Epithelial Genes in Allergic Inflammation

描述（由申请人提供）：过敏性疾病是影响全球1.5亿人的主要全球健康问题。近年来，上皮细胞已成为过敏性炎症发病机制的核心参与者：(1)它们与环境相互作用并启动对环境触发的反应；(2)肺、皮肤和肠道的粘膜上皮作为抵抗病原体和包括过敏原在内的环境暴露的物理屏障；(3)上皮细胞直接参与Th2应答，作为先天免疫应答和Th2免疫之间的关键接口。这些研究的总体目标是阐明上皮细胞参与过敏性疾病发病机制。本中心提出的首要假设是上皮细胞基因在过敏性疾病的发病机制中起核心作用。这一假设将由三个综合项目加以检验，这些项目利用中心进行协调，并在个别项目的范围和能力之外协同扩展项目。该中心将为研究可能在上皮性过敏性炎症中起重要作用的基因和通路提供重要见解，并为设计针对上皮表面的新治疗策略提供基础，例如肺（哮喘）、皮肤（特应性皮炎）或肠道（食物过敏或嗜酸性食管炎）。此外，跨项目的数据整合将为过敏的一个关键问题提供新的见解-过敏性炎症的组织特异性疾病表现的潜在机制是什么？中心的每个项目都集中在不同的上皮细胞基因及其在过敏性疾病中的作用。项目1将研究上皮基因与针对不同粘膜表面的过敏性疾病的关系。项目2将探讨上皮蛋白粘连蛋白-1在过敏性疾病嗜酸性粒细胞性食管炎发病机制中的作用。项目3将重点描述在引发过敏和哮喘的早期先天免疫事件中，上皮源性IL-33由三叶因子2 （TFF2）调节的机制；更好地明确TFF2/IL-33通路在变态反应性疾病发病机制中的作用。

DESCRIPTION (provided by applicant): Allergic disorders are a major global health concern affecting 150 million people worldwide. Recently, epithelial cells have emerged as central participants in the pathogenesis of allergic inflammation: (1) they interface with the environment and initiate the response to environmental triggers; (2) the mucosal epithelium in the lung, skin, and gut functions as a physical barrier against pathogens and environmental exposures including allergens; and (3) epithelial cells have been directly implicated in Th2 responses, serving as a critical interface between innate immune responses and Th2 immunity. The overall objective of these studies is to elucidate the mechanisms by which epithelial cells contribute to the pathogenesis of allergic disorders. The overarching hypothesis of this Center proposal is that epithelial cell genes play a central role in the pathogenesis of allergic disorders. This hypothesis will be tested by three integrated projects that use the Center for coordination and synergistic extension of the projects beyond the scopes and capabilities of the individual projects. This Center will provide important insights into the genes and pathways that may be Important in epithelial driven allergic inflammation and provide a basis for the design of novel therapeutic strategies aimed at the epithelial surface, i.e. lung (asthma), skin (atopic dermatitis), or gut (food allergy or eosinophilic esophagitis). Furthermore, integration of data across projects will provide novel insights into a key question in allergy - What are the mechanisms underlying tissue specific disease manifestations of allergic inflammation? Each project in the Center is focused on distinct epithelial cell genes and their roles in allergic disorders. Project 1 will examine the association of epithelial genes with allergic diseases that target distinct mucosal surfaces. Project 2 will dissect the role of epithelial desmoglein-1 in the pathogenesis of the allergic disorder eosinophilic esophagitis. Project 3 will focus on delineating the mechanisms by which epithelial-derived IL-33 is regulated by trefoil factor 2 (TFF2) during the early innate immune events that initiate allergy and asthma; and better define the role of the TFF2/IL-33 pathway in the pathogenesis of allergic disorders.