Planar Polarity Mechanisms in Mammalian Inner Ear Development

哺乳动物内耳发育中的平面极性机制

基本信息

批准号：
8641337
负责人：
MICHAEL R DEANS
金额：
$ 31.66万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-25 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8641337
关键词：
Acceleration Address Affect Apical Articular Range of Motion Auditory Biological Assay Cell Polarity Cell Separation Cell physiology Cell surface Cells Cochlear duct Complement Cues Detection Development Disease Dissection Epithelium Equilibrium Event Genes Genetic Goals Growth Hair Cells Health Individual Kinocilium Knock-in Mouse Knock-out Knockout Mice Label Labyrinth Lateral Lead Length Mechanics Medial Microarray Analysis Modeling Molecular Motion Movement Mus Organ Outer Hair Cells Pattern Peripheral Phase Positioning Attribute Posture Proteins Relative (related person)Reporter Research Role Saccule and Utricle Sensory Sensory Hair Sensory Receptors Side Signal Transduction Stereocilium Structure System Testing Therapeutic Intervention To specify Transgenic Mice Transgenic Organisms Utricle structure Utricular macula Vestibular Hair Cells Work base body system design emx2 protein equilibration disorder falls macula mouse model mutant nerve supply novel prevent relating to nervous system research study response sound transcription factor

项目摘要

DESCRIPTION (provided by applicant): In the vestibular system of the inner ear, motion is detected via the mechanical deflection of a bundle of stereocilia located at the top of sensory receptor hair cells. The bundle is morphologically and physiologically polarized because only movements of the bundle towards a lone kinocilium positioned at one side of the apical cell surface are able to produce excitatory responses. Thus the range of motion that can be detected by an individual hair cell is determined by the polarized orientation of the stereocilia bundle. As a result, in order to respond to the broadest range of motions the utricle and saccule contain thousands of vestibular hair cells arranged in radiating arrays spanning a range of nearly 360ps of stereocilia bundle orientations. This is achieved in part by dividing the hair cell between two groups divided by a Line of Polarity Reversal (LPR) that have opposing stereocilia bundle orientations and respond to motions in opposite directions. Our goal is to identify the genetic mechanisms that direct the development of planar polarity. This will be addressed through the course of the project using combinations of knockout and transgenic mouse models. Specifically we will test the hypothesis that the core Planar Cell Polarity (PCP) proteins establis an underlying ground polarity that coordinates the orientation of adjacent hair cells regardless of their position relative to the LPR, and that a second patterning mechanism positions the LPR. For these experiments the significance of the PCP-based ground polarity will be established using a combination of single and double knockouts mouse lines that prevent core PCP signaling. This will complement a genetic dissection of Wnt-signaling and its parallel role in positioning the LPR. Finally, additional factors directing formation of the LPR will be identified through genetic labeling and FACS-based isolation of hair cells with opposite bundle orientations followed by microarray analysis. Although focused on the development of vestibular planar polarity, we anticipate that this research will impact our understanding of auditory planar polarity as well as other organ systems that rely upon cellular polarization for growth or function

描述（由申请人提供）：在内耳的前庭系统中，通过位于感觉感受器毛细胞顶部的一束静纤毛的机械偏转来检测运动。该束在形态学和生理学上是极化的，因为只有该束朝向位于顶端细胞表面一侧的单独动纤毛的运动才能产生兴奋反应。因此，单个毛细胞可以检测到的运动范围是由静纤毛束的偏振方向决定的。因此，为了响应最广泛的运动，椭圆囊和球囊包含数千个前庭毛细胞，这些前庭毛细胞排列成辐射阵列，跨越近 360ps 的静纤毛束方向。这部分是通过将毛细胞分为两组来实现的，这两组由极性反转线（LPR）划分，这两个组具有相反的静纤毛束方向并对相反方向的运动做出反应。我们的目标是确定指导平面极性发展的遗传机制。这将在项目过程中使用基因敲除和转基因小鼠模型的组合来解决。具体来说，我们将测试以下假设：核心平面细胞极性 (PCP) 蛋白建立了一个潜在的接地极性，该接地极性可协调相邻毛细胞的方向，无论它们相对于 LPR 的位置，以及第二个图案化机制定位 LPR。对于这些实验，将使用阻止核心 PCP 信号传导的单敲除和双敲除小鼠系的组合来确定基于 PCP 的接地极性的重要性。这将补充 Wnt 信号传导的遗传解剖及其在定位 LPR 中的平行作用。最后，通过基因标记和基于 FACS 的具有相反束方向的毛细胞分离，然后进行微阵列分析，将鉴定指导 LPR 形成的其他因素。尽管重点关注前庭平面极性的发展，但我们预计这项研究将影响我们对听觉平面极性以及依赖细胞极化生长或功能的其他器官系统的理解