The mechanical and ionic roles of cochlear fluids in hearing and hearing loss

项目摘要 耳蜗生理学实验室的一个目标是了解Corti器官的组成部分如何调节耳蜗的功能。 声音引起的Corti器官的振动。一个被称为耳蜗放大（CA）的过程， 世界各地的高强度工作，有关键的组成部分尚未研究。两个广泛关注的问题， 这个建议的地址是：1）基本流体动力粘度如何有助于独特的 处理语音频率的耳蜗尖的频率分析能力，以及2） 盖膜在调节钙离子浓度方面具有中心和生物化学作用， 对毛细胞功能至关重要有三个目标。 需要新的和创新的实验方法来解决这些问题。用于测量 输出变量，我们继续使用光学相干断层扫描（OCT）的方法，我们开创， 记录内耳组织振动。我们使用最先进的共聚焦成像方法应用于整个器官 外植体系统和测量静止和刺激的内耳中的钙离子浓度。 在目标1中，关于问题1，我们还提出确定外淋巴液宏观粘度是否是关键的 心尖频率调谐参数。以及调谐是否依赖于耳蜗的过程， 在行波传播到顶点时在行波内的放大。为了控制粘度，正常外淋巴液 通过真实的时间灌注系统用粘度改变的外淋巴液替换。目标2和3是关于问题2的 在那里我们试图了解钙是如何被顶盖膜储存的以及储存的结果。 所涉及的是使用有缺陷的覆膜结构蛋白的突变壁模型和定量的 荧光测定内淋巴和盖膜中的钙浓度。此外，在Aim 3，我们通过两个模型探讨年龄如何影响覆膜钙螯合， 操纵血管纹的生理机能，这是已知的年龄退化的目标。模型1是慢性的 应用速尿，一种抑制耳蜗内电位的药物。模型2是基因靶向的 血管纹血流的化学改变）。综合起来，这项工作不仅将大大推进 Corti器官功能的基本知识，但开辟了一条药物干预治疗的途径 盖膜钙病理学

Project Summary A goal of the cochlear physiology laboratory is to understand how the components of the organ of Corti tune the sound induced vibration of the organ of Corti. A process known as cochlear amplification (CA), now the subject of intense work around the world, has critical components not yet studied. Two questions of broad interest that this proposal address are; 1) how does the fundamental hydrodynamic viscosity contribute to the unique frequency analysis capacity of the cochlear apex where speech frequencies are processed and 2) does the tectorial membrane in have a central and biochemical role in regulating the calcium ion concentration that is so critical to hair cell function. There are three Aims. New and innovative experimental approaches are needed to address these questions. For the measurement of output variables, we continue to use the optical coherence tomography (OCT) method, that we pioneered, to record inner ear tissue vibration. We use state of the art confocal imaging methods applied to whole organ explant systems and measure calcium ion concentrations in quiescent and stimulated inner ears. In Aim 1, about question 1, we also propose to determine if perilymph macroscopic viscosity is a crucial parameter of apical frequency tuning. As well as whether the tuning is dependent upon the process of cochlear amplification within the traveling wave as it propagates to the apex. To manipulate viscosity, normal perilymph is replaced with altered viscosity perilymph via a real time perfusion system. Aims 2 and 3 are about question 2 where we seek to understand how and with what consequence is calcium stored by the tectorial membrane. Involved is the use of mutant mural models of defective tectorial membrane structural proteins and quantitative fluorescent determination of calcium concentrations in endolymph and tectorial membrane. Additionally, in Aim 3, we explore how age might factor into the tectorial membrane calcium sequestration via two models that manipulate the physiology of the stria vascularis a known target of age degeneration. Model 1 is the chronic application of furosemide, an agent to suppress endocochlear potential. Model 2 is the genetically targeted chemical alteration of stria vascularis blood flow). Taken together the work will significantly advance not only fundamental knowledge of organ of Corti function but open a path to pharmacological interventions to treat tectorial membrane calcium pathology.