| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Thrombus formation plays a critical role in the pathogenesis and pathophysiology of various vascular diseases. Proteinases, such as thrombin, activate proteinase-activated receptors (PARs), thereby exerting the vascular effects, including vasoconstriction, smooth muscle proliferation, vascular hyper-permeability, and production of the endothelium-derived vasoactive substances. However, the roles of PARs in the pathogenesis and pathophysiology of vascular diseases still remain to be elucidated. In the present study, we advanced our earlier studies on the physiological roles of PARs in the regulation of vascular function, and thereby investigated the pathophysiological role of PARs in vascular diseases. Especially, we focused our special attention on the regulation of vascular tone and proliferation, which play a central role in the pathophysiology of vascular diseases. We investigated the role of PARs in the vasospastic response after balloon injury; the role of thrombin and PAR1 in pos
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t-hemorrhagic vasospasm in subarachnoid hemorrhage; the thrombin-mediated vascular tone regulation in the normal pulmonary artery. We investigated the changes in the expression of PARs, the response to PAR agonists, and the signal transduction mechanisms under pathological conditions. We also investigated the molecular mechanisms underlying the endothelial NO production mediated by PAR1 and PAR4. Consequently, we clarified for the first time, (1) Rac1 regulatesd the cell-surface expression of PAR1 by activating the membrane trafficking ; (2) Balloon injury up-regulated the expression of PAR1 and PAR2, thereby enhancing the contractile response to thrombin and trypsin ; (3) Thrombin induced the up-regulation of PAR1 and the enhancement of the contractile response to thrombin in subarachnoid hemorrhage ; (4) Thrombin induced the vasoconstriction in the normal pulmonary artery by elevating [Ca^<2+>]_i and the Ca^<2+> sensitivity of the contractile apparatus ; (5) The activation of PAR4 induced endothelial NO production in a manner independent of the Ca^<2+> signal, and dependent on the phosphatidylinositol 3-kinase/Akt pathway. Less
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