Fellowship/Choi: The Role of ADP-ribosylation factor 6 (Arf6) in Platelet Activation

Grants and Contracts Details


Platelets are anucleate cell fragments in the blood stream that playa key role in hemostasis. Platelet dysfunction is a contributor to cardiovascular diseases such as heart attacks and strokes because abnormal clot formation precipitates blood flow occlusion. Understanding the mechanisms of platelet activation is critical to controlling spurious clot formation. In response to vascular lesions, platelets become activated and undergo a series of morphological changes such as shape change, spreading/adhesion, and secretion of granule contents, for which actin remodeling plays a role. Actin remodeling is known to be a convergent target of different platelet signaling cascades. Our work has identified a new player in this process. In a recent publication (Choi et aI., Blood. 2005, 0011 0.1182/blood-2005-09-3563), we provided the first evidence for the presence and possible function of Arf6 in platelets. Arf6 is a member of the AOP-ribosylation factor (Art) family of small GTPase. In platelets, its transition from GTP- to GOP-bound state is essential for agonist-induced aggregation, spreading, and Rho family activation. In nucleated cells, Arf6 has been shown to affect actin cytoskeleton by regulating phospholipase 0 (PLD), phosphatidylinositol-4-phosphate 5-kinases (PI 5-kinase), and Rho GTPases. Though these molecules are important for platelet function, their control by Arf6 has not been demonstrated and will be the focus of the present proposal. Based on our recent studies, we hypothesize that Arf6 plays an essential role in platelet activation by regulating cytoskeletal rearrangement via affecting Rho family GTPases and phospholipids. To address this hypothesis, we will need to establish how Arf6 is affected by platelet signaling cascades and how it affects downstream events. To accomplish this goal, two specific aims are proposed: Specific Aim 1 is to 'determine upstream regulators of Arf6 in resting and stimulated platelets and Specific Aim 2 is to elucidate the mechanism by which Arf6-GTP affects platelet cytoskeleton. The data from the proposed experiments will indicate how Arf6 responds to platelet activation and will delineate what signaling steps and platelet processes are affected by Arf6GTP/GDP. This data will further illuminate the mechanisms of platelet activation and expand the catalogue of potentially useful therapeutic targets.
Effective start/end date7/1/066/30/08


  • American Heart Association Ohio Valley Affiliate: $42,000.00


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