MECHANISMS REGULATING AIRWAY EOSINOPHILIC INFLAMMATION

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Asthma is a major public health problem. Allergens and viral infections, e.g. respiratory syncytial virus (RSV), are important precipitants of childhood asthma. The pathologic hallmark of asthma is an eosinophilic inflammation. The production of CC chemokines is increased in asthma and they are potent chemoattractants of eosinophils. The central hypothesis of this research proposal is that: In response to RSV infection, the airway cells produce chemokines that attract eosinophils into the airways. The release of eosinophil mediators causes bronchospasm and inflammation leading to asthma. In order to provide a comprehensive understanding of mechanisms regulating airway eosinophilic inflammation, we present four basic research projects. We will delineate the signal transduction mechanism of the CC chemokine receptor-3, the principal chemokine receptor on eosinophils in project 1. We will study the transcriptional regulation of chemokine production by RSV- stimulated epithelial cells in project 2. We will study receptors and cytosolic signaling pathways that mediate RSV activation of eosinophils in project 3. Further, we will dissect the mechanism by which CpG DNA motifs inhibit eosinophilic inflammation in project 4. The proposal utilizes existing and funded collaborators between cross-disciplinary project leaders expert in virology, cell biology, immunology, signal transduction, and control of gene transcription. This unique combination of investigators will address the pathogenesis of airway inflammation at a cellular and molecular level in a most comprehensive and multi- disciplinary manner. The proposal seeks to apply synergistic approaches to solving problems in asthma. Specific aspects of this center will develop and test novel therapeutic agents that target allergic inflammation of asthma and may be adjunct to an effective RSV vaccine.