Development and function in mucociliary epithelia

描述(申请人提供)：粘液纤毛上皮在正常和病理的呼吸道生物学中都占有中心地位，因为它既提供了空气交换的界面，也提供了抵御吸入剂的第一道防线。在这里，我们将研究转录因子RFX2，我们已经证明它是粘液纤毛上皮发育和成熟的两个关键方面所必需的。1)我们的初步数据证实了RFX2在运动纤毛发生中的重要作用。我们将结合一个新的模型系统，活体成像，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)新生的多纤毛细胞来源于位于基底部的间充质干细胞，它们必须向顶端迁移并植入上皮。粘液纤毛生物学中的这一关键过程仍然几乎完全不确定，但我们发现RFX2对于这种插入是必不可少的。我们将再次结合基因组学、生物信息学和活体成像来研究RFX2在这方面的作用。通过快速确定在粘膜纤毛上皮发育的不同过程中涉及的几个新基因的功能，该项目的目标将提供关键的新的 加深了我们对这些重要组织的了解。此外，通过将单个转录因子与粘液纤毛上皮生物学的两个不同方面的控制联系起来，这里的实验也将为我们的理解增加至关重要的新广度。影响：这里提出的实验将导致对粘液纤毛上皮的细胞生物学和遗传学的更详细的了解。这一结果将有助于开发旨在修复或恢复受损组织并改善呼吸道疾病患者粘液清除的再生疗法。

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.