Global analysis of bundle protein transport in mouse vestibular hair cells

小鼠前庭毛细胞束蛋白转运的整体分析

• 批准号: 8313300
• 负责人: JOCELYN F KREY
• 金额: $ 5.22万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-03 至 2014-01-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313300
• 关键词: Actins; Affect; Affinity Chromatography; Age; Apical; Auditory; Biochemical; C-terminal; Carrier Proteins; Cells; Chickens; Cochlea; Defect; Development; Diagnosis; Equilibrium; Foundations; Functional disorder; Future; Genes; Goals; Hair; Hair Cells; Hearing; Hearing problem; Lead; Link; MYO7A gene; Maintenance; Methods; Molecular; Motor; Mouse Protein; Mus; Mutant Strains Mice; Mutation; Myosin ATPase; Natural regeneration; Play; Protein Binding Domain; Proteins; Proteome; Proteomics; Research; Role; Sensory; Staging; Stereocilium; Structure; Surface; Tail; Techniques; Testing; Utricle structure; Vestibular Hair Cells; Wild Type Mouse; deafness; equilibration disorder; improved; mouse model; mutant; postnatal; protein expression; protein protein interaction; protein transport; repaired; research study; therapeutic development

DESCRIPTION (provided by applicant): The perception of sound and balance depends on the mechanosensory function of the hair bundle, a group of actin-filled stereocilia that project from the apical surface of auditory and vestibular hair cells. The study of deafness-linked genes has led to the identification of a number of proteins that are localized to the hair bundle and contribute to its development and function [1]. Despite these advances, the complete network of proteins that constitute the hair bundle and regulate its maturation, maintenance and function remain poorly defined. Although the mechanisms by which proteins are specifically transported to the bundle are also poorly understood, accumulated evidence suggests that myosin motor proteins may play important roles [2]. The goal of this proposal is to identify the bundle proteins that are transported to and maintained within the hair bundle during its formation and to test the hypothesis that myosin-VIIa (MYO7A) plays a role in the transport of these proteins. Using proteomics approaches as well as other biochemical techniques, the aims in this proposal will 1) identify in an unbiased manner the protein networks that are enriched within the hair bundle during and after bundle assembly, 2) determine whether MYO7A plays a role in the transport of specific proteins to the bundle and 3) identify which of these bundle-specific proteins directly or indirectly interact with MYO7A. The results of these studies will significantly contribute to our molecular understanding of bundle assembly and function and could help guide the development of therapeutic strategies for hair cell repair and regeneration. PUBLIC HEALTH RELEVANCE: The studies in this proposal will lead to a more comprehensive understanding of the molecular mechanisms underlying the development and function of auditory and vestibular hair cells. The proposed research will also help determine how deafness-causing mutations in specific genes perturb the assembly and function of the sensory apparatus within the hair cell. The results from these studies may guide the future identification of new deafness genes that will aid in improving the diagnosis and treatments of various hearing and balance disorders.

描述（由申请人提供）：声音和平衡的感知取决于毛束的机械感觉功能，毛束是一组从听觉和前庭毛细胞顶面伸出的充满肌动蛋白的静纤毛。对与毛发相关的基因的研究已经鉴定出许多定位于毛束并有助于其发育和功能的蛋白质[1]。尽管取得了这些进展，但构成毛束并调节其成熟、维持和功能的完整蛋白质网络仍然定义不清。虽然蛋白质特异性运输到束的机制也知之甚少，但积累的证据表明肌球蛋白马达蛋白可能发挥重要作用[2]。这项提议的目的是鉴定束蛋白 在毛束形成过程中，这些蛋白质被运输并维持在毛束内，并检验肌球蛋白-VIIa（MYO 7A）在这些蛋白质的运输中起作用的假设。使用蛋白质组学方法以及其他生物化学技术，本提案中的目标将1）以无偏的方式鉴定在毛束组装期间和之后在毛束内富集的蛋白质网络，2）确定MYO 7A是否在特定蛋白质向毛束的运输中起作用，以及3）鉴定这些毛束特异性蛋白质中的哪一种直接或间接地与MYO 7A结合。 与MYO 7A相互作用。这些研究的结果将大大有助于我们对毛束组装和功能的分子理解，并有助于指导毛细胞修复和再生治疗策略的发展。 公共卫生关系：本研究将有助于更全面地了解听觉和前庭毛细胞发育和功能的分子机制。这项研究还将有助于确定特定基因中引起肥胖的突变如何扰乱毛细胞内感觉器官的组装和功能。这些研究的结果可能会指导未来识别新的耳聋基因，这将有助于改善各种听力和平衡障碍的诊断和治疗。