| Project/Area Number |
15390063
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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 |
General physiology
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| Research Institution | Kanazawa University |
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Principal Investigator |
TAKUWA Yho Kanazawa University, Graduate School of Medical Science, Professor, 医学系研究科, 教授 (60171592)
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| Co-Investigator(Kenkyū-buntansha) |
SUGIMOTO Naotoshi Kanazawa University, Graduate School of Medical Science, Assistant Professor, 医学系研究科, 講師 (80272954)
TAKUWA Noriko Kanazawa University, Graduate School of Medical Science, Research Associate, 医学系研究科, 助手 (70150290)
YOSHIOKA Kazuaki Kanazawa University, Graduate School of Medical Science, Research Associate, 医学系研究科, 助手 (80333368)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥14,800,000 (Direct Cost: ¥14,800,000)
Fiscal Year 2004: ¥6,400,000 (Direct Cost: ¥6,400,000)
Fiscal Year 2003: ¥8,400,000 (Direct Cost: ¥8,400,000)
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| Keywords | sphingosine-1-phosphate / Edg / cell motility / Rac / Rho / ノックアウト / マウス / トランスジェニック |
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| Research Abstract |
In order to delineate physiological and pathophysiological roles of sphingosine-1-phosphate (S1P), we conducted the following in vitro and in vivo investigations. S1P and its receptors regulate cell motility both positively and negatively. The S1P receptors Edg1 and Edg3 mediate Rac stimulation and thereby chemotaxis via Gi, whereas Edg5 mediates Rac inhibition and cell migration inhibition via G12/13 and Rho. Available evidence suggests that S1P could affect vascular smooth muscle accumulation in injured blood vessels. We found that S1P stimulated mRNA expression of platelet-derived growth factor (PDGF) A and B chains in neointimal smooth muscle. This stimulatory effect was mediated via Edg1-Gi-Ras-ERK/p38MAPK and Edg3/Edg5-Rho-Rho kinase. The ERK and p38MAPK mediated stimulation of KLF5 expression, which was necessary and sufficient for PDGF gene expression. S1P inhibits migration of vascular smooth muscle cells. This action was accompanied by Rac inhibition. Interestingly, both G12/13 and Gq were involved in S1P-induced Rac inhibition in vascular smooth muscle cells. In addition to Edg1 and Edg3, vascular endothelial cells express Edg5, which mediates inhibition of endothelial cell migration and capillary like tube formation. We generated Edg1-transgenic and sphingosine kinase-transgenic mice, and analyzed their phenotypes. Preliminary results show that S1P-Edg system is involved in the homeostasis of the cardiovascular system.
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