The Pathogenesis and Genetics of Environmental Asthma

环境性哮喘的发病机制和遗传学

• 批准号: 6677838
• 负责人: David A Schwartz
• 金额: $ 146.02万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6677838
• 关键词: asthma; clinical research; environment; genetics

The overall theme of this Program Project Grant (P01) is to understand further the pathogenesis and genetics of asthma by studying environmental airway disease. We chose this theme for our PPG for the following reasons: 1) the symptoms and signs of asthma constitute a broad clinical phenotype; 2) asthma is a complex genetic disease caused by many biologically unique gene-gene and gene-environment interactions; 3) environmental models of airway disease serve to narrow the biological phenotype of asthma, providing an ideal opportunity to study the pathogenesis and genetics of this complex disease; and 4) this theme builds on existing scientific expertise and ensures a highly interactive program. Since acquired and innate mechanisms of immunity can function independently or interactively to cause or exacerbate asthma, we have chosen to use allergens and/or irritants (endotoxin and ozone) in the proposed projects to narrow the exposure-response phenotype and investigate the pathogenesis and genetics of environmental airway disease. The end result is a highly integrated and focused program that has the potential to make a number of novel, related observations. The primary hypothesis unifying this research program is that investigating environmental airway disease by modeling biologically unique gene-environment-asthma phenotypes will advance our understanding of the pathogenesis and genetics of asthma. The project-specific hypotheses proposal are: Project 1: Polymorphisms of genes expressed by airway cells in asthmatics following specific subsegmental airway challenges predispose individuals to the development of asthma. Project 2: Integrating the assessment of the environmental risk factors with an enhanced understanding of specific asthma susceptibility genes will lead to a coherent understanding of the relationship between genes, environment, and the development of asthma in an African American population. Project 3: Specific gene polymorphisms/mutations contribute to differential susceptibility to Oa-induced lung injury in asthmatic and normal subjects, and specific acquired host factors regulate injury from exposure to O3. Project 4: Alteration in airway SNO metabolism is important in the pathogenesis of asthma resulting in the dysregulation of airway cell apoptosis that contributes to the acute and chronic inflammatory changes seen in asthma. In aggregate, the coupled scientific findings in this program will substantially enhance our understanding of the pathogenesis and genetics of asthma.

该计划项目拨款（P01）的总体主题是通过研究环境气道疾病进一步了解哮喘的发病机制和遗传学。我们为 PPG 选择这个主题的原因如下：1）哮喘的症状和体征构成了广泛的临床表型； 2）哮喘是一种复杂的遗传性疾病，由许多生物学上独特的基因-基因以及基因-环境相互作用引起； 3）气道疾病的环境模型 有助于缩小哮喘的生物学表型，为研究这种复杂疾病的发病机制和遗传学提供理想的机会； 4) 该主题建立在现有科学专业知识的基础上，并确保项目具有高度互动性。由于获得性和先天性免疫机制可以独立或相互作用地发挥作用，导致或加剧哮喘，因此我们选择在拟议的方案中使用过敏原和/或刺激物（内毒素和臭氧） 缩小暴露反应表型并研究环境气道疾病的发病机制和遗传学的项目。最终结果是一个高度集成且重点突出的计划，有可能做出许多新颖的相关观察。统一该研究计划的主要假设是，通过对生物学上独特的基因-环境-哮喘表型进行建模来研究环境气道疾病，将增进我们对哮喘发病机制和遗传学的理解。具体项目假设提案为： 项目 1：哮喘患者在特定亚段气道挑战后气道细胞表达的基因多态性使个体易患哮喘。 项目 2：将对环境风险因素的评估与对特定哮喘易感基因的深入了解相结合，将有助于对非裔美国人群体中基因、环境和哮喘发展之间的关系有一个连贯的了解。 项目 3：特定的基因多态性/突变导致哮喘和正常受试者对 Oa 引起的肺损伤的易感性存在差异，并且特定的获得性宿主因素调节暴露于 O3 造成的损伤。 项目 4：气道 SNO 代谢的改变在哮喘发病机制中很重要，导致气道细胞凋亡失调，从而导致急性和慢性炎症变化 哮喘。总的来说，该计划中的相关科学发现将大大增强我们对哮喘发病机制和遗传学的理解。

项目成果

Proteomic analysis of human bronchoalveolar lavage fluid after subsgemental exposure.

• DOI: 10.1021/pr400066g
• 发表时间: 2013-05-03
• 期刊: Journal of proteome research
• 影响因子: 4.4
• 作者: Foster MW;Thompson JW;Que LG;Yang IV;Schwartz DA;Moseley MA;Marshall HE
• 通讯作者: Marshall HE