Epithelial Genes in Allergic Inflammation

项目摘要 上皮细胞是第一道防线，因为它们与环境接触并启动对环境的反应。 环境触发器我们的AADCRC专注于阐明上皮细胞 有助于过敏性疾病的发病机制。我们发现虽然一些上皮基因与 与组织特异性疾病，其他与疾病的特定组合，并可能有助于 疾病从一个器官发展到另一个器官。众所周知，过敏性疾病表现出相当长的寿命， 科摩罗。“特应性进行曲”概念已成为我们领域的指导原则，然而，它已成为 很明显，只有很小一部分儿童遵循传统的特应性行进。虽然早期AD仍然存在 作为特应性疾病发展的主要危险因素， 特应性行进，包括时间和受影响的器官。特应性进行曲需要修改以包括这一点 异质性，并纳入发病机制的各种组合的特应性游行。本中心 旨在帮助填补这一关键的知识空白。在上一轮融资中，我们建造了美国第一个早期生命， AD的前瞻性纵向队列（儿童特应性皮炎进展为哮喘的机制， MPAACH），并进行了机制研究，以确定上皮途径，促进过敏性炎症 和疾病我们的集体初步数据暗示新的上皮途径是过敏性疾病的关键驱动因素 在给定组织中的持久性以及从一个组织到另一个组织的进展。在此，我们将确定如何 这些通路的作用是促进过敏性和炎症性疾病的发展、持续和进展。 疾病此外，特应性游行需要修改，以包括非白人儿童。绝大多数 在白色人群中进行的研究为特应性行进原则奠定了基础， 我们的数据揭示了当前特应性进行曲概念的显著种族差异。MPAACH占65% 黑人儿童，旨在帮助满足这一关键需求。这一提议的首要假设是， 上皮表面的稳态机制在失调时促进变应性炎症， 有助于过敏性疾病的持续、进展、缓解和消退。这一假设将 通过三个集中于上皮细胞生物学的综合和协同项目进行测试，这些项目将联合收割机 研究过敏相关多个终末器官的流行病学、基础和转化研究方法 应答数据集成和分析核心（DIAC）跨项目的数据集成将提供 对过敏领域一个关键的未回答问题的新见解：为什么过敏性炎症仅限于一种 组织，而它的进展涉及其他个人的其他组织？识别 使个体易患特异性或共有的过敏性疾病的上皮基因/途径将使 寻求专门针对上皮表面的治疗方法，以及治疗和 单独和/或组合的针对变应性病症优化的预防策略。

Project Summary Epithelial cells are the first line of defense as they interface with the environment and initiate the response to environmental triggers. Our AADCRC is focused on elucidating the mechanisms by which epithelial cells contribute to the pathogenesis of allergic disorders. We found that while some epithelial genes are associated with tissue-specific disease, others are associated with specific combinations of disease and may contribute to disease progression from one end-organ to another. It is known that allergic disorders show substantial lifetime comorbidity. The “atopic march” concept has served as a guiding principle in our field, however, it has become evident that only very small proportion of children follow the traditional atopic march. While early-life AD remains a major risk factor for the development of atopic disease, there is significant heterogeneity in presentation of the atopic march including the timing and organ(s) affected. The atopic march needs to be revised to include this heterogeneity and incorporate the pathogenesis of the various combinations of the atopic march. Our Center is designed to help fill this critical knowledge gap. In the last cycle of funding, we built the first US early-life prospective longitudinal cohort of AD (Mechanisms of Progression of Atopic Dermatitis to Asthma in Children, MPAACH) and conducted mechanistic studies to identify epithelial pathways that promote allergic inflammation and disease. Our collective preliminary data implicate novel epithelial pathways as key drivers of allergic disease persistence in a given tissue as well as progression from one tissue to another. Herein, we will determine how these pathways act to promote the development, persistence, and progression of allergic and inflammatory diseases. Further, the atopic march needs to be revised to include non-White children. The vast majority of studies that served as the foundation for the atopic march principle were conducted in White populations, and our data reveal marked racial differences in the current atopic march concept. MPAACH is comprised of 65% Black children and was designed to help fill this critical need. The overarching hypothesis of this proposal is that homeostatic mechanisms at epithelial surfaces, upon dysregulation, promote allergic inflammation and contribute to the persistence, progression, remission and resolution of allergic disease(s). This hypothesis will be tested by three integrated and synergistic projects focused on epithelial cell biology that combine epidemiologic, basic, and translational research approaches to study multiple end-organs involved in allergic responses. Integration of data across projects by the Data Integration and Analysis Core (DIAC) will 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? Identification of the epithelial genes/pathways that predispose individuals to specific or shared allergic disorders will empower the search for therapeutics aimed specifically at the epithelial surface, and the development of treatment and prevention strategies optimized for allergic disorders alone and/or in combination.