The purpose of this project is to develop a selective inhibitor of alpha- thrombin~s activation of platelets and other cells by blocking its ability to cleave the cloned thrombin receptor. This agent, which is called thrombostatin, does not interfere with alpha-thrombin~s ability to form fibrin clots. The specific goals of this proposal are to show the in vivo efficacy of thrombostatin to inhibit alpha-thrombin~s activation of platelets by performing experiments in 4 small animal models that mimic human cardiovascular disease. Further, the proposed studies will examine new potential uses of thrombostatin by demonstrating its role in blocking alpha-thrombin~s effect in neurobiology and inflammation.
Specific Aim 1 : Studies will be performed to determine the efficacy of thrombostatin as an inhibitor of induced carotid artery thrombosis and carotid artery rethrombosis after thrombolytic therapy in tow separate rabbit animal models.
Specific Aim 2 : Investigations will be performed to determine the efficacy of thrombostatin as an inhibitor of platelet activation after rabbit femoral artery balloon injury. Additional studies will determine the anticoagulant effect of thrombostatin in preventing arterial thrombosis after acute plaque disruption in atherosclerotic rabbits.
Specific Aim 3 : Studies will be performed to determine the ability of thrombostatin to inhibit neuronal cell stimulation and fibroblast growth and proliferation by selectively blocking alpha-thrombin's ability to activate these cells through the cloned thrombin receptor. These projects will show that thrombostatin functions as an alpha- thrombin inhibitor in vivo. Further, these studies will show that thrombostatin is an inhibitor of alpha-thrombin activation of the cloned thrombin receptor on any cell. Thrombostatins will inhibit alpha- thrombin's activity without increasing bleeding risk.
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