OTOCONIA DEVELOPMENT AND MAINTENANCE

Otoconia 开发与维护

• 批准号: 7874501
• 负责人: Yunxia Wang Lundberg
• 金额: $ 27.28万
• 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/7874501
• 关键词: Acceleration; Address; Adult; Affect; Affinity; Air; Animals; Apical; Benign; Binding; Biochemical; Cell secretion; Co-Immunoprecipitations; Complex; Crystal Formation; Cytoskeleton; Data; Development; 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; Maintenance; Mediating; Membrane; Membrane Proteins; Morphology; Motion; Mus; Mutant Strains Mice; Nerve Endings; 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; equilibration disorder; 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）：我们的重力和线性加速度对于空间取向和平衡至关重要。这种感觉是通过刺激前庭毛细胞来介导的，这是通过在内耳中的感觉上皮的位移。与Otoconia相关的平衡障碍和头晕是一个重大的健康问题，影响了美国超过600万成年人。这个问题在老年人中更糟。尽管鉴定出许多参与耳核/耳纤维异常涉及的蛋白质，但蛋白质的功能均未定义蛋白质的功能或晶体形成的机制或过程。使用基因靶向策略，我们已经证明了主要的哺乳动物耳鼻蛋白Otoconin-90/95（AS OC90）是Otoconia有机基质的必不可少的组织者，它是通过招募重要的其他成分来钙化而对Otoconia的必不可少的组织者。 OC90无效小鼠具有巨大的“ Otoconia”，数量大大减少，从而导致平衡缺陷。该建议旨在进行深度的定量表达研究和蛋白质生化分析，以解决OC90和耳托蛋白在提供最佳耳鼻钙化钙化中的作用，并确定对耳鼻虫的空间特定发育至关重要的因素。我们将严格检验以下假设：OC90专门募集重要的耳鼻蛋白，耳托蛋白，以形成Otoconia基质和播种，并确定这种特异性的基础机制。然后，我们将使用现有的O> Tectorin Null小鼠生成OC90/A-Tectorin的双重敲除，以测试这两种蛋白质在Otoconia播种中由于与耳托蛋白的相互作用而在Otoconia播种中相互促进的假设。然后，我们将开始研究以识别负责奥托托西病空间特定发展的因素。这些研究将定义一些关键组成部分在确定耳尾症形成方面的作用，并为某些关键组成部分提供机制。