OTOCONIA DEVELOPMENT AND MAINTENANCE

Otoconia 开发与维护

• 批准号: 7434491
• 负责人: Yunxia Wang Lundberg
• 金额: $ 27.56万
• 依托单位: FATHER FLANAGAN'S BOYS' HOME
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7434491
• 关键词: Acceleration; Address; Adult; Affect; Affinity; Air; Animals; Apical; Benign; Binding; Biochemical; Cell secretion; Co-Immunoprecipitations; Complex; Crystal Formation; Cytoskeleton; Data; Depth; Development; Disease; Dizziness; Elderly; Epithelial; Epithelium; Equilibrium; Esthesia; Evoked Potentials; Force of Gravity; Future; Gait; Gene Targeting; Goals; Gravity Perception; Growth; Hair Cells; Head; Health; Human; Immunohistochemistry; In Situ Hybridization; Joint Dislocation; Knock-out; Knockout Mice; Laboratories; Labyrinth; Localized; Maintenance; Mediating; Membrane; Membrane Proteins; Morphology; Motion; Mus; Mutant Strains Mice; Nerve Endings; Numbers; Pattern; Population; Positional Vertigo; Prevention strategy; Process; Protein Analysis; Proteins; Proteoglycan; Recruitment Activity; Research Personnel; Role; Sensory; Sensory Hair; Space Perception; Specificity; Suggestion; Testing; Therapeutic; Tissues; Transgenic Organisms; United States; Vestibular Hair Cells; Western Blotting; calcification; cell type; design; glycanase; macula; novel; numb protein; otoconia; otoconin 90; otogelin; programs; protein function; response; sample fixation; tectorial membrane

DESCRIPTION (provided by applicant): Our sense of gravity and linear acceleration is critical for spatial orientation and balance. Such sense is mediated by stimulation of vestibular hair cells by the displacement of otoconia against the sensory epithelium in the inner ear. Otoconia-related balance disorders and dizziness are a significant health issue that affects over 6 million adults in the United States. This problem is worse in the elderly. Despite the identification of a number of proteins involved in otoconia/otolith abnormalities, neither the functions of the proteins nor the mechanisms or processes of crystal formation are defined. Using a gene targeting strategy, we have demonstrated that the predominant mammalian otoconial protein, otoconin-90/95 (as Oc90), is an essential organizer of the organic matrix of otoconia by recruiting other components important for calcification. Oc90 null mice have giant "otoconia" with a greatly reduced number, which leads to balance deficits. This proposal is designed to perform in- depth quantitative expression studies and protein biochemical analyses to address the roles of Oc90 and otolin in providing optimal otoconia calcification and to identify factors critical for the spatial specific development of otoconia. We will rigorously test the hypothesis that Oc90 specifically recruits an important otoconin, otolin, for otoconia matrix formation and seeding and identify the mechanism underlying such specificity. We will then use the existing o> tectorin null mice to generate double knockouts of Oc90/a-tectorin to test the hypothesis that these two proteins facilitate each other in otoconia seeding due to their mutual interactions with otolin. We will then begin studies to identify factor(s) that are responsible for the spatial specific development of otoconia. These studies will define the roles of and provide a mechanism for some critical components in determining otoconia formation.

描述（由申请人提供）：我们的重力感和线性加速度对于空间定向和平衡至关重要。这种感觉是通过耳石相对于内耳感觉上皮的位移刺激前庭毛细胞来介导的。与耳聋相关的平衡障碍和头晕是一个严重的健康问题，影响着美国超过 600 万成年人。这个问题在老年人中更为严重。尽管鉴定了许多与耳石/耳石异常有关的蛋白质，但这些蛋白质的功能和晶体形成的机制或过程都没有被定义。使用基因靶向策略，我们证明了主要的哺乳动物耳石蛋白，otoconin-90/95（如 Oc90），通过招募其他对钙化重要的成分，是耳石有机基质的重要组织者。 Oc90缺失小鼠具有巨大的“耳石”，但数量大大减少，从而导致平衡缺陷。该提案旨在进行深入的定量表达研究和蛋白质生化分析，以解决 Oc90 和 otolin 在提供最佳耳石钙化方面的作用，并确定对耳石空间特定发育至关重要的因素。我们将严格检验 Oc90 专门招募重要的耳石素（otolin）用于耳石基质形成和播种的假设，并确定这种特异性背后的机制。然后，我们将使用现有的 o> tectorin 无效小鼠产生 Oc90/a-tectorin 的双敲除，以测试这两种蛋白质由于与 otolin 相互作用而在 otoconia 播种中相互促进的假设。然后我们将开始研究以确定导致耳石空间特定发育的因素。这些研究将定义一些关键成分在决定耳石形成中的作用并提供机制。