Chronic lung diseases such as COPD are characterized by a hypersecretion of mucus, which often exacerbates morbidity and hastens mortality. A characteristic of these diseases is that they are often accompanied by mucus stasis and enhanced susceptibility to infection and inflammation. Airway mucins, particularly MUC5AC and MUC5B, are the major constituent of the mucus gel and play an important role in the mucociliary clearance. Over a hundred other proteins contribute mucus structure, of which approximately half are associated with mucins in some fashion, according to recent proteomic studies done in our laboratory. There are very few studies investigating the mucin/mucus composition in COPD, and those that have been published are based on very small populations of patients. Additionally, we do not know whether COPD mucus pathology results from a simple accumulation of "normal" mucus, or whether the mucus has an abnormal mucin composition and/or properties. Our overall hypothesis, based upon our previous and ongoing studies, is that the molecular composition of the mucus and the concentration and macromolecular organization of its mucins are altered in the COPD environment -- both in baseline and during exacerbations. These alterations produce a mucus that has an aberrant rheology, that is poorly transportable by normal ciliary and cough clearance mechanisms. In testing these hypotheses, using a broad range of biochemical, biophysical and proteomics methods, we propose to assess, [i] mucin concentration and the ratio of MUC5AC/MUC5B, [ii] the effects of proteolysis on overall mucin polymeric structure, and [iii] the dynamic interplay between mucins and interacting proteins, using samples of mucus obtained through "Subpopulations and intermediate outcome measures in COPD study" (SPIROMICS), from normal controls, healthy smokers, and COPD patients, both at baseline and exacerbation. At the broadest level, the major scientific goal of this proposal is to compare the measured parameters over a large number of normal controls and COPD patients, and within the patient population, to enable the sub-classifications of COPD patients and discovery of biomarkers, consistent with the main goals of SPIROMICS. The proposed studies are needed to achieve a more integrated view and thus more rational approaches for designing effective therapeutic modalities to the treatment of hypersecretory states such as COPD.

Public Health Relevance

Chronic obstructive lung disease (COPD) is characterized by a hypersecretion of mucus, which often exacerbates morbidity and hastens mortality. At the broadest level, the major scientific goal of this proposal, using samples of mucus obtained through Subpopulations and intermediate outcome measures in COPD study (SPIROMICS) from smokers, and COPD patients, both at baseline and exacerbation, is to compare the mucin properties and mucin-interacting proteins over a large number of normal controls and COPD patients, and within the patient population, to enable the sub-classifications of COPD patients and discovery of biomarkers which is useful in the future as intermediate outcome measures for clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL110906-03
Application #
8521361
Study Section
Special Emphasis Panel (ZHL1-CSR-G (M1))
Program Officer
Croxton, Thomas
Project Start
2011-08-22
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$352,240
Indirect Cost
$114,240
Name
University of North Carolina Chapel Hill
Department
Biochemistry
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Couper, David; LaVange, Lisa M; Han, MeiLan et al. (2014) Design of the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS). Thorax 69:491-4