Exploring the biology of persistent type 2 airway niches in asthma

摘要/摘要 这是对PPG的续订应用，该PPG专注于2型炎症在 哮喘。我们PPG的中心主题是哮喘发生的2型炎症的局灶性 反映了以上皮细胞和免疫为特征的持续性“2型呼吸道小生境”的发展。 细胞重新编程和粘液堵塞的形成。对空气过敏原和其他过敏原的正常稳态反应 吸入性侮辱包括上皮细胞和固有细胞之间的通讯，以招募限制 第二型免疫反应和恢复呼吸道功能。当这些修复机制失效时，正常的呼吸道 免疫程序被适应性反应所取代，这种适应性反应有利于呼吸道2型炎症的持续和 粘液堵塞的形成。这种持续性的“超高”2型炎症发生在 哮喘肺，我们最近在肺部影像中发现的局限性和持续性嗜酸性粘液塞证明了这一点 来自哮喘患者。我们的PPG将在三年内探索这些焦点2型呼吸道壁龛的生物学 首要目标。目标1将确定持续性呼吸道2型中的先天免疫细胞和获得性免疫细胞 小生境被重新编程以维持炎症。目标2将确定呼吸道上皮细胞如何 在2型壁龛中重新编程以维持炎症。目标3将确定上皮细胞和嗜酸性粒细胞如何 在2型气道壁龛中维持粘液凝胶病理。我们的PPG由三个项目组成，由多学科领导 由临床科学家、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提出创新的概念 对于2型高哮喘的发病机制，它将部署强大的尖端技术 针对我们的计划目标的实验方法。我们在追求发现的雄心上是一致的。 有可能导致治疗II型高度哮喘的药物。

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.