The overall goal of my lab is to apply principles of allergic and inflammatory disease pathophysiology in humans to questions at the bench, and in turn to bring fundamental findings made at the bench back to the clinic. A dominant theme is how lipid mediators, nucleotides, and their receptors function in an innate immune network to control the development and maintenance of airway inflammation, a process central to the pathobiology of asthma. We have discovered a critical role for platelets as a source of several pre-formed mediators that permit a rapid induction of type 2 airway inflammation, including high mobility group box 1 (HMGB1) and IL-33. Recruited platelets, most of which are adherent to granulocytes, are essential for the activation of mast cells and group 2 innate lymphoid cells in the airway. The activation of platelets in this setting is driven through the type 2 cysteinyl leukotriene receptor. We have identified nucleotide receptors responsible for respectively eliciting airway inflammation (P2Y12, P2Y2) and suppressing inappropriate activation of type 2 immunity (P2Y6). We are using preclinical models to identify strategies to exploit these findings for therapeutic development. Another area is the control of mast cell development and function in the airway by stromal elements and cytokines. Using single cell genomic strategies, we have recently found striking heterogeneity among airway mast cell populations in humans that are dictated at least in part by elements of local stromal cells that alter transcriptional systems, as well as cytokines (IL-4, TGF-beta) that elicit durable (and likely epigenetic) changes. We are currently examining the impact of cytokine blockade (IL-33, IL-4) on these transcriptional changes through a collaborative U19 grant from NIAID.