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In the lung, airway epithelia function as the first defense line against the invasion of air-borne pathogens. The two major cell types in airway epithelia are goblet cells and multiciliated cells (MCCs). Sticky mucus secreted by goblet cells to the surface of airway epithelia trap inhaled pathogens like virus, bacteria, and other micro-organisms; and the coordinated beating of cilia on top of MCCs sweep away the dirty mucus to keep airway clean. In motile cilia-related lung disorders like Primary Ciliary Dyskinesia (PCD) and Chronic Obstructive Pulmonary Disease (COPD), airway motile cilia are defective. And without the service of airway motile cilia, mucus will accumulate in the airway and eventually block the airway, pathogens inside mucus can irritate the airway and trigger infection. The causes of ciliary defects in these two respiratory diseases are distinct: in PCD, genetic faults lead to underdeveloped motile cilia, which is inherited; in COPD, tobacco smoking results in shortening and various damages of airway motile cilia, which is acquired. Our past study has shown that a microRNA gene family, mir-34/449, is required for the development of motile cilia. Removal of this gene family in mice leads to a significant decrease in both length and number of airway motile cilia, and consequently the mir-34/449 deficient mice develop the PCD symptoms. Consistent with the crucial roles of miR-34/449 miRNAs in airway MCCs, a remarkable decrease of miR-34/449 expression in the lung has been shown to be a response to tobacco smoking and associated with COPD progression. Therefore, a deeper understanding of miR-34/449 miRNAs in airway MCCs will provide essential preliminary data to support the development of an early detection and a treatment of motile cilia-related lung disorders like PCD and COPD. This proposal aims to generate a comprehensive and detailed picture of miR-34/449 miRNAs in mouse and human airway MCCs, and test the feasibility of using miR-34/449 miRNAs and downstream targets to treat motile-cilia related lung diseases. This work will have significant implications on both basic biology and potential clinical applications. |
