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

• 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
• 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

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.

项目概要 斑马鱼模型系统有效地提供了对听力、耳聋、 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 介于斑马鱼和哺乳动物之间。明确地，在细胞水平上，毛细胞的形态是相似的，其 特征细胞器得到保留。在哺乳动物和斑马鱼中，发束具有不同高度的静纤毛。 在分子水平上，静纤毛通过尖端连接连接以允许机械转导。众多基因 当突变时会导致人类或小鼠耳聋，也会导致鱼类耳聋或毛细胞功能障碍。 TMC 突变会导致人类耳聋（DFNB7/11 和 DFNA36）以及毛细胞缺陷 斑马鱼的侧线和耳朵。对小鼠和斑马鱼 Tmcs 的研究表明，含有不同毛细胞的 器官需要不同的 Tmc 蛋白或 Tmc 蛋白的组合来执行其接收信息的特定任务 并对不同类型的机械刺激进行编码。此外，同一器官内的毛细胞可以具有不同的 TMC 要求。例如，侧线神经丘器官内的一些毛细胞需要 Tmc2a，而其他毛细胞则需要 Tmc2a 需要 Tmc2a 和 Tmc2b；这表明这些蛋白质可能共同作用以进行机械转导 这可能会改变这个过程的质量。此外，有证据表明并非所有 Tmc 都是等效的。 器官在表达和发挥功能所需的 Tmc 方面有何不同以及其原因 这些差异目前未知。在这里，我们将研究 Tmcs 在毛细胞中的作用 斑马鱼的机械传导。在具体目标 1 中，我们将确定 Tmcs 对斑马鱼的贡献是否不同 听力。在具体目标 2 中，我们将确定 Tmcs 在毛细胞机械转导和侧线中的作用 - 中介行为。在具体目标 3 中，我们将确定 Tmcs 是否在体内相互作用。这些研究应该 允许更深入地了解毛细胞如何使用特定的 Tmc 来编码听觉和行为刺激。