Structural Basis of Outer Hair Cell Function

外毛细胞功能的结构基础

基本信息

批准号：
8754822
负责人：
FEDERICO KALINEC
金额：
$ 22.05万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8754822
关键词：
Actins Address Affinity Architecture Basilar Membrane Binding Cell Shape Cell membrane Cell physiology Cells Cellular Structures Complement Confocal Microscopy Cytoplasmic Protein Cytoskeletal Modeling Cytoskeleton Data Electron Microscopy Family suidae GLUT-5 protein Goals Hearing Human Immunoprecipitation In Vitro Integral Membrane Protein Knowledge LIMK1 gene Label Lateral Length Light Link Mass Spectrum Analysis Mediating Methods Microfilaments Microscopy Modification Molecular Mus Nature Organ Organ of Corti Outer Hair Cells Pathway interactions Phosphorylation Proteins Recruitment Activity Regulation Role Sensory Signal Transduction Spectrin Speed Stereocilium Structure Techniques Testing Video Microscopy Work abstracting adducin base cell motility cofilin crosslink deafness depolymerization driving force hearing impairment in vivo insight monomer mouse model polymerization pressure profilin rat Pres protein relating to nervous system response sound two-dimensional

项目摘要

Structural Basis of Outer Hair Cell Function Abstract The last two decades witnessed a huge increase in our understanding of outer hair cell (OHC) structure and function. We know, for example, that cochlear amplification is associated with OHC fast motility, which is driven by forces generated in the plasma membrane by conformational changes in thousands of copies of the integral-membrane protein prestin. We know that these forces are harnessed and oriented parallel to the OHC's major axis by the cortical cytoskeleton, a two-dimensional anisotropic network of actin filaments cross- linked by spectrin that underlies the entire OHC lateral plasma membrane, and we know that that is possible because the plasma membrane is linked to cytoskeletal actin filaments by thousands of structural "pillars". We still don't know, however, the nature of these pillars. We don't know how they work, or whether they have any role in the regulation of the prestin-generated force. We don't know either the molecular mechanisms that control OHC length and motility by regulating cytoskeletal organization and its pillar-mediated connection to the plasma membrane. The goal of this proposal is to fill these gaps in our knowledge of OHC's structure and function, a crucial step in our quest to understand cochlear function, malfunctions that involve changes in OHC shape, and protective mechanisms in response to over stimulation, by addressing the following Specific Aims: 1) Demonstrate that proteins GLUT5, Dematin and Adducin are major components of OHC pillars, 2) Determine the role of actin polymerization and depolymerization induced by profilin- and cofilin-mediated signals in the regulation of OHC length and motility, and 3) Determine the role of the RhoA/ROCK-PKC pathway in the modulation of OHC length and motility.

外毛细胞功能的结构基础抽象的过去二十年见证了我们对外毛细胞 (OHC) 结构和功能。例如，我们知道耳蜗放大与 OHC 快速运动相关，即由质膜中数千个拷贝的构象变化产生的力驱动整合膜蛋白prestin。我们知道这些力量的利用和方向与 OHC 的主轴由皮质细胞骨架构成，是肌动蛋白丝交叉的二维各向异性网络由位于整个 OHC 侧质膜下方的血影蛋白连接，我们知道这是可能的因为质膜通过数千个结构“柱”与细胞骨架肌动蛋白丝相连。我们然而，仍然不知道这些支柱的性质。我们不知道它们是如何工作的，也不知道它们是否有 prestin 产生的力的调节中的任何作用。我们也不知道其分子机制通过调节细胞骨架组织及其与细胞骨架介导的连接来控制 OHC 长度和运动性质膜。该提案的目标是填补我们对 OHC 结构和知识的了解空白。功能，这是我们探索耳蜗功能的关键一步，涉及 OHC 变化的故障通过解决以下具体目标，形成应对过度刺激的形状和保护机制： 1) 证明蛋白质 GLUT5、Dematin 和 Adducin 是 OHC 支柱的主要成分，2) 确定 profilin 和 cofilin 介导诱导的肌动蛋白聚合和解聚的作用调节 OHC 长度和运动性的信号，以及 3) 确定 RhoA/ROCK-PKC 的作用 OHC 长度和运动性调节途径。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Linking LIMK1 deficiency to hyperacusis and progressive hearing loss in individuals with Williams syndrome.

DOI：
10.4161/cib.4.2.14491
发表时间：
2011-03-01
期刊：
Communicative & integrative biology
影响因子：
0
作者：
Matsumoto, Nozomu;Kitani, Rei;Kalinec, Federico
通讯作者：
Kalinec, Federico

Acetaminophen and NAPQI are toxic to auditory cells via oxidative and endoplasmic reticulum stress-dependent pathways.

DOI：
10.1016/j.heares.2014.04.007
发表时间：
2014-07
期刊：
HEARING RESEARCH
影响因子：
2.8
作者：
Kalinec, Gilda M.;Thein, Pru;Parsa, Arya;Yorgason, Joshua;Luxford, William;Urrutia, Raul;Kalinec, Federico
通讯作者：
Kalinec, Federico

In vitro assessment of antiretroviral drugs demonstrates potential for ototoxicity.