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）：内耳及其细胞内部的流体室之间的电势和化学组成存在差异。由此产生的电化学梯度充当电池，可为外毛板中的基于膜的电动机供电。电动机与其他生物电动机的不同之处是因为它将电势的差异直接转化为机械力，而不是利用存储在细胞内的化学能。结果，它可以在非常高的频率下产生力，并且外毛细胞使用其“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了解分子和细胞水平上外毛细胞运动的生物学和物理基础。该机理位于细胞的新型侧壁中，这是一种100纳米厚的三层结构，由两个膜组成，它们之间夹着一个细胞骨架网络。电动机的最佳性能需要膜蛋白prestin，细胞内氯化物，低膜胆固醇和完整的侧壁。该项目期间的具体目标是评估这些功能中的每一个。普雷斯汀属于膜蛋白家族，促进阴离子（氯化物等负电离子）通过细胞膜运动。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护的贡献。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）和膜反应性剂（例如奎宁）一起工作，以调节电荷进入膜的电荷运动。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全部使用。这些研究将揭示电动机的频率响应，并显示在内耳频率高频率下的声音如何扩增。了解Prestin功能将提供有关其亲密家庭成员的阴离子运输特性的新信息，这些信息与肺，胰腺，肾脏，肾脏，结肠和内耳有关的疾病牵涉到与阴离子稳态相关的疾病。阐明外毛细胞运动基础的生物学和物理原理将有助于生物纳米技术的新兴领域。这些研究可能会导致听力受损的治疗干预措施改善。这些研究直接适用于理解为什么耳聋遵循外毛细胞的丧失。我们的结果将解释如何在高频上增强内耳振动以改善听力。了解膜蛋白prestin功能将如何提供有关其亲密家庭成员在内的阴离子运输特性的新信息，包括Pendrin，其突变也导致听力损失。除了对听力受损的潜在益处外，阐明外部毛细胞运动基础的物理原理还将有助于生物纳米技术的新兴领域。