IMMUNOLOGIC, GENETIC AND EXPOSURE-RELATED PATHWAYS TO CHILDHOOD ASTHMA

儿童哮喘的免疫、遗传和暴露相关途径

• 批准号: 7571564
• 负责人: Anne L. Wright
• 金额: $ 72.75万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571564
• 关键词: 10 year old; Age; Air; Allergens; Asthma; Birth; Blood specimen; Canis familiaris; Cell physiology; Cells; Characteristics; Child; Childhood; Childhood Asthma; Chronic Disease; Complex; Computer Systems Development; Day Care; Development; Disease; Environment; Environmental Risk Factor; Exhalation; Exposure to; Food; Genes; Genetic; Genetic Variation; Health; IgE; Immune; Immune response; Immune system; Immunologics; Infant; Inhalant dose form; Interleukin-10; Life; Link; Measurement; Mitogens; Natural Immunity; Nitric Oxide; Outcome; Pathway interactions; Pattern; Phenotype; Plant Roots; Population; Predisposition; Prevalence; Prevention; Prevention strategy; Production; Public Health; Questionnaires; Research; Respiratory physiology; Risk; Role; Route; Symptoms; Testing; Time; Variant; Wheezing; airway inflammation; atopy; clinically relevant; cohort; cytokine; design; early childhood; gene environment interaction; improved; monocyte; novel strategies; protective effect; respiratory; response; skin hypersensitivity

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.

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只在特定环境中表现出来。因此，这种竞争性更新的目的是前瞻性地评估早期生命暴露的作用、先天免疫基因的变异、免疫系统成熟以及它们对哮喘相关表型（即持续性喘息、支气管反应性[BR]）发展的相互作用。 ] 和肺功能改变）在儿童时期。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的哮喘样症状、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； 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的发展以及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，使用冷干燥空气评估BR，使用呼出的一氧化氮评估气道炎症；并获取过敏皮肤点刺测试、用于细胞研究和 IgE 的血液样本以及调查问卷。这些哮喘状态的功能测量将评估与以下方面的关系：a) 常见的早期生命暴露之间的相互作用，通过先天免疫基因变异进行前瞻性评估；b) 生命前 5 年免疫系统成熟的特征模式；以及 c) T 调节细胞功能的发育。我们提出了一种新方法，通过识别这些关系的遗传修饰因子来识别复杂暴露的哪些成分可能与其对哮喘的保护作用相关。这些研究尚未在出生后的非选定人群中完成，将极大地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果的后续发展之间的关系，并有望实现这一目标。设计这种常见且复杂疾病的预防策略。 该项目的目的是评估生命早期暴露、先天免疫基因变异、免疫系统成熟的作用，以及它们对儿童期哮喘相关结局发展的相互作用。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 年内得到了广泛的描述。该研究将加深我们对免疫反应随时间的推移与哮喘和肺功能改变的后续发展之间的关系的理解，从而有助于为这种常见且复杂的疾病设计适当的预防策略。