PLATELET CYTOSKELETAL ASSEMBLY & FUNCTION

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The platelet response to physiologic stimuli mediating platelet aggregation at a wound site is crucial to hemostasis. This platelet response and its reversal by prostaglandin I2 are also likely to be important to the pathophysiology of atherosclerosis, thrombophlebitis, and stroke. The long-term objective of this project is to understand the regulation of platelet cytoskeletal assembly during activation (actin polymerization, myosin and actin-binding protein phosphorylation and interaction with actin filaments), reversal of activation-cytoskeletal assembly by PGI2 elevation of platelet cAMP, and the relationship of this cytoskeletal assembly/disassembly to the expression of surface membrane sites mediating activation, adhesion, and aggregation. Towards obtaining this objective, it is proposed to isolate actin-binding protein to determine if its interaction with actin is modified by its in situ phosphorylation by protein kinase C during activation and by cAMP-dependent kinase during the reversal or inhibition of activation-cytoskeletal assembly. Membrane glycoprotein- cytoskeletal complexes have been isolated from PGI2-inactivated platelets. It is proposed to determine whether these complexes are essential to platelet activation as regulated precursors of cytoskeletal assembly and whether the disruption of such complexes is the mechanism by which certain amphiphilic compounds inhibit platelet activation-cytoskeletal assembly.