Maintenance of a ciliated airway surface is essential for normal clearance of inhaled particles and mucous secretions. Insults such as respiratory viral infections or exposure to pollutants can result in airway inflammation, cell injury, loss of ciliated cells and secretory cell hyperplasia. Following such insults, the distribution of epithelial cell types can change rapidly. This project will focus on defining the timing and molecular events involved in phenotypic transitions of ciliated epithelium following acute injury. Our preliminary studies suggest that ciliated cells, after a sub-lethal injury, shed their cilia, remain viable within the epithelial layer, and possibly transition to a secretory cell phenotype. Our central hypotheses is that airway epithelial cells, including ciliated cells, transition from one cell type to another in response to changes in their environment. These studies will use two in vivo injury models (ferrets infected with influenza A virus or acutely exposed to sulfur dioxide).
Our specific aims are 1) to characterize changes in the distribution of cell types and cell kinetics during injury and repair, 2) to mark ciliated cells for identification and tracking after ciliary shedding, 3) to define the kinetics of ciliary protein gene expression during injury and repair and 4) to measure the effects on certain inflammatory mediators on these phenotypic transitions and cell kinetics in airway epithelium. Novel components of this proposal are the development of cilia-specific probes for characterizing the molecular events of ciliogenesis as well as development of techniques for marking ciliated cells to track their course after injury. These studies will further define the molecular responses of airway epithelium to injury and will establish the models and probes needed for studies of gene regulation during these transitions. New information and insights gained from this project will be important dir directing strategies to enhance maintenance and repair of airway from this project will be important for directing strategies to enhance maintenance and repair of airway epithelium during respiratory viral infections.
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