Chronic obstructive pulmonary disease (COPD) associated with cigarette smoking is characterized by non-reversible expiratory airflow obstruction in the small airways. Mucociliary dysfunction is one of the major pathogenic mechanisms of the disease. This project focuses on the genes used by the human airway epithelium to maintain the structure and function of cilia as it faces the stress of chronic cigarette smoking, and evolves through the biologic stages that result in COPD. We hypothesize that COPD is associated with an impaired ability to maintain and regenerate a normal, functional ciliated epithelium because of an inability to maintain the steady state of normal ciliogenesis and/or to repair the ciliated epithelium when injured. To assess this hypothesis, we have identified a representative list of genes participating in the human airway epithelium cilia-related transcriptome by combining a screen of genes expressed in the normal airway epithelium with a literature review of ciliarelated genes identified from species with ciliated cells. Our preliminary studies demonstrate that several genes in the cilia-related transcriptome are down-regulated in the airway epithelium of smokers compared to non-smokers and in patients with COPD compared to normal smokers. In the context that individuals with COPD have abnormal cilia structure and function, and that smoking and COPD alters the expression of cilia-related genes, our proposal has two aims. The goal of aim 1 is to compare the cilia-related transcriptome that the large and small airway epithelium uses in the steady state in COPD and matched normal smokers and non-smokers. In addition to sampling the large airway epithelium, these comparisons will use recent technology developed in our laboratories to use fiberoptic bronchoscopy and brushing to sample the small (10th to 12th order) airway epithelium, the site of the earliest change in COPD. The goal of aim 2 is to identify the cilia-related transcriptome that the airway epithelium uses to repair the loss of ciliated cells in individuals with COPD compared to normal smokers and non-smokers. This will be accomplished by denuding the airway epithelium by brush injury, a stress that allows the assessment of the gene armamentarium that is used for ciliogenesis as it repairs the epithelium over a several week period.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center (P50)
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Special Emphasis Panel (ZHL1)
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Weill Medical College of Cornell University
New York
United States
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