The long term objective of this project is to improve our understanding of mechanisms of blood platelet activation. We have made a novel observation, that the growth factors: kit ligand/stem cell factor (KL/SCF), macrophage-CSF (M-CSF or CSF-1) and platelet derived growth factor (PDGF) are able to modulate platelet aggregation. This proposal is designed to investigate the biochemical basis of modulation of platelet function by these cytokines. The functional consequences of growth factor treatment of platelets, particularly in combination with the platelet agonists ADP, epinephrine (EPI), collagen and thrombin will be studied. These functional studies will focus on modulation of fibrinogen binding, platelet aggregation, and release of serotonin and ATP. We will characterize the surface proteins on platelets which are the receptors for these growth factors and determine receptor numbers and binding affinities. We will investigate the mechanisms by which activation of growth factor receptors on platelets is linked to intracellular events ( e.g., phospholipase A2 activation, protein kinase c modulation, activation of adenylate cyclase system, and tyrosine kinase activity). These events will be correlated with the functional responses of platelets. These studies will help to define physiological and pathophysiological roles of these growth factors in hemostasis, and will guide optimal clinical use of these factors as therapeutics in a variety of disease states. These studies should also provide insights into the regulation of stimulus-response coupling in platelets and will contribute to a general better understanding of the role of receptor activation in signal transduction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
7R29HL050562-05
Application #
2460014
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1993-08-01
Project End
1998-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Chen, J; Herceg-Harjacek, L; Groopman, J E et al. (1995) Regulation of platelet activation in vitro by the c-Mpl ligand, thrombopoietin. Blood 86:4054-62
Grabarek, J; Groopman, J E; Lyles, Y R et al. (1994) Human kit ligand (stem cell factor) modulates platelet activation in vitro. J Biol Chem 269:21718-24