MECHANISMS REGULATING COCHLEAR DEVELOPMENT

调节耳蜗发育的机制

• 批准号: 8581204
• 负责人: Sung-Ho Huh
• 金额: $ 10.11万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581204
• 关键词: Accounting; Acquired Deafness; Adult; Affect; Birds; Cell Proliferation; Cell physiology; Cells; Cochlea; Data; Defect; Development; Diagnosis; Elderly; Embryonic Development; Engineering; Epithelial; Epithelium; FGF20 gene; FGF9 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Future; Gene Targeting; Genes; Goals; Hearing; Hereditary Disease; Infant; Injury; Knock-out; Knockout Mice; Knowledge; Labyrinth; Length; Live Birth; Mesenchyme; Messenger RNA; Methods; Mitotic; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Natural regeneration; Organ of Corti; Otic Vesicle; Outer Hair Cells; Outer Supporting Cell; Pattern; Phenotype; Presbycusis; Regulation; Research; Role; Sensorineural Hearing Loss; Sensory; Signal Pathway; Signal Transduction; Staging; Stem cells; Testing; Therapeutic; Tissues; abstracting; base; cellular targeting; deep sequencing; fibroblast growth factor 9; gene function; hearing impairment; human FGF20 protein; interest; method development; mouse FGF20 protein; mouse model; mutant; prevent; programs; public health relevance; repaired; research study; response; sound; tissue repair

DESCRIPTION (provided by applicant): Dissecting function of FGF signal in cochlear formation Project Summary/Abstract I am interested in the mechanisms by which Fibroblast Growth Factors (FGFs) regulate cochlear formation. Fgf20 is expressed in the developing cochlea and deleting Fgf20 (Fgf20-/-) results in profound hearing loss in otherwise healthy mice. Examination of the inner ears of Fgf20-/- mice revealed that outer hair cells in the organ of Corti the sensory apparatus within the cochlea, were severely disrupted. Specifically, the cochlear sensory epithelium in Fgf20-/- mice contained large regions in which normal cellular differentiation failed to occur. It is likely that this loss of outer hair cells and disruption of ellular organization accounts for the profound hearing loss in these mice. Moreover, deletion of both Fgf9 and Fgf20 resulted in decreased cochlear size, which indicates that FGF9/20 might be important for sensory cell formation. The goal of my proposed research is to identify molecular and cellular functions of FGF9/20 during inner ear development. This knowledge is necessary for future studies that will test whether reactivation of FGF9/20 signaling in the adult inner ear can promote regeneration of the sensory epithelium. Expression patterns and the mutant phenotype demonstrate that FGF9/20 are critical and essential regulators of cochlear development. To consider FGF9/20-based therapies for sensory regeneration, it is essential to understand the normal regulation and function of FGF9/20 during inner ear sensory development. In this proposal, I will identify cellular targets (epithelium vs. mesenchyme) by which FGF20 (and FGF9) can regulate different stages of cochlear development and sensory epithelial patterning and use Next Gen mRNA sequencing to identify downstream targets of FGF9/20 in the developing inner ear. Understanding the mechanisms by which FGF9/20 regulates cochlear development and patterning will be essential to develop methods to therapeutically activate FGF9/20-regulated developmental programs in the adult to promote the repair of damaged sensory tissue.

描述（由申请人提供）：剖析 FGF 信号在耳蜗形成中的功能 项目摘要/摘要 我对成纤维细胞生长因子 (FGF) 调节耳蜗形成的机制感兴趣。 Fgf20 在发育中的耳蜗中表达，删除 Fgf20 (Fgf20-/-) 会导致其他健康小鼠的严重听力损失。对 Fgf20-/- 小鼠内耳的检查显示，柯蒂氏器（耳蜗内的感觉器官）的外毛细胞受到严重破坏。具体来说，Fgf20-/-小鼠的耳蜗感觉上皮包含大片区域，其中正常细胞分化未能发生。外毛细胞的丧失和细胞组织的破坏很可能是这些小鼠严重听力损失的原因。此外，Fgf9 和 Fgf20 的缺失导致耳蜗尺寸减小，这表明 FGF9/20 可能对感觉细胞的形成很重要。我提出的研究目标是确定 FGF9/20 在内耳发育过程中的分子和细胞功能。这些知识对于未来的研究是必要的，这些研究将测试成人内耳中 FGF9/20 信号的重新激活是否可以促进感觉上皮的再生。表达模式和突变表型表明 FGF9/20 是耳蜗发育的关键且必需的调节因子。要考虑基于 FGF9/20 的感觉再生疗法，必须了解 FGF9/20 在内耳感觉发育过程中的正常调节和功能。在本提案中，我将确定 FGF20（和 FGF9）可以调节耳蜗发育和感觉上皮模式不同阶段的细胞靶标（上皮与间充质），并使用下一代 mRNA 测序来识别发育中的内耳中 FGF9/20 的下游靶标。了解 FGF9/20 调节耳蜗发育和模式的机制对于开发治疗性激活成人 FGF9/20 调节发育程序以促进受损感觉组织修复的方法至关重要。