Genetic and Environmental Factors Affecting COPD Exacerbations

影响 COPD 恶化的遗传和环境因素

• 批准号: 7649497
• 负责人: STEVEN D SHAPIRO
• 金额: $ 40.82万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7649497
• 关键词: Acute; Affect; Animal Model; Bacterial Infections; Bacterial Model; CD4 Positive T Lymphocytes; CD8B1 gene; CXCL10 gene; CXCR3 gene; Candidate Disease Gene; Cells; Chronic Obstructive Airway Disease; Cigarette smoke-induced emphysema; Clinical; Data; Elastases; Environmental Risk Factor; Epithelial Cells; Etiology; Fibrosis; Frequencies; Future; Gelatinase B; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Haemophilus influenzae; Healthcare; Human; Human Genetics; Immune response; Immunity; Infection; Inflammation; Inflammatory; Knockout Mice; Knowledge; Leukocyte Elastase; Matrix Metalloproteinases; Modeling; Morbidity - disease rate; Mus; Outcome; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Predisposition; Pulmonary Emphysema; Pulmonary Function Test/Forced Expiratory Volume 1; Recruitment Activity; Research Personnel; Respiratory physiology; Risk; Role; Secondary to; Seminal; Sendai virus; Sepharose; Severities; Single Nucleotide Polymorphism; Smoke; Streptococcus pneumoniae; Symptoms; T-Cell Activation; T-Lymphocyte; Testing; Viral; Virus; Virus Diseases; airway remodeling; alpha 1-Antitrypsin; antimicrobial; base; case control; cigarette smoke-induced; cigarette smoking; cigarette smoking; fighting; genetic association; genetic epidemiology; killings; macrophage; mortality; multidisciplinary; neutrophil; novel; patient population; programs; protective effect

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.

我们对肺气肿的理解，COPD中的空域破坏和扩大，大大超过了我们对气道成分的了解，特别是COPD急性加重。20世纪60年代的两个开创性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。首先是实验发现，在动物模型中滴注弹性蛋白酶导致肺气肿，其次是临床发现，缺乏α-1-抗胰蛋白酶（A1 AT）的患者患肺气肿的风险增加。正如40年前对肺气肿所做的那样，在本提案中，我们将应用21世纪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局由环境病因学和遗传易感性共同决定。因此，在本提案中，我们将产生吸烟与病毒和细菌感染相结合的COPD急性加重的小鼠模型，并且我们将应用基因靶向小鼠来剖析急性加重的发病途径，重点是炎症细胞和蛋白酶对对抗感染、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易感性候选基因和先天性和适应性免疫基因的多态性将影响COPD急性加重的频率和严重程度。我们将开发一个中重度COPD患者（FEV 1 < 50%预测值）人群，并根据研究前三年内的临床病程将患者分为非频繁（0）或频繁（每年2次或2次以上）“加重者”。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性（SNP）与COPD加重的遗传关联。将从COPD连锁研究和既往病例对照遗传关联研究中选择COPD易感性的候选基因;将根据目的1中的动物模型研究选择先天性和适应性免疫的候选基因。

项目成果

Macrophage elastase kills bacteria within murine macrophages.

• DOI: 10.1038/nature08181
• 发表时间: 2009-07-30
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Houghton, A. McGarry;Hartzell, William O.;Robbins, Clinton S.;Xavier Gomis-Rueth, F.;Shapiro, Steven D.
• 通讯作者: Shapiro, Steven D.