Cytoskeletal dynamics in stereocilia maintenance

静纤毛维持中的细胞骨架动力学

基本信息

批准号：
8423327
负责人：
BENJAMIN J PERRIN
金额：
$ 14.44万
依托单位：
UNIVERSITY OF MINNESOTA
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 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8423327
关键词：
Actin-Binding Protein Actins Adult Affect Affinity Aging Apical Auditory Binding Biochemical Biology Bundling Cell Maintenance Cell physiology Cells Cellular Structures Crosslinker Data Dependence F-Actin Family Fellowship Fibroblasts Foundations Frequencies Functional disorder Genes Hair Cells Health Hearing Human Inbreeding Inner Hair Cells Knock-out Knockout Mice Labyrinth Length Life Link Maintenance Measurement Measures Microfilaments Migration Assay Modeling Molecular Morphology Mouse Strains Mus Mutation Noise Noise-Induced Hearing Loss Pathologic Pattern Phenocopy Phenotype Population Presbycusis Protein Isoforms Proteins Regulation Reporter Rest Role Sensory Sensory Hair Stereocilium Structure Surface Testing Therapeutic Intervention Transgenic Mice Transgenic Organisms Work age related base crosslink deafness design fascin hearing impairment in vivo member mouse model mutant plastin postnatal programs protein crosslink recombinase repaired research study stem therapy design

项目摘要

DESCRIPTION (provided by applicant): Progressive hearing loss is a common human health problem that often stems from the loss or dysfunction of sensory hair cells in the inner ear. Actin proteins are central to hair cell structure and function; consequently, understanding the molecular mechanisms of cytoskeletal maintenance is a key step in considering rationally designed therapies for age-related or noise-induced hearing loss. ¿-Actin and ?-actin, two distinct yet closely related actin isoforms, each contribute to the population of filamentous actin in stereocilia. We have previously shown that mice with hair cells lacking either actin isoform form normal stereocilia, but go on to develop different forms of progressive hearing loss. This suggests that ¿-Actin and ?-actin each make unique contributions to stereocilia stability. This proposal is focused on two aspects of actin biology in stereocilia. In Aim 1, we will use existing conditional ¿-Actin and ?-actin knockout mouse lines and a newly developed transgenic actin reporter line to assess actin dynamics in stereocilia in vivo. In Aim 2, we will use cell biologica and biochemical approaches to determine if differential interactions between the actin bundling protein fascin 2 and ¿-actin and ?-actin contribute to distinct stereocilia maintenance mechanisms. Together, completion of these Aims will support a new model of actin regulation during stereocilia maintenance. In the long term, we will use the same suite of universal platforms established in this proposal to assess the roles of other deafness-causing mutant actin binding proteins in modulating stereocilia actin dynamics at the level of molecules, cells and mice.

描述（由适用提供）：渐进的听力损失是一个常见的人类健康问题，通常源于内耳内耳毛细胞的损失或功能障碍。肌动蛋白蛋白质是毛细胞结构和功能的核心。因此，了解细胞骨架维持的分子机制是考虑与年龄相关或噪声引起的听力损失合理设计的疗法的关键步骤。 - 肌动蛋白和 - 肌动蛋白，两个不同但密切相关的肌动蛋白同工型，每种肌动蛋白有助于丝状肌动蛋白的种群在立体中。我们以前已经表明，缺乏肌动蛋白同工型的毛细胞形成正常立体胶质的小鼠，但继续发展出不同形式的进行性听力损失。这表明 - 肌动蛋白和 - 肌动蛋白每个都对立体胶质稳定性做出了独特的贡献。该提议的重点是立体猫肌动蛋白生物学的两个方面。在AIM 1中，我们将使用现有的条件 - 肌动蛋白和 - 肌动蛋白基因敲除小鼠系和新开发的转基因肌动蛋白记者系来评估体内立体胶质肌动蛋白动力学。在AIM 2中，我们将使用细胞生物学和生化方法来确定肌动蛋白束蛋白fascin 2和-Actin和？肌动蛋白之间的差异相互作用是否有助于不同的立体维持机制。共同完成这些目标将支持立体依胶维护期间的肌动蛋白调节的新模型。从长远来看，我们将使用本提案中建立的相同的通用平台来评估其他引起死亡性突变型肌动蛋白结合蛋白在调节分子，细胞和小鼠水平上调节立体胶质素动力学中的作用。