G-PROTEIN COUPLED RECEPTORS IN ASTHMA AND INFLAMMATION

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Mast cells are multifunctional immune cells that play essential roles in allergic and inflammatory diseases. Activation of these cells via the cross-linking of cell surface high-affinity IgE receptors (FCepsilonRI) leads to the explosive release of histamine and generation of lipid-derived mediators. Recent studies demonstrated that activated mast cells also produce a variety of cytokines and chemokines. Recruitment and activation of leukocytes such as basophils and eosinophils, via the activation of chemokine receptors, mediate many functions of mast cells. An important hypothesis of the work described herein is that the state of mast cell/basophil responsiveness is regulated by other inflammatory mediators such as the anaphylatoxin, C3alpha and cytokines/chemokines. In addition to their signal transduction pathways, it is proposed that these modulators regulate the activity of other receptors present on mast cells and basophils. This laboratory has developed a basophilic and a mast cell line that are amenable to genetic manipulation and biochemical as well as functional analysis. Using these systems, we have demonstrated that activation of C3a receptors enhances ( primes ) antigen-stimulated mediator release. Our studies also revealed unexpected differences in the ability of C3a and other G protein coupled receptors to cause degranulation and support chemokine gene expression. We hypothesize that these differences reflect differences in phosphorylation and desensitization of these receptors. The studies to be performed herein will give us a precise understanding of the mechanisms by which by which mast cell/basophil functions are regulated and cross-regulated. This work will broaden our understanding of the molecular basis for the roles of mast cell/basophils in disease processes. In addition, it will likely provide a better rationale for the development of asthma and other inflammatory lung diseases.