ASTHMA, AIRWAY INFLAMMATION AND BETA CHEMOKINE RECEPTORS

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DESCRIPTION (Adapted from the applicant's abstract): The trafficking of lymphocytes and eosinophils to the lung is characteristic of asthma and other lung diseases. The mechanisms by which these cells are localized and activated in the airways are not well understood. The chemokines are a diverse gene family of cationic, heparin binding chemoattractant polypeptides. They are synthesized and released from epithelium, endothelium and hematopoietic cells in response to diverse stimuli. Cytokines, growth factors, virus particles and other autocoids amplify the inflammatory response via chemokines. Multiple chemokines interact with a limited repertoire of G-protein coupled receptors on leukocytes. The investigators hypothesize that the beta chemokine receptors on inflammatory cells are essential to constitutive as well as active eosinophil recruitment to the lung, and lymphocytes trafficking in the sensitized state. This hypothesis will be tested with three specific aims. 1) To identify, clone and characterize murine beta chemokine receptors. Three beta chemokine receptors will be cloned, expressed and biochemically characterized for ligand binding and signalling properties. The in vivo expression of these receptors will be analyzed at the RNA and protein levels. 2) To delete beta chemokine receptors from the mouse genome through gene targeting. Gene knockouts will be prepared in individual ES lines by homologous recombination, giving rise to animals deficient in a single beta chemokine receptor. In order to control for potential receptor redundancy, "double-knockouts" will be targeted in a single line, to yield animals with deficiency of both CCR1 and CCR3. 3) To evaluate the phenotypic consequences of chemokine receptor deletion in models of airways inflammation. The primary inflammatory model will utilize aerosolized albumin in sensitized mice. The successful completion of these aims will yield essential in vivo information clarifying the role of beta chemokines in airways inflammation. Thus, the beta chemokine receptor(s) are potentially a critical target in understanding the pathogenesis and potential management of asthma and other inflammatory lung diseases.