Idiopathic Pulmonary Fibrosis, a Disease Initiated by Mucociliary Dysfunction

ABSTRACT

The overarching goal of this Program is to develop the scientific knowledge needed to predict and prevent the progression of IPF. We postulate that IPF is caused by recurrent injury/repair/regeneration at the bronchoalveolar junction secondary to overexpression of MUC5B, mucociliary dysfunction, retention of particles, ER stress, and disruption of normal reparative and regenerative mechanisms in the distal lung. During the first year of funding, we have (1) obtained local and DoD approvals for human and animal research;(2) enrolled 26 first degree relatives of individuals with IPF and completed all study procedures for Project 1;(3) performed ChIP, MNase, and TF binding assays to show that MUC5B promoter region is hyperchippable and that HIF1 and GCF bind in this region (Project 2);(4) imported and bred new strains of mice (St3gal3, Fut2, Ern2, Ift88, and Arl13b) in Projects 3 and 4;(5) developed and assessed the amounts and glycosylation of Muc5b in mouse models at baseline, and identified changes in polymer size and migration after inflammatory challenge (Project 3);(6) identified 10 weeks post-injury as a key timepoint for increased ciliogenesis in Muc5b Tg mice and began characterization of ciliogenesis in human lung, and (7) presented findings at two international conferences and published two manuscripts.