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.
Idiopathic pulmonary fibrosis (IPF) is a disabling, progressive interstitial lung disease with no known cure and limited therapeutic options that do not halt disease progression. A major and common risk factor for developing IPF is a promoter variant of the MUC5B gene that leads to increased MUC5B expression, yet the mechanistic role of elevated MUC5B in IPF pathogenesis remains unclear due to lack of animal model that can recapitulate its deleterious effects related to mucus. This proposal will develop a ferret model for IPF to provide novel opportunities that define how Muc5b expression contributes to disease progression and evaluate Muc5b-directed therapies, providing a definitive advance for IPF research.