The Role of Ankrd6 in Mammalian Inner Ear Development

Ankrd6 在哺乳动物内耳发育中的作用

• 批准号: 7289296
• 负责人: CHONNETTIA JONES
• 金额: $ 4.88万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7289296
• 关键词: Actins; Activation Analysis; Affect; Antibody Formation; Apical; Biological Models; Cell Polarity; Cellular Morphology; Cochlea; Data; Defect; Detection; Development; Development, Other; Developmental Process; Drosophila eye; Drosophila genus; Duct (organ) structure; Ear; Embryo; Epithelium; Figs - dietary; Genes; Genetic; Genetic Epistasis; Goals; Hair Cells; Hearing; Histology; Homologous Gene; Human; Immunohistochemistry; Invertebrates; Knock-out; Knockout Mice; Labyrinth; Lateral; Lead; Mechanics; Molecular; Molecular Genetics; Morphogenesis; Morphology; Mus; Mutant Strains Mice; Mutation; Neural Tube Closure; Newborn Infant; Organ; Organ of Corti; Orthologous Gene; Pathway interactions; Play; Proteins; RNA; Recombinants; Regulation; Reporter; Research; Research Proposals; Role; Sensory; Sensory Hair; Shapes; Side; Signal Pathway; Signal Transduction; Staging; Stereocilium; Stimulus; Study Subject; Surface; Techniques; Testing; Tissues; Vertebrates; Wing; Zebrafish; deafness; hearing impairment; immunocytochemistry; mutant; novel; polyclonal antibody; research study; sound

DESCRIPTION (provided by applicant): The organ of Corti, the sensory organ of the mammalian inner ear, contains mechanosensory hair cells that are uniformly oriented, such that the V-shaped stereocilia bundles at their lumenal surfaces point to the periphery of the sensory epithelium. This uniform orientation that is parallel to the plane of the sensory epithelium is called Planar Cell Polarity (PCP). The polar morphology of the stereocilia bundles is critical for maximal hearing sensitivity and the proper transduction of the mechanical sound stimulus. Mutations in genes that affect the polarity of the stereocilia lead to deafness. Studies in both invertebrate model systems, such as Drosophila, and vertebrate model systems have identified components of a conserved signaling pathway that regulates PCP. Moreover, recent studies have revealed that mammalian homologs of PCP components play an essential role in regulating PCP in the organ of Corti during inner ear development. However, the molecular mechanisms that establish and maintain this polarity are unclear. Preliminary data from our lab has identified a novel mammalian PCP candidate called Ankrd6. This application proposes three specific aims to examine the role of Ankrd6 in mammalian inner ear development and to test whether Ankrd6 regulates PCP in the organ of Corti. Aim 1 will characterize the spatial and temporal expression of Ankrd6 protein in the development of the mouse inner ear by immunohistochemistry. Aim 2 will characterize the loss of AnkrdG function on mouse inner ear development using targeted mouse knockout strategies. Aim 3 will characterize the molecular and genetic relationships between Ankrd6 and known mammalian PCP components. The research plan will exploit the conservation of the PCP pathway between invertebrates and vertebrates and employ experiments that will combine the strengths of two model systems, Drosophila and mouse. The long-term objective of this proposal is to elucidate the molecular mechanisms that regulate PCP in the organ of Corti in order to understand how genetic perturbations in factors that regulate this essential developmental process might lead to deafness. RELEVANCE. Hearing loss affects 4 in 1000 newborns. Genetic factors are believed to cause at least 50% of cases of congenital hearing loss. This research proposal will examine one of many genetic factors that may contribute to human deafness.

描述（申请人提供）：柯蒂氏器，哺乳动物内耳的感觉器官，包含均匀定向的机械感觉毛细胞，使得其腔表面的 V 形静纤毛束指向感觉上皮的外围。这种与感觉上皮平面平行的均匀方向称为平面细胞极性 (PCP)。静纤毛束的极性形态对于最大听觉灵敏度和机械声音刺激的正确传导至关重要。影响静纤毛极性的基因突变会导致耳聋。对无脊椎动物模型系统（如果蝇）和脊椎动物模型系统的研究已经确定了调节 PCP 的保守信号通路的组成部分。此外，最近的研究表明，哺乳动物的五氯苯酚成分同源物在内耳发育过程中在内耳柯蒂氏器中调节五氯苯酚中发挥着重要作用。然而，建立和维持这种极性的分子机制尚不清楚。我们实验室的初步数据已经确定了一种名为 Ankrd6 的新型哺乳动物 PCP 候选药物。本申请提出了三个具体目标，以检查 Ankrd6 在哺乳动物内耳发育中的作用，并测试 Ankrd6 是否调节 Corti 器官中的 PCP。目标 1 将通过免疫组织化学表征小鼠内耳发育过程中 Ankrd6 蛋白的空间和时间表达。目标 2 将使用靶向小鼠敲除策略来表征小鼠内耳发育中 AnkrdG 功能的丧失。目标 3 将表征 Ankrd6 与已知哺乳动物 PCP 成分之间的分子和遗传关系。该研究计划将利用无脊椎动物和脊椎动物之间 PCP 途径的保守性，并采用结合果蝇和小鼠这两个模型系统的优势的实验。该提案的长期目标是阐明调节柯蒂氏器中 PCP 的分子机制，以便了解调节这一重要发育过程的因素的遗传扰动如何可能导致耳聋。关联。听力损失影响千分之四的新生儿。据信，至少 50% 的先天性听力损失病例是由遗传因素造成的。这项研究计划将检查可能导致人类耳聋的众多遗传因素之一。