Genetic and Environmental Factors Affecting COPD Exacer*

影响 COPD Exacer 的遗传和环境因素*

• 批准号: 7119512
• 负责人: STEVEN D SHAPIRO
• 金额: $ 23.24万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7119512
• 关键词: bacterial disease; chronic obstructive pulmonary disease; clinical research; cytotoxic T lymphocyte; disease /disorder model; emphysema; endopeptidases; gene environment interaction; gene expression; gene targeting; genetic susceptibility; helper T lymphocyte; immunocytochemistry; immunogenetics; laboratory mouse; linkage mapping; medical complication; polymerase chain reaction; questionnaires; respiratory function; respiratory infections; single nucleotide polymorphism; smoking; spirometry; terminal nick end labeling; virus diseases

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.

我们对COPD中肺气肿，空域破坏和扩大的理解大大超过了我们对气道组件的了解，尤其是COPD的急性加重。 1960年代的两次开创性观察导致了弹性蛋白酶：抗野星酶假说，这仍然是肺气肿发病机理的中心主题。首先，实验发现，弹性酶的滴注导致动物模型的肺气肿，其次是临床发现，即α-1-抗胰蛋白酶缺乏症患者（A1 AT）患者的肺气肿风险增加。正如40年前对肺气肿所做的那样，在该提案中，我们将应用21世纪的动物模型和人类遗传学版本，以启动我们对急性加重的理解，这极大地落后于我们对肺气肿的理解。我们的总体假设是，COPD中急性加重的风险和结果取决于环境病因和遗传易感性。因此，在这项建议中，我们将在COPD中产生急性加重的鼠模型，将吸烟与病毒和细菌感染相结合，我们将应用靶向小鼠的病原途径，以剖析急性加剧的致病途径，重点是对炎症细胞和蛋白酶对战斗感染，Airway Remodecemememememememememememememememamememame的影响。我们还将检验我们的假设，即COPD易感性以及先天和适应性免疫基因的候选基因中的多态性将影响COPD加剧的频率和严重性。我们将开发一群中度至重度COPD的患者（FEV1 <50％预测），并将患者分类为非频繁（0）或频繁（每年2个或更多）“恶化者”，根据研究前三年的临床过程。将研究二十个候选基因中的单核苷酸多态性（SNP），以与400名频繁加重者和400个非频繁的加重者中的COPD恶化有关。 COPD敏感性的候选基因将从COPD连锁研究和以前的病例对照遗传关联研究中选择；将根据AIM 1中的动物模型研究选择先天和适应性免疫的候选基因。