Nicotine Abuse /Smoking-Related Disease Susceptibility

描述（由申请人提供）：目的：旨在确定尼古丁 尼古丁依赖导致炎症失调和异常修复，导致慢性阻塞性肺病（COPD），尼古丁成瘾与COPD的联系以及COPD发展的遗传基础。 假设：我们假设吸烟对肺的许多影响，包括 导致COPD的失调的炎症反应和受损的修复部分是由尼古丁与烟碱乙酰胆碱相互作用后诱导的功能改变介导的 受体（nAChR）表达的白细胞或常驻肺细胞。我们还假设， nAChRs的多态性与其他常见的基于基因的多态性结合， 对COPD的易感性。 具体目标：第一个目标将表征白细胞上的nAChR表达，并选择 受体表达与细胞凋亡之间的关系， 功能它将检验尼古丁诱导炎症和抑制修复的能力取决于白细胞和驻留肺细胞上nAChR表达模式的假设。第二个目标是将近交系小鼠品系中nAChR表达模式与COPD易感性相关联。它将检验小鼠肺气肿易感性由nAChR表达模式决定的假设。第三个目标是确定尼古丁受体表达与吸烟者肺功能下降之间的关系。它将检验白细胞nAChR表达模式预测COPD受试者肺功能下降的假设。第四个目标将确定在COPD发展中发挥作用的遗传因素，特别关注尼古丁成瘾遗传学与COPD遗传学之间的关系。它将检验nAChR多态性与其他常见基因多态性结合增加COPD易感性的假设。

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.