Exploring the biology of persistent type 2 airway niches in asthma

摘要/摘要 这是 PPG 的更新应用，重点研究 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 型炎症的焦点性质 反映了持续的“2型气道生态位”的发展，其特征是上皮细胞和免疫 细胞重编程和粘液栓形成。对空气过敏原和其他物质的正常稳态反应 吸入性损伤包括上皮细胞和先天细胞之间的通讯，以招募适应性细胞，从而限制 2型免疫反应并恢复气道功能。当这些修复机制无法正常气道时 免疫程序被适应性反应所取代，有利于气道 2 型炎症的持续存在 粘液塞的形成。这种持续且“超高”的 2 型炎症发生在大脑的局灶性区域。 肺部哮喘，我们最近在肺部图像中发现局灶性和持续性嗜酸性粘液栓就证明了这一点 来自哮喘患者。我们的 PPG 将在三个阶段探索这些局灶性 2 型气道生态位的生物学 总体目标。 AIM 1 将确定 2 型持续性气道中的先天性和适应性免疫细胞如何 生态位被重新编程以维持炎症。 AIM 2 将确定气道上皮细胞的状况 在 2 型生态位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如何 维持 2 型气道壁龛中的粘液凝胶病理学。我们的 PPG 包括由多学科领导的三个项目 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、人体受试者、生物样本和生物信息学。我们的 PPG 提出创新理念 针对 2 型高哮喘的发病机制，它将在 解决我们计划目标的实验方法。我们团结一致，追求发现 这有可能导致 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.