Project Summary
Idiopathic Pulmonary Fibrosis (IPF) is an incurable, chronic, interstitial lung disease
characterized by the accumulation of fibrotic tissue. A major risk factor for developing IPF is a
commonly found gain-of-function SNP (rs35705950) in the promoter for the respiratory mucin,
MUC5B. However, the mechanistic role of MUC5B in developing IPF remains unknown. Murine
animal models have elucidated some fundamental processes of lung fibrosis, but they have
failed to recapitulate key features of the human disease and have been unsuccessful in
identifying therapies that halt or reverse disease progression, likely because they are poorly
suited to replicate the impact of mucus and MUC5B.
This highlights the critical need for 1) an animal model that represents the phenotypic
and mechanistic features of human IPF, including sustained fibrosis; 2) an improved
understanding of molecular mechanisms, including the genetic association with MUC5B
overexpression and the connection to disease pathogenesis; and 3) the identification,
development and evaluation of novel therapeutic targets based on this knowledge. With a
similar lung physiology and cell biology to humans, including Muc5b and other mucus proteins,
we have developed a novel bleomycin exposure model using ferrets. Bleomycin exposed
ferrets exhibit hallmarks of the human condition including persistent, sustained fibrotic lung
disease with collagen-rich fibrosis; Muc5b rich honeycomb cysts; fibroblastic foci; and prominent
airway remodeling displaying characteristic ‘proximalization’ of the distal airway spaces.
Based on these data, our overarching hypothesis is that heightened Muc5b expression
promotes aberrant repair mechanisms to propagate fibrosis, representing a therapeutic target
that can be modeled in ferrets. In Aim 1 we will use genetic and pharmacological approaches to
test the effects of increased and reduced Muc5b expression on fibrotic lung injury and repair,
serving as a validation of model phenotype. In Aim 2 we will determine if smoke exposure (a
potent stimulator of Muc5b expression and risk factor for IPF) predisposes ferrets to progressive
fibrosis and worsens disease severity. In Aim 3 we will determine if Muc5b is a therapeutic
target for pulmonary fibrosis by administering Muc5b-specific antisense oligonucleotides to
reduce Muc5b expression or a novel synthetic biopolymer that normalizes Muc5b protein
structure and function in pathophysiologic airways. The goal is to develop a model of IPF that
provides novel opportunities to define how Muc5b expression contributes to IPF pathogenesis
and evaluate Muc5b-directed therapy, providing a definitive advance for IPF research.