Thrombin, one of the most potent activators of platelets, works through activation of G protein-coupled protease receptors PAR-1 and PAR-4, which upon activation lead to increases in intracellular calcium, Rap1 activation and finally platelet aggregation, the PAR signaling system has been targeted as a site for inhibiting platelet activation because blocking PAR signaling is thought to be crucial in decreasing the risk to bleeding observed in other anti-platelet therapies.
The aim of this research proposal is to identify how thrombin may differentially signal Rap1 mediated platelet activation. Since Rap1 has been implicated in thrombin-induced activation of platelets and may be a crucial mediator signaling inside-out activation of integrin receptor GPIIbllla as well as activating other downstream signaling pathways, I propose to investigate, through the use of specific PAR inhibitors and G protein minigenes, the differential signaling involved from the PAR receptors to Rap1, what this difference in signaling translates to in the form of level of platelet activation and by what means Rap1 is able to activate aggregation and/or secretion in platelets following thrombin, PAR-1 or PAR-4.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL082068-02
Application #
7113603
Study Section
Special Emphasis Panel (ZRG1-DIG-B (21))
Program Officer
Werner, Ellen
Project Start
2005-08-01
Project End
2007-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$48,796
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Voss, Bryan; McLaughlin, Joseph N; Holinstat, Michael et al. (2007) PAR1, but not PAR4, activates human platelets through a Gi/o/phosphoinositide-3 kinase signaling axis. Mol Pharmacol 71:1399-406
Holinstat, Michael; Voss, Bryan; Bilodeau, Matthew L et al. (2007) Protease-activated receptors differentially regulate human platelet activation through a phosphatidic acid-dependent pathway. Mol Pharmacol 71:686-94
Holinstat, Michael; Voss, Bryan; Bilodeau, Matthew L et al. (2006) PAR4, but not PAR1, signals human platelet aggregation via Ca2+ mobilization and synergistic P2Y12 receptor activation. J Biol Chem 281:26665-74