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.

Public Health Relevance

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)

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL120770-01A1
Application #
8754053
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M1))
Program Officer
Gan, Weiniu
Project Start
2014-08-08
Project End
2016-06-30
Budget Start
2014-08-08
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$213,331
Indirect Cost
$75,698
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Evans, Christopher M; Dickey, Burton F; Schwartz, David A (2018) E-Cigarettes: Mucus Measurements Make Marks. Am J Respir Crit Care Med 197:420-422
Juge, Pierre-Antoine; Lee, Joyce S; Ebstein, Esther et al. (2018) MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease. N Engl J Med 379:2209-2219
Monte, Andrew A; Sun, Hao; Rapp-Olsson, Anna Malin et al. (2018) The Plasma Concentration of MUC5B Is Associated with Clinical Outcomes in Paraquat-poisoned Patients. Am J Respir Crit Care Med 197:663-665
Mathai, Susan K; Newton, Chad A; Schwartz, David A et al. (2016) Pulmonary fibrosis in the era of stratified medicine. Thorax 71:1154-1160
Evans, Christopher M; Fingerlin, Tasha E; Schwarz, Marvin I et al. (2016) Idiopathic Pulmonary Fibrosis: A Genetic Disease That Involves Mucociliary Dysfunction of the Peripheral Airways. Physiol Rev 96:1567-91
Araki, Tetsuro; Putman, Rachel K; Hatabu, Hiroto et al. (2016) Development and Progression of Interstitial Lung Abnormalities in the Framingham Heart Study. Am J Respir Crit Care Med 194:1514-1522
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
Nakano, Yasushi; Yang, Ivana V; Walts, Avram D et al. (2016) MUC5B Promoter Variant rs35705950 Affects MUC5B Expression in the Distal Airways in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 193:464-6
Mathai, Susan K; Schwartz, David A (2015) Taking the ""I"" out of IPF. Eur Respir J 45:1539-41
Evans, Christopher M; Raclawska, Dorota S; Ttofali, Fani et al. (2015) The polymeric mucin Muc5ac is required for allergic airway hyperreactivity. Nat Commun 6:6281