Abstract

Thrombin is a multifunctional serine protease generated at sites of vascular injury. Its in vitro actions on platelets, leukocytes, endothelial and mesenchymal cells suggest that thrombin may mediate not only hemostasis and thrombosis but also inflammatory and proliferative responses to vascular damage in vivo. The overall goal of the application is to understand thrombin signaling, thereby providing strategies to prevent unwanted responses to vascular injury such as formation of platelet thrombi overlying ruptured atherosclerotic plaques, the usual cause of unstable angina and myocardial infarction. Knockout of par1, the first thrombin receptor cloned and characterized by the investigator s group, provided definitive evidence for the existence of second thrombin receptor in mouse platelets and for tissue specific roles for distinct thrombin receptors. Dr. Coughlin recently cloned and characterized par3, a second thrombin receptor that is expressed in human bone marrow and mouse megakaryocytes. The proposal seeks to define the role of par3 in vivo and the signaling mechanisms that it utilizes. The investigator seeks to answer the following questions: What are the roles of par1 and par3 in human platelets and other cells? Does par3 account for thrombin signaling in par1 -/- mouse platelets or do still other thrombin receptors exist? Are the signaling mechanisms utilized by par3 distinct from those used by par1, and what is the signaling pathway from par3 activation to platelet secretion and aggregation?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL059202-01
Application #
2445364
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1998-01-01
Project End
2002-11-30
Budget Start
1998-01-01
Budget End
1998-11-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Hamilton, J R; Cornelissen, I; Mountford, J K et al. (2009) Atherosclerosis proceeds independently of thrombin-induced platelet activation in ApoE-/- mice. Atherosclerosis 205:427-32
Camerer, Eric; Cornelissen, Ivo; Kataoka, Hiroshi et al. (2006) Roles of protease-activated receptors in a mouse model of endotoxemia. Blood 107:3912-21
Ludeman, Matthew J; Kataoka, Hiroshi; Srinivasan, Yoga et al. (2005) PAR1 cleavage and signaling in response to activated protein C and thrombin. J Biol Chem 280:13122-8
Su, Xiao; Camerer, Eric; Hamilton, Justin R et al. (2005) Protease-activated receptor-2 activation induces acute lung inflammation by neuropeptide-dependent mechanisms. J Immunol 175:2598-605
Hamilton, J R; Cornelissen, I; Coughlin, S R (2004) Impaired hemostasis and protection against thrombosis in protease-activated receptor 4-deficient mice is due to lack of thrombin signaling in platelets. J Thromb Haemost 2:1429-35
Ludeman, Matthew J; Zheng, Yao Wu; Ishii, Kenji et al. (2004) Regulated shedding of PAR1 N-terminal exodomain from endothelial cells. J Biol Chem 279:18592-9
Kataoka, Hiroshi; Hamilton, Justin R; McKemy, David D et al. (2003) Protease-activated receptors 1 and 4 mediate thrombin signaling in endothelial cells. Blood 102:3224-31
Weiss, Ethan J; Hamilton, Justin R; Lease, Katy E et al. (2002) Protection against thrombosis in mice lacking PAR3. Blood 100:3240-4
Camerer, E; Huang, W; Coughlin, S R (2000) Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci U S A 97:5255-60
Lindner, J R; Kahn, M L; Coughlin, S R et al. (2000) Delayed onset of inflammation in protease-activated receptor-2-deficient mice. J Immunol 165:6504-10

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