Development and function in mucociliary epithelia

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 ciliary beating in multiciliated cells (MCCs) in the airway contribute to the progression of both genetic and acquired airway diseases. Here, we will study the molecular mechanisms controlling development and function of MCCs. The motor proteins that drive ciliary beating are assembled in the cytoplasm, and under the previous version of this award, we discovered a novel organelle in which these motors are concentrated with various factors that direct their assembly. The first Aim of this project will explore the hierarchy of interaction among proteins in these novel organelles; the second will explore the mechanisms by which motors are transported into cilia, and the third will use large-sale proteomic approaches to identify novel protein-protein interactions important for motor assembly and function. By rapidly determining the functions of several new protein involved in distinct processes in MCC development, the Aims in this proposal will provide critical new depth to our understanding of these essential cell. Moreover, by linking these the disparate processes in MCCs, 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 MCCs and ciliary beating. 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.