IMMUNOLOGIC, GENETIC AND EXPOSURE-RELATED PATHWAYS TO CHILDHOOD ASTHMA

描述(申请人提供)：哮喘，在美国最常见的儿童慢性疾病，部分起源于儿童早期免疫系统发育的改变。遗传和环境因素都影响哮喘风险，最近的研究表明，特定的基因变异对哮喘风险的影响可能只在特定的环境中表现出来。因此，这一竞争性更新的目标是前瞻性地评估早期生命暴露、先天免疫基因变异、免疫系统成熟及其相互作用在儿童哮喘相关表型(如持续性喘息、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)评估早期生命暴露与天然免疫基因变异之间的相互作用对生命早期哮喘症状、呼吸道炎症、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岁时持续喘息和肺功能改变之间的关系；以及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反应发展和影响哮喘相关表型易感性方面的作用。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。当这些孩子6-10岁时，我们将评估基线肺功能、使用寒冷干燥空气的BR和使用呼出的一氧化氮的呼吸道炎症；并获得过敏皮肤点刺试验、用于细胞研究和IgE的血液样本和一份问卷。这些哮喘状态的功能测量将被评估与a)前瞻性评估的常见早期生命暴露与先天免疫基因变异之间的相互作用，b)生命最初5年免疫系统成熟的特征模式，以及c)T调节细胞功能的发展。我们提出了一种新的方法，通过识别这些关系的遗传修饰物，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。这些研究尚未在出生后的非选定人群中完成，它们将大大有助于我们理解先天性、调节性和获得性免疫反应随着时间的推移与哮喘相关结局的后续发展的关系，为设计这种常见而复杂的疾病的预防策略提供了希望。 该项目的目的是评估早期生命暴露、先天性免疫基因变异、免疫系统成熟及其相互作用在儿童哮喘相关结局发展中的作用。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，他们的免疫系统发育和呼吸健康在生命的头5年得到了广泛的表征。这项研究将促进我们对免疫反应随时间的变化与哮喘后续发展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.