Epithelial Genes in Allergic Inflammation

过敏性疾病是一个主要的全球健康问题，影响着全球1.5亿人。最近，上皮组织 细胞已成为过敏性炎症发病机制的中心参与者。定义密钥 过敏性炎症发生、持续和发展的上皮驱动因素是这方面的焦点。 申请。尽管上皮细胞越来越多地被认为是启动和启动的关键参与者 过敏性炎症的传播，缺乏专门针对上皮的治疗方法。确实有 在了解上皮细胞通路汇聚促进过敏的机制方面存在很大差距 在设计干预措施之前必须填充的炎症。我们的U19 AADCRC提案旨在 以帮助填补这一关键的知识缺口。由于资源有限，我们为拟议的研究做好了独特的准备 以及我们在过去20年中发展起来的合作。通过协同项目，我们将 探索支持变态反应发生、持续和发展的免疫学机制 并对过敏领域中一个关键的悬而未决的问题提供了新的见解：为什么过敏 炎症在某些情况下仅限于一种组织，而进展到累及其他组织 个人？这些项目包括： 项目1-阐明预测发展为哮喘的AD内型，并剖析 上皮动蛋白家族成员3A(KIF3A)在变态反应性炎症中作用的机制基础 以及疾病的持续性/进展性。 项目2-确定蛋白水解酶/蛋白水解酶抑制物失衡如何促进变态反应性炎症-解剖 上皮源性蛋白酶抑制剂KAZAL-7型丝氨酸蛋白酶抑制剂的作用机制 (SPINK7)促进过敏性炎症。 项目3-剖析新描述的一组粘膜肥大细胞(MMC9)的机制 使大量IL-9、IL-13和肥大细胞蛋白酶1(MCPT-1)发展并放大过敏 促进AD进展为过敏性哮喘的炎症。 这一领域的研究最终将为初级或二级预防提供路线图。 过敏性疾病。因此，这项建议与 RFA-AI-15-032。

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. Defining the key epithelial drivers of the development, persistence, and progression of allergic inflammation is the focus of this application. Although epithelial cells are increasingly recognized as critical participants in the initiation and propagation of allergic inflammation, therapies that specifically target the epithelium are lacking. There are substantial gaps in understanding the mechanisms by which epithelial pathways converge to promote allergic inflammation that must be filled before interventions can be designed. Our U19 AADCRC proposal is designed to help fill this critical knowledge gap. We are uniquely poised for the proposed studies because of resources and collaborations that we have developed over the past 2 decades. Through the synergistic projects, we will explore the immunological mechanisms, which underpin initiation, persistence, and progression of allergic disease and provide novel insights into a key unanswered question in the allergy field: Why is allergic inflammation restricted to one tissue in some cases, while it progresses to involve additional tissues in other individuals? The projects are: Project 1 – To elucidate endotypes of AD that are predictive of progression to asthma and dissect the mechanistic basis of the contribution of epithelial kinesin family member 3A (KIF3A) to allergic inflammation and disease persistence/progression. Project 2 – To determine how protease/protease inhibitor imbalance promotes allergic inflammation - dissect the mechanistic basis by which the epithelial-derived protease inhibitor serine protease inhibitor Kazal-type 7 (SPINK7) promotes allergic inflammation . Project 3 – To dissect the mechanisms by which a newly described population of mucosal mast cells (MMC9) that make large amounts of IL-9, IL-13, and mast cell protease 1 (MCPt-1) develops and amplifies allergic inflammation to promote progression of AD to allergic asthma. Investigations in this domain will ultimately provide a road map for primary or secondary prevention of allergic disease. As such, this proposal is highly aligned with the stated programmatic priorities in the RFA-AI-15-032.