Nicotine Abuse /Smoking-Related Disease Susceptibility

描述(由申请人提供)：目标：目标是确定尼古丁如何 参与导致慢性阻塞性肺疾病(COPD)的失调炎症和异常修复，尼古丁成瘾与COPD的联系，以及COPD发展的遗传基础。 假设：我们假设吸烟对肺部的许多影响，包括 导致COPD的失调的炎症反应和受损的修复在一定程度上是由尼古丁和烟碱乙酰胆碱相互作用引起的功能改变所介导的。 白细胞或常驻肺细胞上表达的受体(NAChRs)。我们还假设 NAChRs的多态与其他常见的基于基因的多态结合在一起会增加 对慢性阻塞性肺疾病易感性。 具体目标：第一个目标将表征白细胞上nAChR的表达并选择 常驻肺细胞，并将决定受体表达与细胞的关系 功能。它将检验这样一个假设，即尼古丁诱导炎症和抑制修复的能力取决于白细胞和常驻肺细胞上nAChR的表达模式。第二个目标是将近交系小鼠的nAChR表达模式与COPD易感性联系起来。它将检验这样一个假设，即小鼠对肺气肿的易感性取决于nAChR的表达模式。第三个目标将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患者肺功能下降的假设。第四个目标将确定在慢性阻塞性肺疾病的发展中发挥作用的遗传因素，特别是侧重于尼古丁成瘾的遗传学与慢性阻塞性肺病之间的关系。它将检验这样一个假设，即nAChR基因的多态与其他常见的基于基因的多态结合在一起，会增加COPD的易感性。

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.