SCOR IN CELLULAR AND MOLECULAR MECHANISMS OF ASTHMA

（申请人的摘要）大多数哮喘病例开始在出生后的头几年期间开始。 生活这表明，很大一部分的风险， 哮喘的发生可归因于复杂的基因和环境 这些早期的互动。了解 免疫系统在生命早期的发育变化， 与哮喘的后续发展相关，对于 制定一级和二级预防战略。在 这个SCOR建议，我们将整合分子，免疫，遗传，基因组， 和流行病学方法来研究免疫，遗传和环境 哮喘初期的相互作用。在项目1中，我们探索 基因与环境的相互作用可能参与了 早期生活中微生物负荷增加对 早期过敏性致敏和哮喘的发展。人口抽样 生活在欧洲农村地区的儿童， 将对已评估的内毒素进行研究。已知的或新发现的 编码内毒素主要成分的基因多态性 将评估反应系统并与内毒素暴露相关， 哮喘相关的结果。在项目2中，遗传和免疫因素， 解释特应性皮炎（湿疹） 在早期生活和哮喘的后续发展将进行探讨。是 众所周知，大多数儿童谁将继续发展哮喘显示， Th 2-偏离的反应，当地的空气过敏原非常早期的生活，但不是所有 表现出这种反应的儿童会患上这种疾病。项目3将 探索复杂的分子机制，确定是否Th 2-偏离 免疫应答将导致人体合成IgG 4、IgE或两者。最后， 我们最近描述了5个新的多态性在启动子区的基因， CD 14基因我们已经证明这些多态性与 学龄儿童血清总IgE水平。项目4将探索生物学 新的近端和远端调控元件的CD 14基因， 从而为先天免疫系统的机制提供了新的见解， 反应可能影响早期过敏和哮喘的易感性。 我们的SCOR提供了一个独特的机会，以全面的方式研究， 环境因素和遗传背景影响 免疫系统在哮喘初期的成熟 过程

(Applicant's Abstract) Most cases of asthma begin during the first years of life. This suggests that a significant proportion of the risk for the development of asthma can be attributed to complex gene by environment interactions occurring during these early years. Understanding the developmental alterations of the immune system in early life that are associated with the subsequent development of asthma, is essential to designing a strategy for primary and secondary prevention of the disease. In this SCOR proposal we will integrate molecular, immunologic, genetic, genomic, and epidemiologic approaches to study the immune, genetic, and environmental interactions that occur at the beginning of asthma. In Project 1 we explore the gene by environment interactions that may be involved in the apparent protective effect of an increased microbial burden in early life on the development of early allergic sensitization and asthma. A population sample of children living in rural areas of Europe and in whom exposure to indoor endotoxin has been assessed will be studied. Known or newly discovered polymorphisms in genes coding for the main components of the endotoxin response system will be assessed and related to endotoxin exposure and asthma-related outcomes. In Project 2, the genetic and immune factors that explain the strong and independent relation between atopic dermatitis (eczema) in early life and the subsequent development of asthma will be explored. It is well known that most children who will go on to develop asthma show Th2-deviated responses to local aeroallergens very early in life, but not all children who do show such responses develop the disease. Project 3 will explore the complex molecular mechanisms that determine if a Th2-deviated response will result in the synthesis of IgG4, IgE or both in humans. Finally, we have recently described five new polymorphisms in the promoter region of the CD14 gene. We have shown that these polymorphisms are associated with total serum IgE levels in school children. Project 4 will explore the biology of novel proximal and distant regulatory elements of the CD14 gene and will thus provide new insights on the mechanisms by which the innate immune response may influence the susceptibility to early allergies and asthma. Our SCOR offers a unique opportunity to study in a comprehensive manner the way in which environmental factors and genetic background influence the maturation of the immune system during the initial phases of the asthma process.