Epithelial Barrier Programs in Asthma and Allergic Disease

描述(由申请人提供)：AADCRC提案的总体目标是定义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。我们结合了呼吸道以及肠道和皮肤上皮细胞生物学方面的专业知识，并使用高保真的细胞和小鼠模型将我们的发现直接转化为人类。因此，AADRC由三个相互关联的项目组成，这三个项目询问：第一，呼吸道上皮细胞如何在一种情况下调节有效的抗病毒防御，而在另一种情况下哮喘(项目1)，第二，在病毒后和过敏性哮喘中，呼吸道上皮细胞如何向过多的粘液细胞重塑(项目2)，以及第三，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解决了各自的问题，并利用一项突破性发现为正在研究的系统设定了新的科学范式。因此，项目1揭开了一条新的干扰素信号通路，它提供了对病毒感染和病毒后哮喘的更好的保护，并且是针对呼吸道上皮细胞屏障的；项目2剖析了一条自噬蛋白的新途径，以支持适当的黏液细胞功能，并以一种使人想起肠道上皮屏障的方式防止气道中的黏液细胞化生；以及项目3定义了一种新的TSLP产生和分泌途径，基于其在皮肤上皮屏障中的表达而驱动呼吸道炎症。每个项目的构建使得第一个目标将使用细胞和鼠标模型建立基本的致病机制，这些模型在项目之间共享，并得到组织和细胞处理核心(核心C)和老鼠模型(核心D)的支持。反过来，每个项目都将实施第二个目标，利用人类受试者和数据分析核心(核心B)提供的患有哮喘和/或特应性皮炎的儿童和成人样本来验证和翻译其研究结果。项目之间共享样本和重叠的科学目标创建了一个可以由一个共同的管理核心(核心A)协调的协同计划。项目和核心互动基于一个总体原则，即每个项目都是从在细胞和小鼠模型中建立分子假说开始的，并将这些模型的发现转化为对患有哮喘和/或过敏的人类的研究。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记物，并为未来开发可能影响疾病过程的治疗策略的生物和/或小分子化合物奠定基础。

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.