The overall goal of this proposal is to understand how dysregulated MUC5B results in the development of fibroproliferative lung disease. This approach is based on two recent advances. First, we have discovered that MUC5B is the strongest risk factor, genetic and otherwise, for familial and sporadic forms of idiopathic pulmonary fibrosis (IPF). The MUC5B promoter SNP rs35705950 has been validated as a risk variant for IPF in six independent studies (1-6), is the strongest known risk factor for the development of both familial and sporadic forms of IPF (odds ratio H 4-8 per allele), and represents a risk variant observed in at least half of the cases of either familial or sporadic IPF Although our GWAS identified 3 established (TERC, TERT, and MUC5B) and 7 novel pulmonary fibrosis loci (5), the MUC5B promoter SNP remained the strongest genetic signal associated with pulmonary fibrosis (OR=4.51 [95%CI=3.91-5.21];P = 7.21x10-95), and subsequent analyses indicate that this SNP accounts for ~39% of the risk of developing IPF. Second, our findings suggest that MUC5B appears to be involved in the pathogenesis of IPF. IPF patients have significantly more MUC5B gene expression than unaffected subjects (1), the MUC5B promoter SNP is associated with enhanced MUC5B expression in both unaffected subjects (1) and patients with IPF (7), MUC5B message and protein are expressed in the pathologic lesions of IPF (1, 8), and we have recently found that Muc5b deficient mice are resistant to both bleomycin and asbestos models of fibroproliferation (see preliminary data). Based on these observations, we speculate that the MUC5B promoter SNP places individuals at risk of developing IPF via chronic mucus hypersecretion and accumulation in the peripheral airspace that impairs mucocilliary transport, results in mucus adhesion in the bronchoalveolar region, and consequently induces and potentiates chronic inflammation and injury (1, 10). We have engineered an efficient, tiered approach to understand how dysregulated MUC5B results in the development of fibroproliferative lung disease. While the R21 phase of the proposal will use an in vitro human cell-derived system to explore basic biological responses to MUC5B, the R33 phase of the proposal will test these findings in three established strains of mice (CCSP-Muc5bTg, SPC-Muc5bTg, and Muc5b-/- mice). Based on what is known about IPF and MUC5B, we hypothesize that chronic mucus hypersecretion impairs mucociliary transport and results in persistent cell injury causing impaired host defense and excessive repair and leading to the development of fibroproliferative lung disease.
Idiopathic pulmonary fibrosis (IPF) is a major public health problem, there are no known treatments to prolong life, and the etiology and mechanisms remain obscure. Patients with IPF have a median survival of 2-3 years. The overall goal of this proposal is to understand how dysregulated MUC5B results in the development of fibroproliferative lung disease. (End of Abstract)
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|Mathai, Susan K; Pedersen, Brent S; Smith, Keith et al. (2016) Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 193:1151-60|
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