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DYNAMIC INTERATION AMONG PROTEINS IN HAIR CELLS

毛细胞中蛋白质之间的动态相互作用

基本信息

批准号：
9022461
负责人：
Jing Zheng
金额：
$ 32.83万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9022461
关键词：
Actins Adhesives Auditory Physiology Auditory system Binding Binding Proteins Biochemical Biological CDH23 gene Cell Adhesion Molecules Cell Differentiation process Cell physiology Cells Centrosome Cochlea Communication impairment Complex Cytoskeletal Proteins Data Development Electrophysiology (science)Environment Epithelial Cells Filament Foundations Genes Goals Hair Cells Hearing In Vitro Individual Inner Hair Cells Investigation Knock-in Mouse Knockout Mice Knowledge Labyrinth Letters Mechanical Stress Mechanics Membrane Proteins Methods Microfilaments Microtubule Bundle Microtubule-Organizing Center Microtubules Minus End of the Microtubule Molecular Mutation Myosin ATPase Neuraxis Organ of Corti Outer Hair Cells PCDH15 gene Patients Pattern Pharmacological Treatment Physiological Physiology Pillar Cell Play Process Protein Isoforms Proteins Role Scaffolding Protein Sense Organs Sensory Receptors Signal Transduction Spectrin Stereocilium Structure Supporting Cell System Testing Therapeutic Tubulin Ursidae Family Work base carcinoembryonic antigen-related cell adhesion molecules cell type crosslink deafness gene therapy in vivo link protein mouse model sound tectorial membrane

项目摘要

DESCRIPTION (provided by applicant): The organ of Corti in the inner ear converts the mechanical force arising from sound waves into electrical signals to inform the central nervous system. To accomplish this task, hair cells and supporting cells in the organ of Corti need complex and sophisticated protein networks to perform their functions. Discovering the individual proteins and their roles in the protein networks of the organ of Corti will enrich our understanding of normal and impaired cochlear physiology. The goal of the proposed work is to determine functions of two newly identified proteins: CEACAM16 and Marshalin. CEACAM16 is a cell adhesion protein that we discovered in the cochlea. In AIM I, we propose to investigate functional roles of CEACAM16 for maintaining the tectorial membrane integrity and the connections between outer hair cells and the tectorial membrane. We will also investigate its relation to the DFNA4 deafness locus in both in vitro and in vivo environments. Marshalin is a microtubule-minus-end binding protein that we identified as a potential CDH23-associated protein. In AIM II, we will examine Marshalin expression patterns in the organ of Corti and investigate Marshalin's function in both hair cells and supporting cells during cochlear development. We'll determine the molecular basis of interactions between Marshalin and its potential associated proteins including CDH23, actin, myosin 7a and spectrin. The investigation will provide much-needed information regarding Marshalin's roles in cross-linking actin filaments and MT filaments during hair cells and supporting cells differentiation, as well as Marshalin's connection with deafness locus DFNB15, one of earliest identified deafness loci. The investigation will also offer further information regarding CDH23 role for stereocilia formation. Various cellular, biochemical and electrophysiological methods, knockout and knockin mouse models, as well as in vivo physiology methods will be used to pursue our goals. The conclusions derived from the proposed work will not only allow the possible identification of new deafness genes, but will also provide the foundation for further understanding of formation of the organ of Corti. Such knowledge is sorely needed to understand many fundamental biological questions that are directly relevant to the molecular bases of normal and disordered communication processes.

描述（申请人提供）：内耳的Corti器官将声波产生的机械力转化为电信号，通知中枢神经系统。为了完成这项任务，毛细胞和Corti器官中的支持细胞需要复杂而复杂的蛋白质网络来执行它们的功能。发现单个蛋白质及其在Corti器官蛋白质网络中的作用将丰富我们对正常和受损耳蜗生理学的理解。这项工作的目标是确定两个新发现的蛋白质：CEACAM16和Marshalin的功能。CEACAM16是我们在耳蜗中发现的一种细胞粘附蛋白。在AIM I中，我们拟研究CEACAM16在维持毛膜完整性以及外毛细胞与被膜之间连接方面的功能作用。我们还将在体外和体内环境中研究其与DFNA4耳聋位点的关系。Marshalin是一种微管-负端结合蛋白，我们将其鉴定为潜在的cdh23相关蛋白。在AIM II中，我们将检查Marshalin在Corti器官中的表达模式，并研究Marshalin在耳蜗发育过程中在毛细胞和支持细胞中的功能。我们将确定Marshalin及其潜在相关蛋白（包括CDH23、actin、myosin 7a和spectrin）之间相互作用的分子基础。该研究将提供关于Marshalin在毛细胞和支持细胞分化过程中肌动蛋白丝和MT丝交联中的作用以及Marshalin与耳聋位点DFNB15（最早发现的耳聋位点之一）的联系的急需信息。该研究还将提供关于CDH23在纤毛形成中的作用的进一步信息。各种细胞，生化和电生理方法，敲除和敲入小鼠模型，以及体内生理学方法将被用来追求我们的目标。本研究的结论不仅为鉴定新的耳聋基因提供了可能，而且为进一步了解Corti器官的形成提供了基础。这些知识对于理解许多与正常和无序通讯过程的分子基础直接相关的基本生物学问题是非常必要的。