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.