PAF STIMULATED PHOSPHOINOSITIDE TURNOVER IN PLATELETS

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Platelet activating factor (PAF), a phospholipid, has an assigned structure of 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (AGEPC). It affects the function of several cells and tissues. The most pronounced effect of this compound is on platelets, a blood cell with important role in cardiovascular processes. AGEPC stimulates platelets and also causes rapid turnover of polyphosphoinositides (PPI). The theme is to elucidate the 'mechanism" and "importance' of AGEPC stimulated PPI turnover in platelets. Based on new experimental findings it is our hypothesis that phosphoinositide phosphodiesterase (phospholipase C) plays a key role in AGEPC stimulated activation of platelets. The following experimental strategies will form the basis of this project [I] To establish characteristics of the key enzyme (phospholipase C) involved in PPI turnover; its regulation by selected agents. [II] Relationship between PPI turnover and AGEPC receptor; Is AGEPC receptor a PPI phosphodiesterase? [III] Study of possible link between PPI turnover and platelet refractoriness (desensitization) to AGEPC. [IV] Study of AGEPC stimulated PPI turnover in platelets with in situ manipulated levels of PPI; or in platelets from pathophysiological states. AGEPC is emerging as a potent mediator (autacoid). PPI turnover is drawing support for being a cell signalling event. How this signal-mechanism is involved in biochemical mode of action of this new mediator (AGEPC) is therefore an important issue. This will be explored using platelets as a model cell.