COBRE: BOYS TOWN NAT RES HOSP: P4: FORMATION & REGULATION OF OTOCONIA

COBRE：男孩镇 NAT RES HOSP：P4：阵型

• 批准号: 7382086
• 负责人: Yunxia Wang Lundberg
• 金额: $ 27.31万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382086
• 关键词: COBRE; BOYS; TOWN; NAT; RES

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Otoconia, crystallites of CaCO3 and proteins, are required for an individual to sense linear acceleration and gravity for spatial orientation and balance control. Dysfunction of this system is a critical clinical problem, particulady in the elderly, yet little is known about the mechanisms that regulate otoconial biosynthesis. Otoconia appear to be in a dynamic state of equilibrium highly susceptible to adverse effects of aging, infections, diseases and genetic mutations, but the molecular mechanisms of these problems are largely unknown. Our overall hypotheses are that (1) the interplay of multiple specific protein components of otoconia and their embedding membrane determines their site-specific formation; (2) Otoconial protein homeostasis is essential to normal otoconia function; and (3) OC90, a major protein component of otoconia, is essential for the formation of otoconia by sequestering Ca. OC90 mutant mice will manifest a functional deficit of the inner ear, with the vestibule as the focus of this proposal. Specifically in this proposal, we will (1) identify other murine otoconial proteins and their cellular origin, to help identify factors that may contribute to otoconia formation. We will identify any interactions among OC90, otogelin, and other proteins in otoconia, its embedding membrane or the sensory epithelium by co-precipitation on PS10 protein chips to test hypothesis #1. (2) We will examine whether disrupted otoconin homeostasis caused the abnormal and malfunctioning otoconia in aging (C57BI/6J) and degenerating otoconia (head-tilt mice) by protein profiling on H4 chips, and examine changes in the deposition of otoconial proteins in embryos and newborn pups that have disrupted calcium homeostasis (tilt, PMCA-/- mice). (3) Then we will test hypothesis #3 by examining the spatial coordination of OC90 expression and Ca transportation, and by making two mutant mouse lines, one null and the other carting only one functional (PLA2L) domain, to study the role of OC90 in otoconia formation and gravity sensing, as well as in cochlea function. Combined with future sophisticated behavioral, physiological and gene/protein profiling studies, we will demonstrate the role of OC90 in bodily balancing, the molecular mechanisms of site-specific formation, regulation and proper maintenance of otoconia. Thus we will contribute to understanding inner ear development, function, physiology and pathology.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。 Otoconia（Caco3和蛋白质的微晶）是个人需要线性加速度和重力以进行空间取向和平衡控制所必需的。该系统的功能障碍是一个关键的临床问题，特别是老年人，但对调节耳尾生物合成的机制知之甚少。奥托可症似乎处于高度容易受到衰老，感染，疾病和遗传突变的不良影响的平衡状态，但是这些问题的分子机制在很大程度上是未知的。我们的总体假设是（1）Otoconia的多种特异性蛋白质成分及其嵌入膜的相互作用决定了其特定地点的形成； （2）耳尾蛋白稳态对于正常的耳鼻肌功能至关重要； （3）OC90是Otoconia的主要蛋白质成分，对于通过隔离Ca形成Otoconia至关重要。 OC90突变小鼠将以前庭的重点表现出内耳的功能不足。具体来说，我们将（1）识别其他鼠耳尾蛋白及其细胞来源，以帮助确定可能有助于奥托托西病的因素。我们将通过在PS10蛋白芯片上共沉淀以检验假设1，确定OTOCONIA中OC90，Otogelin和其他蛋白质之间的任何相互作用。 （2）我们将检查奥托托蛋白稳态的干扰是否引起衰老（C57BI/6J）的耳鼻肌异常和功能失调，并通过蛋白质分析H4芯片上的蛋白质分析，并检查了在H4芯片上的蛋白质分析，并检查了在胚胎中的持续变化，从而使Otococonial Protium（新生）的变化（the）的蛋白质（头部倾斜小鼠）均导致了Otococonial Protise（新生）的变化。 PMCA - / - 小鼠）。 （3）然后，我们将通过检查OC90表达和CA转运的空间配位以及使两种突变小鼠系，一个无效的一个NULL和另一个功能（PLA2L）结构域来研究假设3，以研究OC90在Otoconia形成和重力传感中的作用，以及在Cochlea函数中的作用。结合未来复杂的行为，生理和基因/蛋白质分析研究，我们将证明OC90在身体平衡，位点特异性形成的分子机制，调节和适当维持耳状症中的作用。因此，我们将有助于理解内耳的发育，功能，生理和病理学。