MECHANISMS REGULATING COCHLEAR DEVELOPMENT

项目概述/摘要本人对成纤维细胞生长因子（Fibroblast Growth Factors, FGFs）调控耳蜗形成的机制很感兴趣。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，耳蜗内感觉器官Corti的外毛细胞严重受损。具体来说，Fgf20-/-小鼠的耳蜗感觉上皮包含大片区域，其中正常的细胞分化无法发生。很可能是这种外毛细胞的损失和细胞组织的破坏导致了这些小鼠的严重听力损失。此外，Fgf9和Fgf20的缺失导致耳蜗大小减小，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鉴定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信号的再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是耳蜗发育的关键和必要的调节因子。为了考虑基于FGF9/20的感觉再生疗法，了解FGF9/20在内耳感觉发育过程中的正常调节和功能是至关重要的。在本提案中，我将确定FGF20（和FGF9）可以调节耳蜗发育不同阶段和感觉上皮模式的细胞靶点（上皮与间质），并使用Next Gen mRNA测序来确定FGF9/20在发育中的内耳中的下游靶点。了解FGF9/20调节耳蜗发育和模式的机制，对于开发方法来治疗激活成人中FGF9/20调节的发育程序以促进受损感觉组织的修复至关重要。

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.