SCOR IN CELLULAR AND MOLECULAR MECHANISMS OF ASTHMA

(申请者摘要)大多数哮喘病例都始于 生活。这表明，很大一部分风险是 哮喘的发生与环境的复杂基因有关 早年发生的相互作用。了解 早期生命中免疫系统的发育变化 与随后的哮喘发展相关，是至关重要的 制定疾病一级和二级预防战略。在……里面 在这个SCOR提案中，我们将把分子、免疫学、遗传学、基因组、 和流行病学方法来研究免疫、遗传和环境 哮喘初期发生的相互作用。在项目1中，我们探索 基因与环境的相互作用可能涉及到明显的 生命早期微生物负荷增加对水生动物的保护作用 早期过敏性过敏和哮喘的发展。一个人口样本为 生活在欧洲农村地区的儿童，他们暴露在室内 已对内毒素进行评估，将对其进行研究。已知的或新发现的 内毒素主要成分编码基因的多态性 将评估应对系统，并与内毒素暴露和 与哮喘相关的结果。在项目2中，遗传和免疫因素 解释特应性皮炎(湿疹)之间强烈而独立的联系 将对哮喘的早期生命和后续发展进行探讨。它是 众所周知，大多数将继续发展为哮喘的儿童表现出 在生命早期对局部空气变应原的Th2偏离反应，但不是全部 表现出这种反应的儿童会患上这种疾病。项目3将 探索决定Th2是否偏离的复杂分子机制 应答将导致在人类体内合成IgG4和/或IgE。最后， 我们最近描述了5个新的基因启动子区的多态。 CD14基因。我们已经证明，这些多态与 学龄儿童血清总IgE水平。项目4将探索生物 CD14基因和Will的新的近端和远端调控元件 从而对先天免疫的机制提供了新的见解 反应可能会影响对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来全面研究 环境因素和遗传背景如何影响 哮喘初期免疫系统的成熟 进程。

(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.