SERPINE2 as a Candidate COPD Susceptibility Gene

描述（由申请人提供）：COPD是美国第四大死亡原因，预计到2020年将成为世界第三大最常见死亡原因和第五大最常见残疾原因。COPD通常由直接或被动暴露于香烟烟雾引起。长时间的香烟烟雾暴露会导致炎症细胞的募集，随后是空气空间的破坏和肺气肿。α-1-抗胰蛋白酶（SERPINA 1）活性的缺乏是肺气肿发生的遗传易感性的主要因素。压倒性的证据表明，在一般人群中存在导致COPD发展的其他遗传因素。使用遗传连锁，微阵列基因表达谱和遗传关联研究的组合，我们已经确定丝氨酸蛋白酶抑制剂（Serpin）E2作为一种新的候选易感基因COPD。SERPINE 2是凝血酶和纤溶酶的主要组织和细胞相关抑制剂，但不是弹性蛋白酶，并且已显示促进细胞外基质产生并抑制细胞凋亡。这种蛋白质在肺系统中的作用以前尚未探索。我们已经证明：1）SERPINE 2的基因位于2号染色体上先前定义的早发性COPD的连锁区域内，当假设基因与吸烟环境相互作用时，具有峰值连锁的最大证据; 2）SERPINE 2表达在肺发育期间受到调节，最大表达与肺泡结构的建立一致; 3）SERPINE 2表达与人COPD患者中不良生理功能的测量显著相关; 4）在基于家族的群体中观察到多个SERPINE 2多态性和单倍型与COPD的遗传关联，并且在病例对照群体中得到复制; 5）SERPINE 2在小气道和中气道内的传导气道上皮中以及在分层气道的基底细胞中表达。我们假设SERPINE 2缺乏导致对香烟烟雾诱导的肺损伤和肺气肿的易感性。为了开始鉴定该蛋白在肺成熟、稳态和对COPD的易感性中的作用，我们将：1）检查SERPINE 2在正常肺稳态中的生理作用和2）测试SERPINE 2在小鼠暴露于香烟烟雾后维持肺结构中的生理作用。

DESCRIPTION (provided by applicant): COPD represents the fourth leading cause of death in the United States, and is predicted to become the third most common cause of death and the fifth most common cause of disability in the world by the year 2020. COPD is often induced by direct or passive exposure to cigarette smoke. Prolonged cigarette smoke exposure can lead to inflammatory cell recruitment followed by airspace destruction and emphysema. Deficiency in the activity of a-1-antitrypsin (SERPINA1) is a major factor of genetic susceptibility for the development of emphysema. Overwhelming evidence suggests the presence of additional genetic factors contributing to the development of COPD in the general population. Using a combination of genetic linkage, microarray gene expression profiling and genetic association studies we have identified serine protease inhibitor (Serpin) E2 as a novel candidate susceptibility gene for COPD. SERPINE2 is a major tissue and cell-associated inhibitor of thrombin and plasmin, but not elastase, and has been shown to promote extracellular matrix production and inhibit apoptosis. The role of this protein in the pulmonary system has not been previously explored. We have shown that: 1) The gene for SERPINE2 lies within a previously defined linkage region for early-onset COPD on chromosome 2, with maximal evidence for peak linkage when assuming a gene-by-smoking environment interaction; 2) SERPINE2 expression is regulated during lung development, with maximal expression coincident with establishment of alveolar structure; 3) SERPINE2 expression is significantly correlated with measures of poor physiological function in human COPD patients; 4) Genetic association with COPD is observed for multiple SERPINE2 polymorphisms and haplotypes in a family-based population and has been replicated in a case-control population; 5) SERPINE2 is expressed in conducting airway epithelium, within small and intermediate airways, and in basal cells of stratified airways. We hypothesize that SERPINE2 deficiency leads to susceptibility to cigarette smoke-induced lung damage and emphysema. In an effort to begin to identify the role of this protein in lung maturation, homeostasis and susceptibility to COPD we will; 1) examine the physiological role of SERPINE2 in normal lung homeostasis and 2) test SERPINE2 for a physiological role in maintenance of lung structure following cigarette smoke exposure in mice.