Three-dimensional and Multiscale Organ of Corti Biomechanics

描述（由申请人提供）：目前还没有一个与Corti器官细胞结构、基底膜力学和耳声发射（OAE）一致的耳蜗放大统一理论。我们的中心假设是，在Corti器官中的网状板和基底膜之间的系统组织的Y形结构元件共同形成基底膜的最佳频率区域中的耳蜗放大的机制，其中成角度的外毛细胞（OHC）提供指向顶部的累积“前馈”力，并且相对成角度的趾骨突起提供指向基部的“反馈”力。前馈和反馈（FF/FB）放大理论将使用解剖学现实的流体耦合三维有限元计算模型的小鼠和沙鼠器官的Corti，构建从双光子和共聚焦显微镜图像进行测试。在根据先前的生理测量和建模结果进行验证后，新模型将用于测试FF/FB力对耳蜗放大的影响，以及覆膜和基底膜力学的影响。假设FF/FB放大器概念与刺激频率OAE和畸变产物OAE的理论和测量兼容，并且对Corti器官结构的选择性修饰将产生可预测的结果，将在模型中和实验中使用野生型小鼠和具有缩短的顶盖膜的α-顶盖蛋白突变小鼠（TectaC 1509 G/+）进行测试。耳蜗模型通常假设OHC力输出与立体纤毛力输入成比例，其中假设增益与耳蜗位置和频率无关。我们将通过创建一个OHC受体电位模型来改进这一点，该模型考虑了基底外侧电导和细胞壁电容，然后我们将联合收割机与解剖学和生理学上的躯体运动现实模型相结合，以确定作为位置和频率函数的真实值。然后，将得到的<$（x，r，f）模型集成到我们的FF/FB建模框架中，作为对我们中心假设的进一步测试。预计直接源自本研究的科学贡献是：1）Corti器官中Y形元件的详细3D描述，从底部到顶点，跨越不同的OHC行; 2）将此信息并入计算模型中，用于测试FF/FB放大器理论与现实解剖学; 3）更好地理解OAE的产生和传播机制与FF/FB放大理论的关系;以及4）增强了对OHC基底外侧电导、受体电位和体细胞运动对耳蜗放大的贡献的理解。由此产生的模型将为未来的耳蜗力学研究提供强大的新工具，包括那些涉及正常，转基因和再生的小鼠耳蜗，以及由于人类和小鼠之间的同源物，人类耳蜗。 公共卫生相关性：这项拟议的研究将有助于解决数百万永久性感音神经性听力损失患者的需求，使公众健康受益，这些患者依赖声学助听器作为目前唯一的治疗方式。拟议研究的结果可以为提高这些助听器的有效性提供关键信息，从而设计更好的放大算法，纳入基于生理学的响度模型，并改进实现助听器算法的计算机芯片的设计。所提出的解剖学上精确的3D耳蜗模型还可以通过提供一个计算框架来加速以耳蜗结构再生为中心的未来生物干预的发展，在该框架内可以初步评估和比较各种治疗策略。

DESCRIPTION (provided by applicant): There is not yet a single unifying theory of cochlear amplification consistent with the organ of Corti cytoarchitecture, basilar membrane mechanics, and otoacoustic emissions (OAEs). Our central hypothesis is that the systematically organized Y-shaped structural elements between the reticular lamina and basilar membrane in the organ of Corti collectively form a mechanism for cochlear amplification in the best-frequency region of the basilar membrane, in which the angled outer hair cells (OHCs) provide an accumulating "feed- forward" force directed apically, and the oppositely angled phalangeal processes provide a "feed-backward" force directed basally. The feed-forward and feed-backward (FF/FB) amplification theory will be tested using anatomically realistic fluid-coupled 3D finite element computational models for the mouse and gerbil organs of Corti, constructed from two-photon and confocal microscopy images. After validation against previous physiological measurements and modeling results, the new models will be used to test the effects of FF/FB forces on cochlear amplification, as well as the effects of tectorial and basilar membrane mechanics. The hypothesis that the FF/FB amplifier concepts are compatible with theories and measurements of stimulus- frequency OAEs and distortion-product OAEs, and that selective modifications to the structure of the organ of Corti will produce predictable results, will be tested both in the model and experimentally using wild-type mice and alpha-tectorin protein mutated mice (TectaC1509G/+) that feature a shortened tectorial membrane. Cochlear models have typically assumed that the OHC force output is proportional to the stereociliary force input, with a gain ¿ assumed to be independent of cochlear location and frequency. We will improve upon this by creating a model for the OHC receptor potential that accounts for the basolateral conductances and cell wall capacitance, which we will then combine with an anatomically and physiologically realistic model for somatic motility in order to determine realistic values for ¿ as a function of location and frequency. The resulting ¿(x,r,f) model will then be integrated into our FF/FB modeling frameworks as a further test of our central hypothesis. The scientific contributions stemming directly from this research are expected to be 1) a detailed 3D description of the Y- shaped elements in the organ of Corti across the different OHC rows, from base to apex; 2) an incorporation of this information into computational models for testing the FF/FB amplifier theories with realistic anatomy; 3) an improved understanding of how mechanisms of OAE generation and propagation relate to the FF/FB amplification theory; and 4) an enhanced understanding of the contributions of OHC basolateral conductances, receptor potential, and somatic motility to cochlear amplification. The resulting models will provide powerful new tools for future cochlear mechanics studies, including those involving normal, genetically modified, and regenerated mouse cochleae, and, due to homologs between humans and mice, the human cochlea as well. PUBLIC HEALTH RELEVANCE: The proposed research will benefit public health by helping to address the needs of the millions of individuals with permanent sensorineural hearing loss who depend on acoustic hearing aids as the only form of treatment for their condition currently available. The results of the proposed research could provide critical information for improving the effectiveness of these hearing aids, leading to the design of better amplification algorithms, the incorporation of physiology-based loudness models, and improvements to the design of the computer chips that implement hearing-aid algorithms. The proposed anatomically accurate 3D cochlear models may also accelerate the development of future biological interventions centered around the regeneration of cochlear structures, by providing a computational framework within which various therapeutic strategies can be initially evaluated and compared.