Grants and Contracts Details
Description
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.
Status | Finished |
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Effective start/end date | 7/1/06 → 6/30/08 |
Funding
- American Heart Association Ohio Valley Affiliate: $42,000.00
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