Cochlear mechanics in the mouse

 描述(申请人提供)：声压在哺乳动物耳蜗区产生力量，最终产生一种沿耳蜗管纵向传播的振动行波。这一过程区别于非哺乳动物耳蜗组织的关键特征是放大，即数千个外毛细胞产生的力使行波变得尖锐并放大。我们的首要目标是了解形成Corti器官的3D多细胞和无细胞排列的复杂生物力学如何协同工作来创造耳蜗放大。具体地说，我们将确定这一过程，它源于宽调的基底膜，如何创造尖锐的频率调谐和高灵敏度。这个问题在基础科学层面上意义重大，因为这些生物物理过程是以精确的频率分辨率听到空气中分子布朗运动上方的声音的能力的基础。这个问题仍然没有得到解决，而且具有重要的临床意义，因为听力损失通常是由于耳蜗放大能力的丧失造成的。我们的中心假设是，除了基底膜和周围流体的被动力学所提供的过滤之外，Corti器官的机械特性还提供了额外的过滤，这调节了OHC力的产生，从而产生了观察到的灵敏度和尖锐的频率调谐。为了验证这一假设，我们开发了一种创新技术，称为体积光学相干层析成像振动测量(VOCTV)。除了允许在活体内测量传统的基底膜运动外，VOCTV还允许测量整个Corti器官的声音诱导振动。我们建议使用VOCTV来研究Corti器官组件之间的相互作用，并评估它们与小鼠耳蜗尖转角内的耳蜗放大之间的关系。在目标1中，我们首次提出在活体内测量野生型小鼠耳蜗尖转角内的横向和径向振动运动。我们将使用3D定位来比较不同器官的Corti结构的反应，评估频率响应和耳蜗放大的增益。在目标2中，我们建议测量几个转基因小鼠品系在顶端旋转时的振动运动，这些品系具有选择性地改变Corti力学器官的分子变化。通过这种方法，我们将探索基于prestin的电动、立体纤毛束力学、覆盖膜行波和毛细胞/支持细胞模式的机械贡献。总而言之，这些数据将被解读，以检验我们的假设。如果我们的假设是正确的，那么在Corti器官内进行尖锐调谐的差异运动对于产生哺乳动物耳蜗器的敏感度和尖锐调谐是必要的。

 DESCRIPTION (provided by applicant): Sound pressure produces force across the mammalian cochlear partition, ultimately creating a vibratory traveling wave that propagates longitudinally up the cochlear duct. The key feature distinguishing this process from the non-mammalian cochlea is amplification, whereby forces produced by thousands of outer hair cells (OHCs) sharpen and amplify the traveling wave. Our overarching objective is to understand how the complex biomechanics of the 3D multi-cellular and acellular arrangement that forms the organ of Corti work together to create cochlear amplification. Specifically, we will determine how this process, which stems from the broadly- tuned basilar membrane, creates sharp frequency tuning and high sensitivity. This question is significant on a basic science level because these biophysical processes underlie the ability to hear sounds just above the Brownian motion of molecules in air with an exquisite frequency resolution. This question remains unsolved and is clinically important because hearing loss is typically due to loss of cochlear amplification. Our central hypothesis is that the mechanical properties of the organ of Corti provide additional filtering beyond that provided by the passive mechanics of the basilar membrane and surrounding fluid, and that this modulates OHC force production to give rise to the observed sensitivity and sharp frequency tuning. To test the hypothesis, we have developed an innovative technology, termed Volumetric Optical Coherence Tomography Vibrometry (VOCTV). Besides permitting traditional basilar membrane motion measurements in vivo, VOCTV also permits the measurement of sound-induced vibrations throughout the organ of Corti. We propose to use VOCTV to study the interactions between components of the organ of Corti and assess how they relate to cochlear amplification within the apical turn of the mouse cochlea. In Aim 1, we propose to measure transverse and radial vibratory motions within the apical turn of the wild- type mouse cochlea in vivo for the first time. We will use 3D localization to compare the responses of different organ of Corti structures, assessing both the frequency response and the gain of cochlear amplification. In Aim 2, we propose to measure vibratory motions within the apical turn of several transgenic mouse strains that have molecular changes designed to selectively alter of organ of Corti mechanics. Through this approach, we will probe the mechanical contributions of prestin-based electromotility, stereociliary bundle mechanics, tectorial membrane traveling waves, and hair cell/supporting cell patterning. Together, these data will be interpreted so as to test our hypothesis. If our hypothesis is true, sharply-tuned differential motion within the organ of Corti is necessary to generate the sensitivity and sharp tuning of the mammalian cochlea.