Platelet-activating factor(PAF) is a phospholipid-derived mediator which has been implicated in cutaneous inflammation, thus antagonists of PAF could form the basis of novel antiinflammatory treatments. My previous studies have demonstrated that keratinocytes both synthesize and express functional receptors for PAF. This project tests the hypothesis that PAF has proinflammatory effects on keratinocytes through two separate lines of investigation which will be conducted concurrently. First, an in vivo murine model system will be developed to evaluate: 1) the epicutaneous effects of specific PAF receptor (PAF-R) agonists and antagonists; 2) the potential antiinflammatory effects of potent PAF-R antagonists on experimentally-induced dermatitis. Second, an in vitro model system of the PAF-R will be developed through retroviral-mediated gene transfer of both the wild-type and truncated mutant PAF-R (which does not undergo homologous desensitization) into the PAF-R-negative epidermoid cell line KB. This PAF-R model system will allow characterization of the morphological and functional effects of the PAF-R in epidermal cells. These two separate lines of investigation will provide both information as well as tools for future studies to dissects the role of PAR in the complex cytokine network found in the skin, information which could be translated into novel therapeutic strategies.
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