Cytoskeletal Regulation of Outer Hair Cell Motility

外毛细胞运动的细胞骨架调节

基本信息

批准号：
6758563
负责人：
FEDERICO KALINEC
金额：
$ 36.45万
依托单位：
HOUSE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2007-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Cochlear outer hair cells (OHCs) are unique sensory-motor cells responsible for signal amplification and frequency discrimination in the mammalian inner ear. Strong evidence suggests that the motile response of OHCs to chemical or electrical stimulation provides the mechanical effectors to the "cochlear amplifier," the active mechanism that enhances approximately 100-fold the peak of the sound-induced basilar membrane motion. Our long-term goal is to understand the molecular mechanisms involved in the regulation of OHC motility. Based on previous studies in non-auditory cell populations, we hypothesize that OHC motility is regulated by structural and functional changes in the cytoskeleton. The recent identification of the small Rho GTPases RhoA, Rac 1 and Cdc42 as mediators in an acetyicholine (ACh)-activated signaling pathway that modulates OHC motility, offers now the opportunity to address this hypothesis at molecular and cellular levels. Moreover, our preliminary results indicate that some downstream effectors of Rho GTPases -belonging to the ACh-activated signaling pathway- are important for OHCs' mechanical homeostasis. Since these downstream effectors mediate Rho-promoted processes such as actin-spectrin association and plasma membrane-cytoskeleton interaction, these results provide a solid foundation for further investigation of the role of the cytoskeleton in the regulation of OHC motility. In this proposal, we will use a combination of electrophysiological, molecular biology, microscopical and image analysis techniques in order to: 1. Identify downstream effectors of Rho GTPases involved in the regulation of OHC motility, 2. Determine the connection pattern between Rho GTPases and their downstream effectors, and 3. Establish the structural changes induced by ACh on the OHC cytoskeleton. We are confident that accomplishing these aims will provide essential information about the role of the cytoskeleton in the regulation of OHC motility as well as critical insights into the basic mechanisms of both normal human hearing and deafness.

描述（由申请人提供）：人工耳蜗外毛细胞（OHC）是负责哺乳动物内耳中信号扩增和频率区分的独特感觉运动细胞。有力的证据表明，OHC对化学或电刺激的运动响应为“耳蜗放大器”提供了机械效应子，该活动的活动机制增强了声音诱导的基底膜运动峰的大约100倍。我们的长期目标是了解OHC运动调节所涉及的分子机制。根据先前在非原告细胞群体的研究，我们假设OHC运动受细胞骨架的结构和功能变化的调节。现在，在调节OHC运动性的乙酰氨酸（ACH）激活的信号传导途径（ACH）激活的信号通路中，小的Rho GTPase RHOA，RAC 1和CDC42作为介体的鉴定，现在为在分子和细胞水平上解决这一假设提供了机会。此外，我们的初步结果表明，Rho GTPases的某些下游效应因素 - 向ACH激活的信号传导途径 - 对OHCS的机械稳态很重要。由于这些下游效应子介导了Rho促进的过程，例如肌动蛋白 - 光谱蛋白关联和质膜 - 膜骨架相互作用，因此这些结果为进一步研究细胞骨架在OHC运动调节中的作用提供了稳固的基础。 In this proposal, we will use a combination of electrophysiological, molecular biology, microscopical and image analysis techniques in order to: 1. Identify downstream effectors of Rho GTPases involved in the regulation of OHC motility, 2. Determine the connection pattern between Rho GTPases and their downstream effectors, and 3. Establish the structural changes induced by ACh on the OHC cytoskeleton.我们相信，实现这些目标将提供有关细胞骨架在OHC运动调节中的作用以及对正常人类听力和耳聋的基本机制的重要信息。