Three-dimensional and Multiscale Organ of Corti Biomechanics

三维多尺度柯蒂氏器官生物力学

• 批准号: 8327994
• 负责人: Anthony J Ricci
• 金额: $ 49.44万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-05 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327994
• 关键词: Accounting; Acoustics; Address; Algorithms; Amplifiers; Anatomy; Basilar Membrane; Biological; Biomechanics; Cell Wall; Cochlea; Computer Simulation; Confocal Microscopy; Coupled; D Cells; Data; Development; Effectiveness; Electric Capacitance; Elements; Frequencies; Future; Generations; Gerbils; Goals; Hair Cells; Hearing; Hearing Aids; Hodgkin Disease; Homologous Gene; Human; Image; Indium; Individual; Inner Hair Cells; Intervention; Left; Liquid substance; Location; Loudness; Measurement; Mechanics; Modeling; Modification; Mus; Mutate; Mutation; Natural regeneration; Organ of Corti; Outer Hair Cells; Output; Pathology; Pattern; Physiological; Physiology; Process; Property; Proteins; Public Health; Research; Resolution; Sensorineural Hearing Loss; Shapes; Stapes; Stereocilium; Stimulus; Testing; Therapeutic; Translations; Validation; Variant; Wild Type Mouse; base; cell motility; computer design; computer framework; design; electrical property; feeding; helicotrema; improved; otoacoustic emission; receptor; sound; stem; tectorial membrane; theories; three-dimensional modeling; tool; two-photon; voltage

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.

描述（由申请人提供）：目前还没有一个与柯蒂细胞结构、基底膜力学和耳声发射（OAE）一致的耳蜗放大理论。我们的中心假设是系统组织的 Y 形结构元素。柯蒂氏器中的网状层和基底膜之间共同形成基底膜最佳频率区域的耳蜗放大机制，其中成角度的外毛细胞（OHC）提供指向顶端的累积“前馈”力，而成角度的指骨突提供指向基部的“反馈”力。前馈和后馈（FF/）。 FB）放大理论将使用小鼠和沙鼠 Corti 器官的解剖学真实流体耦合 3D 有限元计算模型进行测试，该模型由双光子和共焦构建在对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 FF/ 基底膜力学的影响。 FB 放大器概念与刺激频率 OAE 和失真产物 OAE 的理论和测量兼容，并且对柯蒂氏器结构的选择性修改将产生可预测的结果，将在模型和实验中进行测试野生型小鼠和 α-tectorin 蛋白突变小鼠 (TectaC1509G/+) 具有缩短的盖膜，耳蜗模型通常假设 OHC 力输出与静纤毛力输入成正比，增益 ¿假设与耳蜗位置和频率无关，我们将通过创建一个考虑基底外侧电导和细胞壁电容的 OHC 受体电位模型来改进这一点，然后我们将其与躯体运动的解剖学和生理学现实模型相结合。为了确定 ¿ 的实际值作为位置和频率的函数。 (x,r,f) 模型将被集成到我们的 FF/FB 建模框架中，作为对我们中心假设的进一步测试，预计直接源于这项研究的科学贡献是 1) Y-的详细 3D 描述。柯蒂氏器中不同 OHC 行（从基部到顶端）的形状元件；2) 将这些信息纳入计算模型中，以通过真实的解剖学测试 FF/FB 放大器理论；3) 更好地理解 OAE 的机制；一代和传播与 FF/FB 放大理论有关；4) 加深对 OHC 基底外侧电导、受体电位和体运动对耳蜗放大的贡献的理解，所得模型将为未来的耳蜗力学研究提供强大的新工具。这些正常的、转基因的和再生的小鼠耳蜗，以及由于涉及人类和小鼠之间的同源物，也包括人类耳蜗。 公共健康相关性：拟议的研究将有助于满足数百万患有永久性感音神经性听力损失的人的需求，从而造福公共健康，这些人依赖声学助听器作为目前可用的治疗方法，可以提供关键信息。为了提高这些助听器的有效性，导致设计出更好的放大算法，结合基于生理学的响度模型，以及改进实现助听器算法的计算机芯片的设计。解剖学上准确的 3D 耳蜗模型还可以通过提供一个计算框架来加速未来以耳蜗结构再生为中心的生物干预措施的发展，在该框架内可以对各种治疗策略进行初步评估和比较。