Mucus hypersecretion and airway hyperreactivity (AHR) are significant features of asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD). In spite of these well-recognized pathological associations, the mechanisms by which AHR is mediated by the chief glycoprotein components of respiratory mucus, the secreted polymeric mucins, are unknown. Autopsy studies show that 98% of the airways of patients who die from fatal asthma have extensive mucus plugging. MUC5AC and MUC5B are the major secreted airway mucins. Their production (especially that of MUC5AC) increases significantly in asthma, CF, and COPD, and in animal models of these diseases. Furthermore, blockade of mucus secretion reduces AHR by ~80%. These findings provide the basis for the overall goal of this proposal, which is to assess the functional consequences of mucus secretion on lung function. The central hypothesis of this proposal is that secreted Muc5ac and Muc5b play essential roles in the development of airway hyperreactivity by promoting mucus thickening, airway lumen occlusion, and distal airway closure. Studies will be conducted in human airway epithelial cell cultures and knockout mice in order to achieve the following specific aims:
Aim 1 : Determine the role of polymeric mucin secretion in mucus layer thickening.
Aim 2 : Determine the functional consequences of polymeric mucin secretion on AHR.

Public Health Relevance

Mucus overproduction and hypersecretion are cardinal features that are strongly associated with morbidity and mortality in asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD). Our studies are aimed at understanding how mucus is secreted, how it is altered in lung disease, and what the functional consequences of these are, using genetically engineered mice and cells grown in culture. Achievement of these goals will provide insights into novel treatments of obstructive lung diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080396-05
Application #
8316176
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Banks-Schlegel, Susan P
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$381,546
Indirect Cost
$132,465
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
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