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.

该计划项目赠款（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理和遗传学。由于以下原因，我们为我们的PPG选择了这个主题：1）哮喘的症状和迹象构成广泛的临床表型； 2）哮喘是由许多生物学独特的基因基因和基因环境相互作用引起的复杂遗传疾病。 3）气道疾病的环境模型 用于缩小哮喘的生物学表型，为研究这种复杂疾病的发病机理和遗传学提供理想的机会。 4）这个主题以现有的科学专业知识为基础，并确保了高度互动的计划。由于获得的免疫力和先天机制可以独立或交互作用以引起或加剧哮喘，因此我们选择在拟议中使用过敏原和/或刺激剂（内毒素和臭氧） 项目以缩小暴露反应表型并研究环境气道疾病的发病机理和遗传学。最终结果是一个高度集成和集中的程序，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 - 莎玛疾病表型进行建模来研究环境气道疾病，这将提高我们对哮喘发病机理和遗传学的理解。特定于项目的假设提案是：项目1：气道细胞在哮喘患者中表达的基因的多态性在特定的亚段气道之后挑战倾向于哮喘的发展。 项目2：将对环境风险因素的评估与对特定哮喘易感性基因的了解增强的评估将导致对非裔美国人人群中基因，环境和哮喘发展之间关系的连贯理解。 项目3：特定的基因多态性/突变有助于哮喘和正常受试者对OA诱导的肺损伤的敏感性，并且特定的获得的宿主因子调节暴露于O3的损伤。 项目4：气道SNO代谢的改变在哮喘的发病机理中很重要，导致气道细胞凋亡失调，这导致了急性和慢性炎症变化 哮喘。总体而言，该计划中的耦合科学发现将大大增强我们对哮喘发病机理和遗传学的理解。

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