MECHANISMS REGULATING COCHLEAR DEVELOPMENT

说明书(申请人提供)：解剖成纤维细胞生长因子信号在耳蜗形成中的作用项目摘要/摘要我对成纤维细胞生长因子(FGFs)调节耳蜗形成的机制很感兴趣。FGF20在发育中的耳蜗中表达，缺失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，耳蜗内的感觉器官Corti器官中的外毛细胞受到严重破坏。具体地说，FGF20-/-小鼠的耳蜗感觉上皮含有无法发生正常细胞分化的大片区域。这种外毛细胞的丢失和细胞组织的破坏很可能是这些小鼠听力严重丧失的原因。此外，Fgf9和FGF20的缺失导致了耳蜗大小的减小，这表明FGF9/20对感觉细胞的形成可能是重要的。我提出的研究的目标是确定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，这些研究将测试重新激活成人内耳中的FGF9/20信号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不可少的调节因子。要考虑以FGF9/20为基础的感觉再生疗法，有必要了解FGF9/20在内耳感觉发育过程中的正常调节和功能。在这项提议中，我将确定FGF20(和FGF9)调控耳蜗发育和感觉上皮模式不同阶段的细胞靶点(上皮和间质)，并使用下一代mRNA测序来确定FGF9/20在发育内耳中的下游靶点。了解FGF9/20调节耳蜗发育和模式形成的机制对于开发治疗激活FGF9/20调节的成人发育程序以促进受损感觉组织修复的方法至关重要。

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.