Epithelial Genes In Allergic Inflammation

描述（由申请人提供）：上皮细胞是接触环境暴露的第一批细胞，负责启动对疾病环境触发因素（包括常见过敏原）的反应。他们越来越多地被认为是特应性疾病发展的积极参与者。在过去的几年中，已经确定了与特应性易感性增加相关的几个基因和介质;其中许多在粘膜和表皮中表达，进一步支持上皮细胞表面的事件可能驱动疾病过程。这些研究的长期目标是阐明上皮细胞参与过敏性疾病发病机制的机制。本中心建议的重点是剖析过敏驱动的上皮基因在儿童过敏性疾病中的作用。具体而言，该中心的建议包括3个项目，每个项目都侧重于上皮来源的基因和基因产物。Rothenberg的项目将定义儿童哮喘中上皮基因的遗传学。Khurana的项目将剖析上皮来源的eotaxin 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和哮喘中过敏驱动的上皮基因，特别是几丁质酶的生物学。每个项目都将利用一个充分表征的过敏性疾病（哮喘、过敏性鼻炎、食物过敏、嗜酸性食管炎）儿童队列，这些儿童居住在大辛辛那提俄亥俄州大都会区。每个项目中产生的遗传、表型和健康结果数据将由一个中心核心整合，并独立分析，并与其他每个项目一起分析，以确定潜在的遗传、生物和环境相互作用。这项研究的公共卫生影响将是显著的。通过这项研究的结果，我们将能够提供以下方面的信息： 1.上皮细胞驱动过敏性疾病发展的机制; 2.与儿童过敏性疾病相关的上皮基因; 3.基因型，以确定儿童患严重哮喘的风险更大; 4.儿童哮喘的遗传生物标志物;以及 5.变应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.