Epithelial Genes In Allergic Inflammation

描述(申请人提供)：上皮细胞是第一个遇到环境暴露的细胞，它们负责启动对环境引发疾病的反应，包括常见的过敏原。他们越来越多地被认为是特应性疾病发展的积极参与者。在过去的几年里，已经发现了几个与特应性疾病易感性增加相关的基因和介质；其中许多基因和介质在粘膜和表皮中表达，进一步支持了上皮细胞表面的事件可能是驱动疾病过程的因素。这些研究的长期目标是阐明上皮细胞在变态反应性疾病发病机制中的作用。该中心提案的重点是剖析过敏驱动的上皮基因在儿童变态反应性疾病中的作用。具体地说，该中心的提案包括3个项目，每个项目都侧重于上皮来源的基因和基因产品。Rothenberg的项目将定义儿童哮喘上皮基因的遗传学。库拉纳的项目将剖析上皮源性嗜酸性粒细胞趋化因子3在嗜酸性食管炎发病机制中的作用。Wills-Karp的项目将专注于过敏驱动的上皮基因的生物学，特别是过敏和哮喘中的几丁质酶。每个项目都将利用居住在大辛辛那提俄亥俄州大都市区的一群患有过敏性疾病(哮喘、过敏性鼻炎、食物过敏、嗜酸性食管炎)的儿童。每个项目中产生的遗传、表型和健康结果数据将由一个中央核心集成，并与其他每个项目一起进行独立和联合分析，以确定潜在的遗传、生物和环境相互作用。这项研究对公众健康的影响将是巨大的。通过这项研究的结果，我们将能够提供有关以下方面的信息： 1.上皮细胞驱动变态反应性疾病发展的机制； 2.儿童变态反应性疾病相关的上皮基因； 3.确定患严重哮喘风险较高的儿童的基因类型； 4.儿童哮喘的遗传生物标志物；以及 5.过敏性疾病治疗干预的新靶点。

DESCRIPTION (provided by applicant): Epithelial cells are the first cells that encounter environmental exposures and they are responsible for initiating the response to environmental triggers of disease, including common allergens. They are increasingly recognized as active participants in the development of atopic disorders. Over the past few years, several genes and mediators associated with increased susceptibility to atopy have been identified; many of these are expressed in the mucosa and epidermis, further supporting that events at epithelial-cell surfaces might be driving disease processes. The long-term objective of these studies is to elucidate the mechanisms by which epithelial cells contribute to the pathogenesis of allergic disorders. The focus of this Center proposal is to dissect the role of allergy-driven epithelial genes in allergic disorders of childhood. Specifically, this Center proposal includes 3 projects, each focusing on epithelial-derived genes and gene products. Project by Rothenberg will define the genetics of epithelial genes in childhood asthma. Project by Khurana will dissect the role of epithelial-derived eotaxin 3 in the pathogenesis of eosinophilic esophagitis. Project by Wills-Karp will focus on the biology of allergy-driven epithelial genes, specifically chitinases, in allergy and asthma. Each project will utilize a well-characterized cohort of children with allergic disorders (asthma, allergic rhinitis, food allergy, eosinophilic esophagitis) who live in the Greater Cincinnati Ohio Metropolitan Region. The genetic, phenotypic, and health outcome data generated in each project will be integrated by a central core and analyzed independently and in conjunction with each of the other projects to identify potential genetic, biologic, and environmental interactions. The public health impact of this study will be significant. Through the results of this study, we will be able to provide information regarding: 1. mechanisms by which epithelial cells drive the development of allergic disease; 2. the relevant epithelial genes with regard to allergic disorders of childhood; 3. genotypes to identify children that are at greater risk for severe asthma; 4. genetic biomarkers of childhood asthma; and 5. novel targets for therapeutic intervention for allergic disorders.