Measuring and Modeling the Effects of Reticular Lamina Flexibility on Outer Hair Cell Bundle Phase and Cochlear Amplification

测量和模拟网状层灵活性对外毛细胞束相位和耳蜗放大的影响

基本信息

批准号：
10676401
负责人：
Gabriel Alberts
金额：
$ 4.17万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676401
关键词：
3-Dimensional Affect Air Anatomy Animals Apical Auditory system Autopsy Basilar Membrane Binding Biological Cells Characteristics Cochlea Computer Models Data Diagnosis Diameter Elements Epithelium External auditory canal Frequencies Future Gerbils Hearing Human Hydrogen Image Imaging technology Knowledge Labyrinth Length Location Measurement Measures Mechanics Membrane Methods Modeling Modernization Motion Mus Nature Optical Coherence Tomography Organ of Corti Outer Hair Cells Output Pathology Persons Phalanx Phase Physics Pillar Cell Process Radial Research Resolution Rest Sensory Shapes Source Stapes Structure Structure-Activity Relationship System Technology Testing Tissues Wild Type Mouse base bone capsule cell motility flexibility hearing impairment improved in vivo insight meter microCT mosaic nanometer nanoscale normal hearing novel imaging technology particle pressure response round window sound tectorial membrane three-dimensional modeling vibration

项目摘要

ABSTRACT The mammalian auditory system has evolved into a biological marvel with high sensitivity that can largely be traced to nonlinear amplification by the organ of Corti (OoC)—the sensory epithelium within the cochlea of the inner ear. Despite decades of research, the inaccessibility of the inner ear’s bony capsule and the technological challenges of measuring and modeling nanometer-scale vibrations in a multi-physics system have made it difficult to uncover OoC structure-function relationships. However, increased computational capabilities and novel imaging technologies such as optical coherence tomography (OCT) now make it possible to capture OoC motion in more detail than ever before, which is revolutionizing our understanding of cochlear amplification. The most well-understood aspect of amplification is the somatic motility of outer hair cells (OHCs), and recent data measuring OoC motion across the three rows of OHCs suggests that the reticular lamina (RL) is flexible and not a stiff plate as was thought for over a century. Our central hypothesis is that RL flexibility sets the phase of OHC bundle motion and is therefore necessary for cochlear amplification. To test this hypothesis, we will measure OoC motion from multiple angles from healthy cochleae of living, normal-hearing mice using a high-resolution OCT system in both the lower-frequency apical region and higher-frequency basal region of mice. We will measure distinct radial locations along the RL and along the junctions between OHCs and Deiters’ cells corresponding to the three OHC rows, at multiple frequencies and sound pressure levels. We will also measure along the basilar membrane (BM) to fully characterize RL motion in relation to the motion of the BM and other OoC structures. These measurements will test our hypothesis by providing empirical evidence for the degree of RL flexibility in the radial and transverse directions across different frequencies and levels at two different cochlear locations. We will also use the measurements to develop detailed, multi-physics, finite-element cochlear models, which will give us insight into the relationship between the RL and tectorial membrane and the drive to OHC bundles. Both the apical and basal models will contain key elements of OoC cytoarchitecture including the interdigitated Y-shape building blocks made from OHCs, Deiters’ cells, and the phalangeal processes of Deiters’ cells, sandwiched between the basilar membrane and the RL mosaic. We aim to produce motion in the models comparable to post-mortem (passive) and in-vivo (active) OCT measurements and will investigate the effects of RL stiffness on OHC-bundle phase and cochlear amplification. Completion of these aims will have wide-reaching implications. Not only will this research uncover fundamental knowledge about the nature of hearing, but it has the potential to contribute to improved understanding, diagnoses, and treatment of human cochlear pathologies.

抽象的哺乳动物的听觉系统已经进化成为一个生物奇迹，具有高灵敏度，很大程度上可以通过追溯到柯蒂氏器（OoC）的非线性放大——耳蜗内的感觉上皮尽管经过数十年的研究，内耳的骨囊仍然难以接近，而且技术也很先进。在多物理系统中测量和建模纳米级振动的挑战使其成为可能很难揭示 OoC 结构-功能关系，但是，计算能力和功能都增强了。光学相干断层扫描 (OCT) 等新型成像技术现在可以捕获 OoC 比以往任何时候都更详细的运动，这彻底改变了我们对耳蜗放大的理解。扩增最广为人知的方面是外毛细胞 (OHC) 的体细胞运动，最近的数据测量三排 OHC 上的 OoC 运动表明，网状层 (RL) 是灵活的，而不是一个多世纪以来我们一直认为的硬板是 RL 灵活性决定了 OHC 的阶段。束运动，因此对于耳蜗放大是必要的。为了检验这一假设，我们将进行测量。使用高分辨率的活体、正常听力小鼠的健康耳蜗从多个角度进行 OoC 运动我们将在小鼠的低频顶端区域和高频基底区域进行 OCT 系统。测量沿 RL 以及沿 OHC 和 Deiters 细胞之间连接处的不同径向位置对应于三个 OHC 行，我们还将在多个频率和声压级上进行测量。沿着基底膜 (BM) 来充分表征 RL 运动与 BM 和其他运动的关系这些测量将通过提供关于 OoC 程度的经验证据来检验我们的假设。 RL 在两个不同频率和水平上的径向和横向方向的灵活性我们还将利用测量结果来开发详细的、多物理的、有限元的耳蜗。模型，这将使我们深入了解 RL 和盖膜之间的关系以及 OHC 束。顶端和基底模型都将包含 OoC 细胞结构的关键元素，包括由 OHC、Deiters 细胞和 Deiters 指骨突制成的叉指 Y 形构件细胞夹在基底膜和 RL 镶嵌之间，我们的目标是在模型中产生运动。与死后（被动）和体内（主动）OCT 测量相当，并将研究以下因素的影响 OHC 束相和耳蜗放大上的 RL 刚度将具有广泛的影响。这项研究不仅揭示了有关听力本质的基础知识，而且还具有以下意义。有助于提高对人类耳蜗病理的理解、诊断和治疗的潜力。