Genetic and Environmental Factors--COPD Exacerbations

我们对肺气肿、COPD的空气破坏和扩大的了解，大大超过了我们对呼吸道成分的了解，特别是COPD的急性加重。20世纪60年代的两个开创性的观察导致了弹性蛋白酶：抗弹性蛋白酶假说，该假说仍然是肺气肿发病机制的中心主题。首先是在动物模型中注射弹性蛋白酶导致肺气肿的实验发现，其次是临床发现α-1-抗胰蛋白酶(A1-AT)缺乏的患者患肺气肿的风险增加。就像40年前对肺气肿所做的那样，在这项提议中，我们将应用21世纪版本的动物模型和人类遗传学，试图启动我们对急性加重的理解，这大大落后于我们对肺气肿的理解。我们的总体假设是，COPD急性加重的风险和结果是由环境病因和遗传易感性决定的。因此，在这项建议中，我们将建立吸烟与病毒和细菌感染相结合的COPD急性加重的小鼠模型，并将应用基因靶向小鼠来剖析急性加重的发病途径，重点研究炎症细胞和蛋白酶在对抗感染、呼吸道重塑和随后的肺气肿中的作用。我们还将验证我们的假设，即COPD易感候选基因以及先天和获得性免疫基因的多态将影响COPD恶化的频率和严重程度。我们将发展一组中到重度COPD患者(预计FEV1和Lt；50%)，并根据患者在研究前三年的临床病程将患者分为非频繁(0)或频繁(每年2例或更多)“恶化者”。研究人员将在400名频繁加重者和400名非频繁加重者中研究20个候选基因的单核苷酸多态(SNPs)与COPD恶化的遗传关联。COPD易感性的候选基因将从COPD连锁研究和先前的病例对照遗传关联研究中选择；天然免疫和获得性免疫的候选基因将基于目标1中的动物模型研究而选择。

Our understanding of emphysema, the airspace destruction and enlargement in COPD, greatly outweighs our knowledge regarding the airway component, particularly acute exacerbations of COPD. Two seminal observations in the 1960s led to the elastase:antielastase hypothesis which remains the central theme in the pathogenesis of emphysema. First, was the experimental finding that instillation of elastases led to emphysema in animal models, and second was the clinical finding that patients with deficiency in alpha-1- antitrypsin (A1 AT) were at increased risk for emphysema. As was done for emphysema 40 years ago, in this proposal we will apply 21st century versions of animal models and human genetics in an attempt to launch our understanding of acute exacerbations which greatly lags behind our understanding of emphysema. Our overall hypothesis is that the risk and outcome of acute exacerbations in COPD are determined by the environmental etiology combined with genetic susceptibility. Thus, in this proposal, we will generate murine models of acute exacerbations in COPD combining cigarette smoking with viral and bacterial infection, and we will apply gene targeted mice to dissect pathogenetic pathways of acute exacerbations with an emphasis on inflammatory cells and proteinase effects on fighting infection, airway remodeling and subsequent emphysema. We will also test our hypothesis that polymorphisms in candidate genes for COPD susceptibility and innate and adaptive immunity genes will influence the frequency and severity of COPD exacerbations. We will develop a population of patients with moderate to severe COPD (FEV1 < 50% predicted) and will classify the patients as either non-frequent (0) or frequent (2 or more per year) "exacerbators" based upon their clinical course during the three years before the study. Single nucleotide polymorphisms (SNPs) in twenty candidate genes will be studied for genetic association with COPD exacerbations in 400 frequent exacerbators and 400 non-frequent exacerbators. Candidate genes for COPD susceptibility will be selected from COPD linkage studies and previous case-control genetic association studies; candidate genes for innate and adaptive immunity will be selected based on the animal model studies in Aim 1.