KIF3A in Allergic Inflammation - Atopic Dermatitis to Asthma

过敏性疾病是影响全球1.5亿人的主要全球健康问题。最近， 细胞已经成为变应性炎症发病机制的主要参与者。确定主要 过敏性炎症的发展、持续和进展的上皮驱动因素是本研究的重点。 应用程序.虽然上皮细胞越来越被认为是启动和 由于过敏性炎症的传播，缺乏特异性靶向上皮的治疗。有 在理解上皮途径交汇促进过敏的机制方面存在巨大差距 在设计干预措施之前，必须填补炎症。我们的U19 AADCRC提案旨在 来帮助填补这一关键的知识空白。由于资源所限，我们已作好准备进行拟议的研究 以及我们在过去20年里发展起来的合作。通过协同项目，我们将 探索免疫学机制，其基础的启动，持续，和过敏性疾病的进展， 疾病，并提供了一个关键的过敏领域悬而未决的问题新的见解：为什么过敏 在某些情况下，炎症仅限于一种组织，而在其他情况下，炎症进展到涉及其他组织。 个人？这些项目是： 项目1-阐明AD的内型，其可预测哮喘的进展，并分析AD的 上皮驱动蛋白家族成员3A（KIF 3A）对过敏性炎症作用的机制基础 和疾病持续/进展。 项目2-确定蛋白酶/蛋白酶抑制剂失衡如何促进过敏性炎症-解剖 上皮来源的蛋白酶抑制剂丝氨酸蛋白酶抑制剂Kazal-7型 （SPINK7）促进过敏性炎症。 项目3-剖析新描述的粘膜肥大细胞（MMC9）群体的机制 使大量IL-9、IL-13和肥大细胞蛋白酶1（MCPt-1）产生并放大过敏反应 炎症促进AD向过敏性哮喘的进展。 这一领域的调查最终将为初级或二级预防提供路线图， 过敏性疾病因此，本建议与2010年12月25日至26日期间所述方案优先事项高度一致。 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.