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.
The airway is lined by a fascinating tissue called the mucociliary epithelium. The key feature of this tissue is to promote exchange of gases (oxygen and carbon dioxide) between the air and the blood, but another critical function of this tissue is performed by two key cell types, one that secretes mucus and the other decorated by tiny motile projections called cilia. The mucus forms a layer of disposable protection against inhaled particles and germs, while the cilia keep the mucus moving, replacing the old with new. Airway diseases such as asthma and COPD are exacerbated by defects (either congenital or induced) in the function of this mucociliary system. We propose here to use a battery of diverse approaches (novel animal models, genetic manipulations, time-lapse movies, large-scale genomic analysis, and computational biology) to accelerate the understanding of the development 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.
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