; Thick; Time; Work; base; deafness; density; design; electrical potential; electrical property; glycosylation; hearing impairment; improved; multidisciplinary; mutant; nanometer; novel; rat Pres protein; research study; response; salicylate; size; sound; vibration; voltage

DESCRIPTION (provided by applicant): There are differences in electrical potential and chemical composition between the fluid compartments of the inner ear and the inside of its cells. The resulting electrochemical gradients act as a battery to power a membrane-based motor in the outer hair cell. The motor differs from other biological motors because it converts a difference in electrical potential directly into a mechanical force rather than utilizing chemical energy stored within cells. As a result it can generate force at very high frequencies and the outer hair cell uses its "electric motor" to enhance the sensitivity and frequency selectivity of hearing. The goal of our multidisciplinary team is to understand the biological and physical basis of the outer hair cell motor at the molecular and cellular level. The mechanism resides in the cell's novel lateral wall, a 100 nanometer thick, three-layer structure composed of two membranes with a cytoskeletal network sandwiched between them. Optimal performance of the motor requires the membrane protein prestin, intracellular chloride, low membrane cholesterol and an intact lateral wall. The specific objectives of this project period are to evaluate each of these features. Prestin belongs to a family of membrane proteins that facilitate the movement of anions (negatively charged ions such as chloride) through the cell membrane. The structure and function of prestin are analyzed and the contributions of the lateral wall membranes to the modulation and maintenance of the electrochemical gradients necessary for cell function are examined. Coordinated theoretical and experimental approaches are used to identify how prestin works together with anions, other membrane components (including cholesterol) and membrane reactive agents (such as quinine) to modulate the movement of electrical charge into and out of the membrane. Molecular and cellular biology, bioinformatics, biophysics, neuroscience, chemical physics, and bioengineering approaches will all be used. These studies will reveal the frequency response of the motor and show how sound is amplified at high frequencies in the inner ear. Understanding prestin function will provide new information on the anion transport properties of its close family members, which are implicated in diseases associated with anion homeostasis within the lung, pancreas, kidney, colon and inner ear. Elucidation of the biological and physical principles underlying the outer hair cell motor will contribute to the emerging field of biological nanotechnology. These studies may lead to improved therapeutic interventions for the hearing impaired. The studies are directly applicable to understanding why deafness follows the loss of outer hair cells; our results will explain how inner ear vibrations are enhanced at high frequencies to improve hearing. Understanding how the membrane protein prestin functions will provide new information on the anion transport properties of its close family members including pendrin, a mutation of which also leads to hearing loss. In addition to potential benefits to the hearing impaired, elucidation of the physical principles underlying the outer hair cell motor will contribute to the emerging field of biological nanotechnology.

描述（由申请人提供）：内耳的流体室与其细胞内部之间的电位和化学成分存在差异。由此产生的电化学梯度充当电池，为外毛细胞中的基于膜的电机提供动力。该电机与其他生物电机不同，因为它将电势差直接转换为机械力，而不是利用细胞内存储的化学能。因此，它可以产生非常高频率的力，外毛细胞利用其“电动机”来增强听力的灵敏度和频率选择性。我们多学科团队的目标是在分子和细胞水平上了解外毛细胞运动的生物学和物理基础。该机制存在于细胞的新颖侧壁中，这是一种 100 纳米厚的三层结构，由两层膜组成，两膜之间夹有细胞骨架网络。运动的最佳性能需要膜蛋白 prestin、细胞内氯、低膜胆固醇和完整的侧壁。该项目期间的具体目标是评估每个功能。 Prestin 属于膜蛋白家族，可促进阴离子（带负电的离子，例如氯离子）穿过细胞膜。分析了 prestin 的结构和功能，并检查了侧壁膜对细胞功能所需的电化学梯度的调节和维持的贡献。协调的理论和实验方法用于确定 prestin 如何与阴离子、其他膜成分（包括胆固醇）和膜反应剂（例如奎宁）一起调节电荷进出膜的运动。分子和细胞生物学、生物信息学、生物物理学、神经科学、化学物理学和生物工程方法都将被使用。这些研究将揭示电机的频率响应，并展示声音如何在内耳中以高频放大。了解 prestin 功能将提供有关其近亲的阴离子转运特性的新信息，这些特性与肺、胰腺、肾脏、结肠和内耳内阴离子稳态相关的疾病有关。阐明外毛细胞马达的生物学和物理原理将有助于新兴的生物纳米技术领域。这些研究可能会改善听力受损者的治疗干预措施。这些研究可直接用于理解为什么耳聋会随着外毛细胞的丧失而发生。我们的结果将解释内耳振动如何在高频下增强以改善听力。了解膜蛋白 prestin 的功能将提供有关其近亲家族成员（包括 pendrin）阴离子转运特性的新信息，pendrin 的突变也会导致听力损失。除了对听力受损者的潜在好处外，阐明外毛细胞运动的物理原理还将有助于新兴的生物纳米技术领域。