Mechanics of the Cochlear Outer Hair Cell

外毛细胞（OHC）是正常哺乳动物听力所必需的。 它们通过将电能转化为机械能的能力来放大内耳中的声音振动。干扰力产生机制会导致听力损失。 产生这种力的机制尚不清楚，但它存在于OHC的侧壁。外侧壁是一个优雅的三层复合纳米结构，在OHC中与力的产生一样在结构上引人注目。 该提案的长期目标是了解外侧壁的纳米级机械解剖结构促进OHC电机械力产生的机制，特别是在声频下。实验和理论方法将确定侧壁的组织如何引导机械力沿着OHC的轴线并补偿粘性阻尼。 我们将研究两种可能的分子机制的特点，一种是由马达蛋白的平面内构象变化驱动，另一种是由平面外挠曲电弯曲驱动。 将使用当代电生理学和先进的光学技术。 具体目标1将检验侧壁的弹性特性随膜电位变化的假设。 将使用光镊并在不同保持电位下的微量移液器抽吸和渗透挑战条件下测量局部细胞壁应变。具体目标2将使用偏振倏逝光照明确定响应于OHC的主动和被动长度变化的质膜平面外弯曲的幅度。 具体目标3是确定细胞侧壁细胞骨架在维持细胞形状和传递主动力中的作用。 在细胞骨架的损伤和恢复过程中细胞的电动反应将允许确定其主动力传递。 具体目标4将导致一个完整的纳米级模型的OHC积极的力量生产。 它将包括三层外侧壁机械解剖结构的完整动态描述。 该模型将使我们能够预测力变形关系的OHC在声波频率，它将满足所有的标准OHC力的生产机制。

Outer hair cells (OHC) are required for normal mammalian hearing. They amplify sound vibrations in the inner ear through their ability to convert electrical to mechanical energy. Interfering with the force generating mechanism results in hearing loss. The mechanism responsible for this force production is unknown but it resides in the OHC's lateral wall. The lateral wall is an elegant, three layered, composite nanostructure that is as structurally conspicuous in the OHC as the force production. The long-term goal of this proposal is to understand the mechanism by which the nanoscale mechanical anatomy of the lateral wall facilitates OHC electomechanical force production, particularly at acoustic frequencies. Experimental and theoretical approaches will determine how the organization of lateral wall directs mechanical force along the OHC's axis and compensates for viscous damping. We will investigate the characteristics of two plausible molecular mechanisms, one driven by in-plane conformational changes of a motor protein and the other by out-of-plane flexoelectric bending. Contemporary electrophysiological and advanced optical techniques will be used. Specific Aim 1 will test the hypothesis that the elastic properties of the lateral wall vary with membrane potential. Local cell wall strains will be measured with optical tweezers and under conditions of micropipet aspiration and osmotic challenge at different holding potentials. Specific aim 2 will establish the magnitude of out-of-plane bending of the plasma membrane in response to active and passive length changes of the OHC using polarized evanescent illumination. Specific aim 3 is to establish the role of the lateral wall cytoskeleton in maintaining cell shape and transmitting active forces. The cell's electromotile response during damage and recovery of the cytoskeleton will allow a determination of its active force transmission. Specific aim 4 will result in a complete nanoscale model of OHC active force production. It will include full dynamic description of the trilaminar lateral wall mechanical anatomy. The model will allow us to predict force-deformation relationships for the OHC at acoustic frequencies and it will meet all the criteria for the mechanism of OHC force production.