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（由应用提供）：尚无与皮质细胞结构，基底膜机理和耳声发射（OAES）器官（OAES）的器官一致的单一统一扩增理论。 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 opposite angled phaselageal processes provide a基本的“反馈”力。将使用由两光子和共聚焦显微镜图像构建的小鼠和晶状体器官的解剖学逼真的液体耦合的3D有限元计算模型来测试馈送和回馈（FF/FB）放大理论。在验证了先前的物理测量和建模结果之后，新模型将用于测试FF/FB力对耳蜗扩增的影响，以及Tecorial和基底膜机制的影响。 FF/FB放大器概念与刺激频率OAE和失真产品OAE的理论和测量的假设以及对Corti器官结构的选择性修改将产生可预测的结果，将在模型中和实验中使用该型号的小鼠和Alpha-typector+Algpha-tector+）进行测试。缩短的tecorial膜。人工耳蜗模型通常假定OHC力输出与立体力输入成正比，而增益假定与人工耳蜗的位置和频率无关。我们将通过为OHC受体电位创建模型来改进这一点，该模型解释了基底性电导和细胞壁电容，然后我们将与解剖和物理上现实的体细胞运动模型相结合，以确定oost和频率的函数的现实值。然后，将结果`（x，r，f）模型将集成到我们的FF/FB建模框架中，以进一步测试我们的中心假设。直接来自这项研究的科学贡献预计为1）从基础到顶点的不同OHC行，对Corti器官中Y形元素的详细3D描述； 2）在计算模型中的一项融合信息，用于测试具有逼真的解剖结构的FF/FB放大器理论； 3）对OAE产生和传播的机制与FF/FB扩增理论的关系有了深刻的了解； 4）对OHC基底外侧电导，受体电位和对耳蜗扩增的躯体运动的贡献增强了理解。最终的模型将为未来的人工耳蜗研究提供强大的新工具，包括涉及正常，一般修改和再生小鼠耳蜗的工具，并且由于人类和小鼠之间的同源物，也是人的耳蜗。 公共卫生相关性：拟议的研究将通过帮助满足数百万具有永久性感知听力损失的人的需求，从而使公共卫生受益，这些人依赖于声学听力辅助工具是目前可用的疾病的唯一治疗形式。拟议研究的结果可以提供关键信息，以提高这些助听器的有效性，从而设计出更好的扩增算法，基于生理的响度模型的结合以及改进实施助听器算法的计算机芯片的设计。提出的解剖学上精确的3D人工耳蜗模型还可以通过提供一个计算框架来加速围绕耳蜗结构再生的未来生物学干预措施，并提供一个计算框架，其中最初可以评估和比较各种治疗策略。