SERPINE2 as a Candidate COPD Susceptibility Gene

描述(由申请人提供)：慢性阻塞性肺病是美国第四大死因，预计到2020年将成为世界第三大常见死因和第五大最常见的残疾原因。慢性阻塞性肺疾病通常是由直接或被动暴露在香烟烟雾中引起的。长期暴露在香烟烟雾中会导致炎性细胞聚集，继而破坏空气空间和肺气肿。α-1-抗胰蛋白酶(SERPINA1)活性缺乏是肺气肿发生的主要遗传易感性因素。压倒性证据表明，在普通人群中存在其他导致慢性阻塞性肺疾病发展的遗传因素。结合遗传连锁、微阵列基因表达谱和遗传关联研究，我们确定丝氨酸蛋白酶抑制因子(Serpin)E2是COPD的一个新的候选易感基因。Serpine2是凝血酶和纤溶酶的主要组织和细胞相关抑制物，但不是弹性蛋白酶，已被证明能促进细胞外基质的产生和抑制细胞凋亡。这种蛋白质在肺系统中的作用以前还没有被探索过。我们发现：1)Serpine2基因位于2号染色体上早发性COPD的一个预先定义的连锁区域内，当假定吸烟环境与基因相互作用时，最大的连锁证据是峰值连锁；2)Serpine2的表达在肺发育过程中受到调节，最大表达与肺泡结构的建立一致；3)在COPD患者中Serpine2的表达与生理功能低下的程度显著相关；4)在以家庭为基础的人群中观察到多种Serpine2多态和单倍型与COPD的遗传关联，并在病例对照人群中复制；5)Serpine2表达于传导气道上皮、中、小气道和复层气道的基底细胞。我们假设，Serpine2缺乏导致吸烟引起的肺损伤和肺气肿的易感性。为了开始确定这种蛋白在肺成熟、稳态和对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学作用；2)测试Serpine2在小鼠吸烟暴露后维持肺结构的生理作用。

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.