Genetic and Environmental Factors Affecting COPD Exacerbations

影响 COPD 恶化的遗传和环境因素

基本信息

项目摘要

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的空气破坏和扩大,大大超过了我们对气道成分的了解,特别是COPD的急性加重。在20世纪60年代的两个开创性的观察导致了弹性酶:抗弹性酶假说,这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入弹性蛋白酶导致肺气肿,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共同决定的。因此,在本课题中,我们将建立COPD合并吸烟合并病毒和细菌感染的急性加重小鼠模型,并应用基因靶向小鼠解剖急性加重的发病途径,重点研究炎症细胞和蛋白酶在抗感染、气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易感性候选基因以及先天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。我们将研究一组中度至重度COPD患者(预测FEV1 < 50%),并根据患者在研究前三年的临床病程将其分为非频繁(0例)或频繁(每年2例或更多)“加重者”。将研究20个候选基因的单核苷酸多态性(snp)与400例频繁加重者和400例非频繁加重者COPD加重的遗传关联。候选COPD易感性基因将从COPD连锁研究和既往病例对照遗传关联研究中选择;将在Aim 1的动物模型研究基础上选择先天免疫和适应性免疫的候选基因。

项目成果

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STEVEN D SHAPIRO其他文献

STEVEN D SHAPIRO的其他文献

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{{ truncateString('STEVEN D SHAPIRO', 18)}}的其他基金

The Emphysematous Microenvironment Promotes Lung Tumorigenesis and Progression
肺气肿微环境促进肺肿瘤的发生和进展
  • 批准号:
    8680330
  • 财政年份:
    2011
  • 资助金额:
    $ 71.33万
  • 项目类别:
Genetics of Asthma and COPD
哮喘和慢性阻塞性肺病的遗传学
  • 批准号:
    7218219
  • 财政年份:
    2006
  • 资助金额:
    $ 71.33万
  • 项目类别:
Genetic and Environmental Factors Affecting COPD Exacer*
影响 COPD Exacer 的遗传和环境因素*
  • 批准号:
    7353842
  • 财政年份:
    2005
  • 资助金额:
    $ 71.33万
  • 项目类别:
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
  • 财政年份:
    2005
  • 资助金额:
    $ 71.33万
  • 项目类别:
Genetic and Environmental Factors Affecting COPD Exacerbations
影响 COPD 恶化的遗传和环境因素
  • 批准号:
    7270546
  • 财政年份:
    2005
  • 资助金额:
    $ 71.33万
  • 项目类别:
Genetic and Environmental Factors Affecting COPD Exacer*
影响 COPD Exacer 的遗传和环境因素*
  • 批准号:
    7119512
  • 财政年份:
    2005
  • 资助金额:
    $ 71.33万
  • 项目类别:
Genetic and Environmental Factors Affecting COPD Exacerbations
影响 COPD 恶化的遗传和环境因素
  • 批准号:
    7649497
  • 财政年份:
    2005
  • 资助金额:
    $ 71.33万
  • 项目类别:
The 2003 Gordon Conference on Elastin and Elastic Tissue
2003 年戈登弹性蛋白和弹性组织会议
  • 批准号:
    6680447
  • 财政年份:
    2003
  • 资助金额:
    $ 71.33万
  • 项目类别:
Macrophage Elastase in Host Defense
巨噬细胞弹性蛋白酶在宿主防御中的作用
  • 批准号:
    6874953
  • 财政年份:
    2002
  • 资助金额:
    $ 71.33万
  • 项目类别:
Macrophage Elastase in Host Defense
巨噬细胞弹性蛋白酶在宿主防御中的作用
  • 批准号:
    6479543
  • 财政年份:
    2002
  • 资助金额:
    $ 71.33万
  • 项目类别:

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