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放大内耳的声音振动。干扰力的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。侧壁是一个优雅的三层复合纳米结构，在OHC结构上与力的产生一样显眼。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热碳电机械力产生的机制，特别是在声波频率下。实验和理论方法将确定侧壁的组织如何沿着OHC轴引导机械力并补偿粘性阻尼。我们将研究两种可能的分子机制的特征，一种是由马达蛋白的面内构象变化驱动的，另一种是由面外挠曲电弯曲驱动的。将使用当代电生理学和先进的光学技术。特异性目标1将检验外侧壁弹性特性随膜电位变化的假设。在不同保持电位下，用光学镊子和微移液管吸吸和渗透挑战条件下测量局部细胞壁菌株。具体目标2将建立质膜的面外弯曲的大小，以响应主动和被动长度变化的OHC使用偏振倏逝照明。具体目的3是建立外壁细胞骨架在维持细胞形状和传递主动力方面的作用。在细胞骨架损伤和恢复过程中，细胞的电运动反应将使其主动力传递的测定成为可能。具体目标4将产生一个完整的热盐主动力产生的纳米尺度模型。它将包括三椎体外侧壁机械解剖的完整动态描述。该模型将使我们能够预测声频下热砂的力-变形关系，并且它将满足热砂力产生机制的所有标准。

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.