The recruitment of eosinophils to the airways involves the coordinated action of eosinophil cell surface receptors, endothelial cells, interstitial matrix proteins, and airway epithelial cells. The activation and migration of the eosinophils are controlled by adhesion molecules and chemotactic factors which signal through shared families of transmembrane cell surface receptors that are coupled to heterotrimeric G-proteins. Gq proteins are couple to ligand-bound surface receptors that activate subsequent intracellular signaling proteins including phospholipases and adenylyl cyclase. Activation of these intracellular effectors results in signal amplification through molecules such as IP3, CA+2, and cAMP, which, in turn, regulate ligand binding affinities (i.e., focal adhesion contacts) and cellular activation (i.e., actin mobilization), required for migration of leukocytes. We propose to identify the role of Gq in eosinophil recruitment and activation using a mouse model of allergic asthma. The specific objectives of this proposal are: (1) to determine the role of Gq-coupled receptors in eosinophil chemotaxis and adhesion, (2) to characterize the role of Gq in cell-cell interactions and other cell types involved in eosinophil trafficking in vivo; (3) develop an eosinophil lineage-specific Gq knockout to distinguish its role in eosinophil trafficking and downstream eosinophil effector functions (eosinophil induced pathological and physiological changes).
