Genetic and Environmental Factors--COPD Exacerbations

遗传和环境因素——慢性阻塞性肺病加重

• 批准号: 7008368
• 负责人: STEVEN D SHAPIRO
• 金额: $ 44.13万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7008368
• 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.

我们对肺气肿、慢性阻塞性肺病中的气腔破坏和扩大的理解远远超过了我们对气道成分、特别是慢性阻塞性肺病急性加重的了解。 20 世纪 60 年代的两项开创性观察得出了弹性蛋白酶：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，实验发现在动物模型中注射弹性蛋白酶会导致肺气肿，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。正如 40 年前针对肺气肿所做的那样，在这项提案中，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，这远远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与遗传易感性相结合决定的。因此，在本提案中，我们将建立结合吸烟与病毒和细菌感染的慢性阻塞性肺病急性加重的小鼠模型，我们将应用基因靶向小鼠来剖析急性加重的发病途径，重点关注炎症细胞和蛋白酶对抵抗感染、气道重塑和随后的肺气肿的作用。我们还将检验我们的假设，即 COPD 易感性候选基因以及先天性和适应性免疫基因的多态性将影响 COPD 恶化的频率和严重程度。我们将开发中度至重度 COPD（FEV1 < 预测值的 50%）患者群体，并根据研究前三年内的临床病程将患者分类为非频繁（0）或频繁（每年 2 次或更多）“加重者”。将研究 20 个候选基因中的单核苷酸多态性 (SNP)，以了解 400 种频繁加重者和 400 种非频繁加重者与 COPD 加重的遗传关联。 COPD易感性候选基因将从COPD连锁研究和既往病例对照遗传关联研究中选出；先天性和适应性免疫的候选基因将根据目标1中的动物模型研究来选择。