Chronic Obstructive Pulmonary Disease (COPD) is a global health concern that is predicted to become the third most common cause of mortality and the fifth commonest cause of morbidity in the world by 2020. COPD is now ranked the fourth leading cause of death in the US and Europe with a mortality rate that has more than doubled in the last 20 years. Airway hypersecretion is a cardinal feature in COPD and is a significant contributor to exacerbations and mortality. Our long- term goal is to investigate the pathophysiology of hypersecretion in COPD and develop potential clinical interventions and possible preventive measures. Cigarette smoking has been identified to be a major risk factor for the onset of COPD. However, the relationship between nicotine (a major component of tobacco) and mucin hypersecretion has not been thoroughly investigated. The objective of this project is to investigate nicotine induced mucin secretory response in airway epithelial goblet cells and the underlying mechanisms leading to mucin hypersecretion. Our previous results indicated that an ion-exchange mechanism plays a crucial role in airway mucin secretion and other secretion models. In this study, we plan to test the general hypothesis that nicotine can mobilize the bound granular Ca2+ by ion-exchange processes to increase free granular Ca2+ concentration ([Ca2+]G) that is subsequently released to the cytoplasm to cause cytosolic Ca2+ ([Ca2+]C) increase. Increases in [Ca2+]G and [Ca2+]C can further facilitate Ca2+- mediated mucin secretion from goblet cells. We plan to test two Specific Aims: 1. To test the hypothesis that nicotine can trigger mucin release from goblet cells via Ca2+-mediated secretory pathway;2. To test the hypothesis that nicotine triggered ion-exchange mechanisms facilitate mucin secretion of goblet cells. We plan to use cultured porcine goblet cells as model system. Various fluorescent dyes will be loaded in the cells to monitored Ca2+ and pH changes. We expect to confirm our hypothesis that nicotine can facilitate ion-exchange processes in mucin granules. With the understanding of nicotine-induced ion-exchange, potential therapeutic strategies for COPD can be developed in the future studies.

Public Health Relevance

Airway hypersecretion is a cardinal feature in COPD (Chronic Obstructive Pulmonary Disease) and is a significant contributor to exacerbations and mortality. The objective of this project is to investigate nicotine induced mucin secretory response in airway epithelial goblet cells and the underlying mechanisms leading to mucin hypersecretion.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15HL095039-01A1
Application #
7725791
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Punturieri, Antonello
Project Start
2009-07-15
Project End
2013-06-30
Budget Start
2009-07-15
Budget End
2013-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$212,052
Indirect Cost
Name
University of California Merced
Department
None
Type
Schools of Engineering
DUNS #
113645084
City
Merced
State
CA
Country
United States
Zip Code
95343
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