Development and function in mucociliary epithelia

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Abstract: The mucociliary epithelium plays a key role in both normal and pathological airway biology, as it provides the first line of defense against inhaled agents. Defects in the structure or function of multiciliated cells (MCCs) in the mucociliary epithelium contribute to the progression of both genetic and acquired airway diseases. Here, we will study the molecular mechanisms controlling development and function of MCCs. 1) Our previous work demonstrated an essential role for the RFX2 transcription in motile ciliogenesis, and here we combine a novel model system, in vivo imaging, and a high-content screen for protein localization to ask how Rfx2 target genes govern actin assembly that in turn is crucial for ciliogenesis. 2) Our previous work has also generated a deeper appreciation of the complexity of molecular heterogeneity along the length of motile cilia. We will define the molecular hierarchy by which this heterogeneity is established and we link these mechanisms to cilia beating. 3) Dynein arms are complex multi-protein machines that drive ciliary beating and our protein localization screen suggests that the assembly process is compartmentalized in a novel, MCC-specific organelle. We will explore the molecular and cell biological mechanism underlying this novel organelle's function. By rapidly determining the functions of several new genes involved in distinct processes in mucociliary epithelial development, the Aims in this proposal will provide critical new depth to our understanding of these essential tissues. Moreover, by linking these 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.