Nicotine Abuse /Smoking-Related Disease Susceptibility

描述（由申请人提供）：目的：目的是确定尼古丁

DESCRIPTION (provided by applicant): OBJECTIVE: The goals are to determine how nicotine contributes to the dysregulated inflammation and abnormal repair that leads to chronic obstructive lung disease (COPD), the link of nicotine addiction to COPD and the genetic basis for the development of COPD. HYPOTHESIS: We hypothesize that many of the effects of smoking on the lung including the dysregulated inflammatory response and impaired repair that lead to COPD are mediated, in part, by functional alterations induced following the interaction of nicotine with nicotinic acetylcholine receptors (nAChRs) expressed on leukocytes or resident lung cells. We also hypothesize that polymorphisms in nAChRs couple with other common gene-based polymorphisms to increase susceptibility to COPD. SPECIFIC AIMS: The first aim will characterize nAChR expression on leukocytes and selected resident lung cells, and will determine the relationship between receptor expression and cell function. It will test the hypothesis that nicotine's ability to induce inflammation and inhibit repair are dependent on the pattern of nAChR expression on leukocytes and resident lung cells. The second aim will correlate patterns of nAChR expression in inbred mouse strains to susceptibility to COPD. It will test the hypothesis that susceptibility to emphysema in mice is determined by the pattern of nAChR expression. The third aim will determine the relationship between nicotine receptor expression and lung function decline in cigarette smokers. It will test the hypothesis that the pattern of leukocyte nAChR expression predicts lung function decline in COPD subjects. The fourth aim will identify genetic factors that play a role in the development of COPD, focusing, in particular, on the relationships between the genetics of nicotine addiction and those of COPD. It will test the hypothesis that polymorphisms in nAChR couple with other common gene-based polymorphisms to increase susceptibility to COPD.