The role of multiciliated cell dysfunction in pathogenesis of IPF

Project Summary/ Abstract The goal of this proposal is to determine if mucociliary clearance (MCC) dysfunction in idiopathic pulmonary fibrosis (IPF) is due to abnormal multiciliated cell differentiation and function. Recent evidence suggests that IPF may be a mucociliary disease caused by recurrent injury/inflammation/repair at the bronchoalveolar junction,

which is initiated and exacerbated by overexpression of MUC5B and reduced mucociliary function, retention of particles, and enhanced lung injury. Motile cilia of multiciliated cells beat in a coordinated manner to propel inhaled contaminants trapped by the mucus layer out of the lungs via MCC. Defects in airway clearance can precipitate and/or exacerbate acute

infections and chronic inflammatory conditions in pulmonary disease. In mice, our lab demonstrated that Muc5b concentration in bronchoalveolar epithelia is related to impaired MCC and to the extent and persistence of bleomycin-induced lung fibrosis, raising the question how disrupted motile cilia structure affects MCC and how

that leads to IPF. Even though ciliary abnormalities such as short, misaligned or ultrastructural cilia have been reported in other pulmonary diseases, the origin of multiciliated cells, ciliary abnormalities, and its effect on MCC dysfunction associated with MUC5B RNA and MUC5B protein in IPF has not been studied yet.

My preliminary studies using wild-type mice have demonstrated that there are some regenerated motile cilia with ciliary abnormalities upon airway damage. Further, association of MUC5B and cilia gene expression also found in human IPF airway epithelial cells, providing a rationale for examining the role of multiciliated cells in this

disease. Thus, the aim of this proposal is to address the central hypothesis that MUC5B/Muc5b overexpression in distal airway progenitor cells enhances ciliated cell fate acquisition, ciliary structural defects, and impaired mucociliary clearance during repair following injury. This hypothesis will be tested in 3 Specific Aims: 1). Identify

the origin of multiciliated cells with cilia abnormalities and investigate their response in the bleomycin model of lung fibrosis; 2). Test the hypothesis that mucociliary clearance dysfunction due to motile cilia abnormalities is enhanced by Muc5b in the bleomycin lung fibrosis model.; 3). Determine the effect of the MUC5B promoter

variant on structure of motile cilia and mucociliary function of multiciliated cells in IPF lung. The proposed work will solve an existing challenge by defining the origin of multiciliated cells in the bleomycin model and by identifying function of disrupted motile cilia of multiciliated cell, allowing to elucidate their role in

pathogenesis in IPF model. This work and the integrated training plan will allow the investigator to establish comprehensive knowledge on lung injury and regeneration and expertise and skills to subsequently define the molecular mechanism leading to successful lung tissue regeneration in a future independent research career.