and specific aims): The agents responsible for recruiting eosinophils (Eo) to sites of asthma and other diseases remain ill-defined. Chemotactic factors (CFs) are among the current suspects. However, CFs often are relatively weak Eo-stimuli, have greater potency on neutrophils (Neu), and thus seem better suited to mediate Neu-based inflammatory rather than Eo-based allergic reactions. Evidence indicates that a newly described eicosanoid, 5-oxoETE, has extreme potency, power, and selectivity in stimulating Eo migration. It resembles classical CFs in operating through presumptive receptors (Rs) that link to pertussis toxin (PT)-sensitive heterotrimeric G proteins (GPs). However, it differs from known CFs not only in strength and Eo-selectivity but also in its limited ability to stimulate non-chemotactic responses as well as its apparently complete reliance on PT-sensitive GPs. Other CFs rely on both PT-insensitive and PT-sensitive GPs. The application postulates that 5-oxoETE has a restricted range of proallergic actions on Eo; these actions proceed via dedicated Rs; these Rs link to a distinctive, identifiable subset of GPs; and these GPs regulate a correspondingly distinctive, identifiable subset of cell signals and responses.
The specific aims are to: 1) Define 5-oxoETE's ability to stimulate selected responses and signals relevant to these responses in Eo and Neu; 2) Demonstrate 5-oxoETE-Rs and EPs in Eo, Neu, and differentiated HL-60 cells; and 3) Deduce the signals and functional responses regulated by specific GP classes.
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