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年将成为世界上第三大常见死亡原因和第五大致残原因。慢性阻塞性肺病通常由直接或被动暴露于香烟烟雾引起。长时间接触香烟烟雾可导致炎症细胞聚集，随之而来的是空气破坏和肺气肿。a-1抗胰蛋白酶（SERPINA1）活性缺乏是肺气肿发生的遗传易感性的主要因素。大量证据表明，在普通人群中存在其他遗传因素导致COPD的发生。结合遗传连锁、微阵列基因表达谱和遗传关联研究，我们已经确定丝氨酸蛋白酶抑制剂（Serpin） E2是COPD的一种新的候选易感基因。SERPINE2是凝血酶和纤溶酶的主要组织和细胞相关抑制剂，但不是弹性酶，并且已被证明可以促进细胞外基质的产生和抑制细胞凋亡。这种蛋白在肺系统中的作用以前没有被探索过。我们已经证明：1)SERPINE2基因位于先前定义的2号染色体上早发性COPD的连锁区域，当假设基因与吸烟环境相互作用时，最大证据表明存在峰值连锁；2) SERPINE2的表达在肺发育过程中受到调控，最大表达与肺泡结构的建立一致；3)人类COPD患者SERPINE2表达与生理功能不良指标显著相关；4)在以家庭为基础的人群中观察到多个SERPINE2多态性和单倍型与COPD的遗传关联，并在病例对照人群中得到了重复；5) SERPINE2在导气管上皮、小气道和中气道内以及层状气道的基底细胞中表达。我们假设SERPINE2缺乏导致香烟引起的肺损伤和肺气肿易感性。为了开始确定这种蛋白在肺成熟、体内平衡和COPD易感性中的作用，我们将；1)检测SERPINE2在正常肺稳态中的生理作用，2)检测SERPINE2在香烟烟雾暴露后小鼠肺结构维持中的生理作用。

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.