IMMUNOLOGIC, GENETIC AND EXPOSURE-RELATED PATHWAYS TO CHILDHOOD ASTHMA

描述（由申请人提供）：哮喘是美国儿童最常见的慢性疾病，部分源于儿童早期免疫系统发育的改变。遗传和环境因素都影响哮喘风险，最近的研究表明，特定基因变异对哮喘风险的影响可能只在特定环境中表达。因此，这项竞争性更新的目的是前瞻性地评估早期生活暴露、先天免疫基因变异、免疫系统成熟及其相互作用在儿童时期哮喘相关表型（即持续性喘息、支气管反应性[BR]和肺功能改变）发展中的作用。该项目的具体目标是：1)评估生命早期暴露与先天免疫基因变异之间的相互作用对生命最初十年哮喘样症状、气道炎症、BR和肺功能的影响；2)建立儿童早期适应性免疫反应的成熟模式与8岁时持续性喘息和肺功能改变的关系；3)确定IL-10产生、T调节细胞和单核细胞在生命早期调节免疫反应发展和影响哮喘相关表型易感性中的作用。拟议的项目将利用现有的近500名儿童出生队列，即婴儿免疫研究。当这些儿童6-10岁时，我们将评估基线肺功能，使用冷干燥空气的BR和使用呼出的一氧化氮的气道炎症；并获得过敏皮肤点刺试验、细胞研究和IgE的血液样本以及一份调查问卷。将评估哮喘状态的这些功能测量与以下因素的关系：a)早期生活暴露与先天免疫基因变异之间的相互作用（前瞻性评估）；b)生命前5年免疫系统成熟的特征模式；c) T调节细胞功能的发展。我们提出了一种新的方法，通过确定这些关系的遗传修饰因子，来确定复杂暴露的哪些成分可能与它们对哮喘的保护作用有关。这些尚未在非选择人群中完成的研究将大大有助于我们理解先天、调节和适应性免疫反应随着时间的推移与哮喘相关结果的后续发展之间的关系，为设计这种常见和复杂疾病的预防策略带来希望。

DESCRIPTION (provided by applicant): Asthma, the most common chronic disease of childhood in the US, originates in part in altered immune system development in early childhood. Both genetic and environmental factors influence asthma risk, and recent research suggests that the effect of particular gene variants on asthma risk may only be expressed in particular environments. Thus, the objective of this competitive renewal is to assess, prospectively, the roles of early life exposures, variation in innate immunity genes, immune system maturation, and their interactions on the development of asthma related phenotypes (i.e. persistent wheeze, bronchial responsiveness [BR] and lung function alterations) in childhood. Specific aims of the project are to: 1) Assess the influence of interactions between early life exposures and innate immunity gene variants on asthma-like symptoms, airway inflammation, BR and lung function in the first decade of life; 2) Establish the relation between patterns of maturation of adaptive immune responses in early life and the development of persistent wheeze and lung function alterations at age 8; and 3) Determine the roles of IL-10 production, T regulatory cells, and monocytes in regulating development of immune responses early in life and in influencing susceptibility to asthma-related phenotypes. The proposed project will utilize an existing birth cohort of almost 500 children, the Infant Immune Study. When these children are 6-10 years old, we will assess baseline lung function, BR using cold dry air, and airway inflammation using exhaled nitric oxide; and obtain allergy skin prick tests, blood samples for cellular studies and IgE, and a questionnaire. These functional measurements of asthma status will be assessed for relation with a) interactions between common early life exposures, assessed prospectively, with innate immunity gene variants, b) characteristic patterns of immune system maturation in the first 5 years of life, and c) the development of T regulatory cell function. We propose a novel approach to identifying which components of complex exposures may be relevant to their protective effect against asthma, by identifying genetic modifiers of these relations. These studies, which have not yet been accomplished in a non-selected population followed from birth, will contribute substantially to our understanding of the relation of innate, regulatory, and adaptive immune responses over time to the subsequent development of asthma related outcomes, holding promise for the design of prevention strategies for this common and complex disease. The objective of this project is to assess the roles of early life exposures, variation in innate immunity genes, immune system maturation, and their interactions on the development of asthma-related outcomes in childhood. The project will be conducted in a birth cohort of almost 500 children, the Infant Immune Study, whose immune system development and respiratory health has been extensively characterized in the first 5 years of life. The study will advance our understanding of the relation of immune responses over time to the subsequent development of asthma and lung function alterations, and will thereby contribute to the design of appropriate prevention strategies for this common and complex disease.