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，部分起源于儿童早期免疫系统发育的改变。遗传和环境因素都会影响哮喘风险，最近的研究表明，特定基因变异对哮喘风险的影响可能仅在特定环境中表达。因此，本竞争性更新的目的是前瞻性评估早期生活暴露、先天免疫基因变异、免疫系统成熟及其相互作用对儿童期哮喘相关表型（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中哮喘样症状、气道炎症、BR和肺功能的影响; 2）建立生命早期适应性免疫反应成熟模式与8岁时持续性喘息和肺功能改变之间的关系;和3）确定IL-10产生、T调节细胞和单核细胞在调节生命早期免疫应答的发展和影响哮喘相关表型的易感性中的作用。拟议的项目将利用现有的近500名儿童的出生队列，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，使用冷干燥空气进行BR，使用呼出的一氧化氮进行气道炎症;并获得过敏皮肤点刺试验，用于细胞研究和IgE的血液样本以及问卷调查。将评估哮喘状态的这些功能测量与以下方面的关系：a）前瞻性评估的常见早期生命暴露与先天免疫基因变体之间的相互作用，B）生命前5年免疫系统成熟的特征模式，以及c）调节性T细胞功能的发育。我们提出了一种新的方法，以确定哪些成分的复杂暴露可能与其对哮喘的保护作用，通过识别这些关系的遗传修饰。这些研究尚未在出生后的非选择性人群中完成，将大大有助于我们理解先天性，调节性和适应性免疫反应随时间的推移与哮喘相关结局的后续发展的关系，为这种常见而复杂的疾病的预防策略的设计带来希望。 该项目的目的是评估早期生活暴露，先天免疫基因变异，免疫系统成熟及其相互作用对儿童哮喘相关结果发展的作用。该项目将在近500名儿童的出生队列中进行，即婴儿免疫研究，其免疫系统发育和呼吸系统健康在生命的前5年已得到广泛表征。这项研究将促进我们对免疫反应与哮喘和肺功能改变的关系的理解，从而有助于为这种常见而复杂的疾病设计适当的预防策略。

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.