Exploring the biology of persistent type 2 airway niches in asthma

摘要/摘要 这是PPG的更新申请，重点是2型炎症持续存在的机制， 哮喘我们PPG的中心主题是哮喘中发生的2型炎症的局部性质 反映了持续的“2型气道小生境”的发展，其特征在于上皮细胞和免疫细胞因子。 细胞重编程和粘液栓形成。对空气过敏原和其他过敏原的正常稳态反应 吸入的损伤包括上皮细胞和先天细胞之间的通信，以募集限制细胞增殖的适应性细胞。 2型免疫反应和恢复气道功能。当这些修复机制破坏正常气道时 免疫程序被适应性反应所取代，适应性反应有利于气道2型炎症的持续， 形成粘液栓。这种持续性和“超高”的2型炎症发生在病灶区域， 我们最近在肺部影像中发现的局灶性和持续性嗜酸性粘液栓证实了哮喘肺 哮喘病人的。我们的PPG将在三个方面探索这些局灶性2型气道小生境的生物学 总体目标。目的1将确定先天性和适应性免疫细胞在持续性气道2型 壁龛被重新编程以维持炎症。AIM 2将确定气道上皮细胞如何 在2型壁龛中重新编程以维持炎症。AIM 3将确定上皮细胞和嗜酸性粒细胞 2型气道小生境中持续粘液凝胶病理学。我们的PPG包括三个由多学科领导的项目， 临床科学家、免疫学家和细胞生物学家组成的团队。这些项目由三个核心支持- 管理，人类受试者，生物标本和生物信息学。我们的PPG提出创新概念 2型高哮喘的发病机制，它将部署强大的尖端技术， 实验方法，以满足我们的计划目标。我们团结在一起，立志于发现 有可能导致2型高哮喘的治愈性治疗。

Summary / Abstract This is a renewal application for a PPG that focuses on mechanisms of persistence of type 2 inflammation in asthma. The central theme of our PPG is that the focal nature of type 2 inflammation that occurs in asthma reflects the development of persistent “type 2 airway niches” that are characterized by epithelial cell and immune cell reprogramming and mucus plug formation. Normal homeostatic responses to aeroallergens and other inhaled insults include communications between epithelial cells and innate cells to recruit adaptive cells that limit type 2 immune responses and restore airway function. When these repair mechanisms fail the normal airway immune program is replaced by adaptive responses that favor persistence of airway type 2 inflammation and formation of mucus plugs. This persistent and “ultra high” type 2 inflammation occurs in focal regions of the asthma lung, as evidenced by our recent finding of focal and persistent eosinophilic mucus plugs in lung images from patients with asthma. Our PPG will explore the biology of these focal type 2 airway niches in three overarching aims. AIM 1 will determine how innate and adaptive immune cells in the persistent airway type 2 niche are reprogrammed to sustain inflammation. AIM 2 will determine how airway epithelial cells are reprogrammed in type 2 niches to sustain inflammation. AIM 3 will determine how epithelial cells and eosinophils sustain mucus gel pathology in type 2 airway niches. Our PPG comprises three projects led by multidisciplinary teams of clinical scientists, immunologists and cell biologists. The projects are supported by three cores - administration, human subjects, and biospecimens and bioinformatics. Our PPG proposes innovative concepts for the pathogenesis of type 2-high asthma and it will deploy powerful and cutting edge technologies in the experimental approaches that address our program aims. We are united in our ambition to aim for discoveries that have the potential to lead to curative treatments for type 2-high asthma.