Cigarette smoking causes disease in the lungs. The lungs comprise the airways that conduct air to the gas-exchanging region of the lungs, the alveoli. Cigarette smoke damages both the airway and the alveoli. The airway damage results in symptoms of bronchitis and shortness of breath. Surprisingly, little is known about the mechanisms by which smoking damages the airways. In this grant application we propose to advance knowledge about the mechanism of smoking-induced airway damage. We propose to do this through studies in human subjects. Over the past three years we have been funded by the National Institutes of Health (NIH) to collect samples of airway tissue from the airways of smokers and healthy controls. We have collected these samples using bronchoscopy – a technique whereby a flexible fiberoptic instrument (a long tube) in passed through the mouth and vocal cords into the airway. Biopsies can be taken through the bronchoscope using a special forceps tipped wire. Our NIH funded studies have been focused on establishing the changes that occur in mucus cells in the airway of smokers and the patterns of gene expression related to mucus overproduction that occur in smoker airways. We do not need all the tissue we collected for these studies, and this application proposes to use these same tissues for a wide-ranging study of the expression patterns of all genes in the airways of smokers. The science of genomics involves the study of all genes in the human genome. The human genome is the collection of all genes in all chromosomes in a human cell. Gene chip technology allows the simultaneously measurement of the expression patterns of most if not all human genes in relatively small samples of tissue. We propose to use gene chips to measure the expression patterns of thousands of genes in airway biopsy tissue from smoker healthy controls and a disease control (asthmatics). The tissue sample we have come from smokers with and without airflow obstruction and with and without bronchitis. By examining the gene expression profile of airway tissue from smokers and controls and smokers with and without obstruction or symptoms, we should be able to identify specific patterns of gene expression in the airways of smokers and in smoker subgroups. The advantage of this approach lies in the fact that we will measure all genes in the genome and so we will have the ability to detent unsuspected changes in gene expression. In other words, our study is not biased to what we think the abnormalities in smoker airways might be but toward detecting any gene abnormalities that occur in the airway as a result of smoking. There is much we do not know about how smoking cause airway disease. This study proposes to shed light on these unknowns and prompt further investigations that may lead to the discovery of novel disease mechanisms and novel treatment strategies.