2007 Fiscal Year Final Research Report Summary
Novel antithrombotic strategy based on the functional regulation of factor VIII/VWF complex
| Project/Area Number |
17390304
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Nara Medical University |
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Principal Investigator |
YOSHIOKA Akira Nara Medical University, Faculty of Medicine, Professor (40106498)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMA Midori Nara Medical University, Faculty of Medicine, Associate Professor (30162663)
SUGIMOTO Mitsuhiko Nara Medical University, Faculty of Medicine, Assistant Professor (80192128)
MATSUMOTO Masanori Nara Medical University, Faculty of Medicine, Assistant Professor (60316081)
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| Project Period (FY) |
2005 – 2007
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| Keywords | factor VIII / VWF / physiologic blood flow / thrombosis / flow chamber |
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| Research Abstract |
Fatal arterial thrombosis such as myocardial infarction or stroke is assumed to be triggered by hemostatic mechanisms which are originally essential for human defense. Hemostasis is established by the concerted functions of platelet adhesion/aggregation and blood coagulation mechanisms. Interestingly, von Willebrand factor (VWF) that plays a paramount role in platelet adhesion/aggregation is known to form a binary complex in plasma with the coagulation factor VIII which is the major blood coagulation factor. Thus, the purpose of the present study is to clarify the activation or inactivation mechanisms of this crucial molecular complex (factor VIII/VWF) under whole blood flow conditions, and to establish the novel antithrombotic strategy based on the functional regulation of factor VIII/VWF complex.
With regard to the factor VIII regulation, we have studied the activation/inactivation of factor VIII by a fibrinolytic factor plasmin. As a result, the cleavage of Arg-336 within factor VIII
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molecule was thought to be a central mechanism of plasmin-catalyzed factor VIII inactivation. Thus, we suggest the presence of a regulatory role of plasmin through direct proteolitic reaction in the coagulation reaction as well as fibrinolytic activity.
Next, with regard to the VWF regulation, we have studied the molecular mechanisms of ADAMTS13 activity under whole blood flow conditions, The proper function of VWF is essential for normal hemostasis, but the excessive function of VWF links to arterial thrombosis. ADAMTS13 is assumed to regulate the VWF function in vivo by reducing the multimer size that directly represents the thrombogenic activity of VWF, while the precise action mechanisms remain to be clarified. Using an in vitro perfusion chamber system, we have studied the ADAMTS13 activity on the process of platelet thrombus formation on a collagen surface under whole blood flow conditions. Inhibition studies with a function-blocking anti-ADAMTS13 antibody, combined with immunostaining of thrombi with an and-VWF monoclonal antibody that can specifically reflect the VWF-cleaving activity of ADAMTS13, demonstrated visual evidence for a shear-rate dependent action of ADAMTS13 that limits thrombus growth at the on-going thrombus generation process. Our results revealed a regulating mechanism on mural thrombogenesis to exquisitely prevent arterial occlusion under high shear rate conditions. Less
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Research Products
(24 results)
