The Pathogenesis and Genetics of Environmental Asthma

本项目资助计划(P01)的总主题是通过研究环境呼吸道疾病来进一步了解哮喘的发病机制和遗传学。我们在PPG中选择这个主题是因为：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-基因和基因-环境相互作用引起；3)呼吸道疾病的环境模型 为了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了一个理想的机会；4)这一主题建立在现有科学专业知识的基础上，并确保了一个高度互动的计划。由于后天免疫机制和先天免疫机制可以独立或相互作用地引起或加重哮喘，我们选择在建议的 缩小暴露-反应表型并研究环境呼吸道疾病的发病机制和遗传学的项目。最终的结果是一个高度集成和专注的计划，有可能进行一些新的、相关的观察。统一这一研究计划的基本假设是，通过模拟生物学上独特的基因-环境-哮喘表型来研究环境呼吸道疾病将促进我们对哮喘发病机制和遗传学的理解。该项目特定的假设建议是：项目1：哮喘患者在特定的亚段气道挑战后，呼吸道细胞表达的基因多态性使个人易于发生哮喘。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增强了解相结合，将导致对基因、环境和非裔美国人人群中哮喘发展之间的关系的一致理解。项目3：特定的基因多态/突变导致哮喘和正常受试者对Oa诱导的肺损伤的不同易感性，以及特定的获得性宿主因素调节接触臭氧造成的损伤。项目4：气道SNO代谢的改变在哮喘的发病机制中起重要作用，导致呼吸道细胞凋亡的失调，从而导致急性和慢性炎症改变 哮喘。总而言之，这个项目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。

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.