Development and function in mucociliary epithelia

描述（由申请人提供）：纤毛粘膜上皮在正常和病理气道生物学中都处于中心位置，因为它既提供了空气交换的界面，又提供了抵抗吸入剂的第一道防线。在这里，我们将研究转录因子RFX2，我们已经证明RFX2在纤毛粘膜上皮发育和成熟的两个关键方面是必不可少的。1)我们的初步数据表明RFX2在运动纤毛发生中起重要作用。我们将结合一个新的模型系统，体内成像，以及一套独特的基因组和生物信息学方法来研究RFX2在多纤毛细胞中的作用。2)新生的多纤毛细胞起源于基部的间充质干细胞，这些干细胞必须向顶端迁移并插入上皮。粘液纤毛生物学中的这一关键过程几乎完全不确定，但我们发现RFX2对这一插入至关重要。我们将再次结合基因组学、生物信息学和体内成像来研究RFX2在这种情况下的作用。通过快速确定参与纤毛粘膜上皮发育不同过程的几个新基因的功能，该项目的目标将提供关键的新方法

DESCRIPTION (provided by applicant): The mucociliary epithelium holds a central position in both normal and pathological airway biology, as it provides both the interface for air exchange and the first line of defense against inhaled agents. Here, we will study the transcription factor RFX2, which we have shown is essential for two crucial aspects of mucociliary epithelial development and maturation. 1) Our preliminary data demonstrate an essential role for RFX2 in motile ciliogenesis. We will combine a novel model system, in vivo imaging, and a unique suite of genomic and bioinformatic approaches to study the role of RFX2 in the multi-ciliated cells. 2) Newly-born multi-ciliated cells arise from basally-located mesenchymal stem cells that must migrate apically and insert into the epithelium. This crucial process in mucociliary biology remains almost totally undefined, but we find that RFX2 is essential for this insertion. We will again combine genomics, bioinformatics and in vivo imaging to study the role of RFX2 in this context. By rapidly determining the functions of several new genes involved in distinct processes in mucociliary epithelial development, the aims in this project will provide critical new depth to our understanding of these essential tissues. Moreover, by linking a single transcription factor to the control of two such disparate aspects of mucociliary epithelial biology, the experiments here will add crucial new breadth to our understanding as well. Impact: Experiments proposed here will lead to a more detailed understanding of the cell biology and genetics of mucociliary epithelia. The results will aid in the development of regenerative therapies aimed at repairing or restoring damaged tissue and improving mucus clearance in patients with airway disease.