Understanding the role of Tmc proteins in hair cell mechanotransduction of zebrafish

了解 Tmc 蛋白在斑马鱼毛细胞机械转导中的作用

基本信息

批准号：
10862032
负责人：
Brian Michael McDermott
金额：
$ 57.28万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10862032
关键词：
Acceleration Acoustics Auditory Behavior Biochemical Biological Assay Biological Models Cell physiology Cochlea Complement Complex Computer Models Cysteine Data Defect Dependence Detection Dimerization Dyes Ear Electrophysiology (science)Family Fishes Fluorescence Frequencies Functional disorder Genes Genomics Hair Hair Cells Hearing Height Heterodimerization Homodimerization Human Image Individual Ion Channel Ions Link Mammals Maps Mediating Methods Modeling Molecular Morphology Motion Mus Mutagenesis Mutate Mutation Organ Organelles Physiology Plasmids Play Positioning Attribute Process Property Proteins Role Saccule structure Scanning Electron Microscopy Stereocilium Stimulus System Testing Vestibule Water Work Zebrafish calcium indicator deafness dimer experimental study in vivo insight lateral line mRNA Expression mechanical stimulus mechanotransduction member mutant neuromast novel patch clamp prepulse inhibition reconstitution response sound success

Acceleration Acoustics Auditory Behavior Biochemical Biological Assay Biological Models Cell physiology Cochlea Complement Complex Computer Models Cysteine Data Defect Dependence Detection Dimerization Dyes Ear Electrophysiology (science)Family Fishes Fluorescence Frequencies Functional disorder Genes Genomics Hair Hair Cells Hearing Height Heterodimerization Homodimerization Human Image Individual Ion Channel Ions Link Mammals Maps Mediating Methods Modeling Molecular Morphology Motion Mus Mutagenesis Mutate Mutation Organ Organelles Physiology Plasmids Play Positioning Attribute Process Property Proteins Role Saccule structure Scanning Electron Microscopy Stereocilium Stimulus System Testing Vestibule Water Work Zebrafish calcium indicator deafness dimer experimental study in vivo insight lateral line mRNA Expression mechanical stimulus mechanotransduction member mutant neuromast novel patch clamp prepulse inhibition reconstitution response sound success

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项目摘要

PROJECT SUMMARY The zebrafish model system has effectively offered insights into the molecular mechanisms of hearing, deafness, and hair cell function. Its success partly lies in the morphological and genomic similarities related to hearing between zebrafish and mammals. Explicitly, at the cellular level, the morphology of the hair cell is similar and its signature organelles are conserved. In mammals and zebrafish, the hair bundle has stereocilia of graded heights. At the molecular level, the stereocilia are joined by tip links to permit mechanotransduction. Numerous genes that when mutated cause deafness in humans or mice, also cause deafness or hair cell dysfunction in fish. Mutations in TMCs cause deafness forms DFNB7/11 and DFNA36 in humans and defects in the hair cells of the lateral line and ear in zebrafish. Studies on mouse and zebrafish Tmcs indicate that different hair cell-containing organs require different Tmc proteins or combinations of Tmc proteins to carry out their specific task in receiving and encoding different types of mechanical stimuli. Moreover, hair cells within the same organ can have different Tmc requirements. For instance, some hair cells within a lateral line neuromast organ require Tmc2a and others require both Tmc2a and Tmc2b; this indicates that these proteins may work together for mechanotransduction and this could change the quality of this process. Moreover, there is evidence that all Tmcs are not equivalent. How the organs differ in terms of the Tmcs that they express and require for functioning and the reasons for these differences are currently unknown. Here, we will examine the roles of Tmcs in hair cell mechanotransduction in zebrafish. In Specific Aim 1, we will determine if Tmcs contribute differently to zebrafish hearing. In Specific Aim 2, we will determine the role of Tmcs in hair cell mechanotransduction and lateral line- mediated behavior. In Specific Aim 3, we will determine whether Tmcs interact in vivo. These studies should allow a deeper understanding of how hair cells use particular Tmcs to encode stimuli for hearing and behavior.

项目摘要斑马鱼模型系统有效地提供了对听力，耳聋，耳聋的分子机制的见解。和毛细胞功能。它的成功部分在于与听力相关的形态和基因组相似性在斑马鱼和哺乳动物之间。明确地，在细胞水平上，毛细胞的形态相似，其形态相似签名细胞器是保守的。在哺乳动物和斑马鱼中，头发束具有分级高度的立体胶质。在分子水平上，立体胶质通过尖端链路连接，以允许机械转移。许多基因当突变引起人类或小鼠的耳聋时，还会引起鱼类的耳聋或毛细胞功能障碍。 TMC中的突变引起耳聋形成DFNB7/11和人类中的DFNA36，以及在毛细胞中的缺陷斑马鱼的侧线和耳朵。小鼠和斑马鱼TMC的研究表明，含毛细胞的不同器官需要不同的TMC蛋白或TMC蛋白的组合来执行其接受的特定任务并编码不同类型的机械刺激。此外，同一器官内的毛细胞可能具有不同的 TMC要求。例如，横向线神经层器官中的某些毛细胞需要TMC2A等同时需要TMC2A和TMC2B；这表明这些蛋白质可能会一起用于机械转移这可能会改变此过程的质量。此外，有证据表明所有TMC都不等效。器官在表达和需要功能所需的TMC方面有何不同这些差异目前未知。在这里，我们将检查TMC在毛细胞中的作用斑马鱼中的机械转导。在特定目标1中，我们将确定TMC是否对斑马鱼有不同的贡献听力。在特定的目标2中，我们将确定TMC在毛细胞机械转导和侧线 - 介导的行为。在特定的目标3中，我们将确定TMC是否在体内相互作用。这些研究应该让您更深入地了解毛细胞如何使用特定的TMC编码刺激以进行听力和行为。