Epithelial Barrier Programs in Asthma and Allergic Disease

描述（由申请人提供）：本AADCRC提案的总体目标是确定上皮细胞屏障在哮喘和过敏性疾病发病机制中的作用，并利用该信息预防此类疾病。我们结合了气道、肠道和皮肤上皮细胞生物学方面的专业知识，并使用高保真度的细胞和小鼠模型直接将我们的发现转化为人类。因此，AADRC由三个相互关联的项目组成，首先，气道上皮细胞如何在一种条件下介导有效的抗病毒防御，而在另一种条件下介导哮喘（项目1），第二，气道上皮细胞如何在病毒后和过敏性哮喘中向粘液细胞过剩的方向重塑（项目2），第三，皮肤上皮损伤如何触发从特应性皮炎到哮喘的进程（项目3）。每个项目都用一种新颖但重叠的分子方法来解决各自的问题，并利用突破性的发现为所研究的系统建立一个新的科学范式。因此，项目1揭示了一种新的IFN信号通路，它提供了对病毒感染和病毒后哮喘的更好保护，并且是针对气道上皮细胞屏障的；项目2揭示了自噬蛋白支持粘膜细胞正常功能和防止气道粘膜细胞化生的新途径，类似于肠上皮屏障；项目3定义了一种新的TSLP产生和分泌途径，该途径基于其在皮肤上皮屏障中的表达驱动气道炎症。每个项目的第一个目标是利用项目之间共享的细胞和小鼠模型建立基本的致病机制，并得到组织和细胞处理核心（Core C）和小鼠模型（Core D）的支持。反过来，每个项目将进行第二个目标，使用Core提供的用于人类受试者和数据分析（Core B）的哮喘和/或特应性皮炎儿童和成人样本来验证和翻译其发现。在项目之间共享样本和重叠的科学目标创建了一个协同计划，可以通过共同的行政核心（Core a）进行协调。Project和Core的相互作用基于这样一个总体原则，即每个Project都从细胞和小鼠模型中的分子假设构建开始，并将这些模型的发现转化为哮喘和/或过敏人类的研究。在每个项目中，我们的目标是验证疾病过程的临床有用的生物标志物，并为未来开发可能影响该过程的生物和/或小分子量化合物作为治疗策略奠定基础。

DESCRIPTION (provided by applicant): The overall goal of this AADCRC proposal is to define the role of the epithelial cell barrier in the pathogenesis of asthma and allergic disease and to use that information to prevent this type of disease. We combine expertise in airway as well as gut and skin epithelial cell biology, and we use cell and mouse models with high fidelity to directly translate our findings to humans. The AADRC therefore consists of three interrelated Projects that ask, first, how airway epithelial cells mediate effective antiviral defense under one condition but asthma under another (Project 1), second, how airway epithelial cells remodel towards an overabundance of mucous cells in post-viral and allergic asthma (Project 2), and third, how epithelial injury in the skin triggers the march from atopic dermatitis to asthma (Project 3). Each project addresses the respective question with a novel but overlapping molecular approach to mechanism and takes advantage of a breakthrough discovery to set a new scientific paradigm for the system under study. Thus, Project 1 unravels a new IFN signaling pathway that offers improved protection against viral infection and post-viral asthma and is specific to the airway epithelial cell barrier; Project 2 dissects a new pathway for autophagy proteins to support proper mucous cell function and prevent mucous cell metaplasia in the airway in a manner reminiscent of the intestinal epithelial barrier; and Project 3 defines a new TSLP production and secretion pathway that drives airway inflammation based on its expression in the skin epithelial barrier. Each Project is constructed so that the first aim will establish a basic pathogenic mechanism using cell and mouse models that are shared among projects and supported by the Cores for tissue and cell processing (Core C) and mouse models (Core D). In turn, each Project will conduct a second aim to validate and translate its findings using samples from children and adults with asthma and/or atopic dermatitis supplied by the Core for human subjects and data analysis (Core B). Sharing samples and overlapping scientific goals among projects create a synergistic program that can be coordinated by a common Administrative Core (Core A). Project and Core interactions are based on the overall principle that each Project begins with molecular hypothesis building in cell and mouse models and translates findings from these models to studies of humans with asthma and/or allergy. In each project, we aim to validate a clinically useful biomarker of the disease process and lay the groundwork for the future development of biological and/or small molecular weight compounds that might influence the process as a therapeutic strategy.