Pathophysiological roles of the sphingosine-1-phosphate signaling system in vivo
Project/Area Number |
20590288
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
General medical chemistry
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Research Institution | Ishikawa Prefectural Nursing University |
Principal Investigator |
TAKUWA Noriko Ishikawa Prefectural Nursing University, 看護学部・健康科学講座, 教授 (70150290)
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Project Period (FY) |
2008 – 2010
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Project Status |
Completed (Fiscal Year 2010)
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Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
|
Keywords | スフィンゴシン-1-リン酸 / 遺伝子改変動物 / がん血管新生 / 心筋リモデリング / S1P2受容体 / G蛋白共役型受容体 / 低分子量G蛋白 / ノックアウトマウス / 骨髄移植実験 / マトリックスメタロプロテアーゼ / 心筋線維化 / スフィンゴシンキナーゼ / トランスジェニックマウス / 酸化ストレス / TGFbeta-Smad system / 生理活性脂質 / 腫瘍血管新生 / 細胞遊走 / 血管内皮 |
Research Abstract |
Sphingosine-1-phosphate (S1P) is a plasma lipid mediator that is produced by sphingosine kinase 1 (SphK1) in erythrocytes to mediate diverse biological activities via 5 members of the G protein-coupled S1P receptor subtypes. We previously cloned S1PR2 as an orphan G protein-coupled receptor and identified S1P as the physiological ligand. In fact S1PR2 turned out to be the first G protein-coupled receptor that negatively regulates cell migration. In the present study we generated SphK1 transgenic mice and S1PR2 knockout mice to investigate in vivo roles for the S1P signaling system. We found that SphK1 transgenic mice show resistance against acute myocardial ischemia whereas they develop spontaneous cardiac remodeling and fibrosis through mechanisms involving S1PR3 and transactivation of TGFβ signaling pathway and reactive oxygen-dependent processes. We also found that deletion of S1PR2 resulted in enhancement of tumor angiogenesis and tumor growth. Studies in cultured lung endothelial cells and bone marrow transplantation experiments indicated that S1PR2 expressed on vascular endothelial cells and bone marrow-derived myeloid cells in concert inhibit tumor angiogenesis, resulting in suppression of tumor progression, providing molecular basis for anti-angiogenic cancer therapy with S1PR2-selective agonist.
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Report
(4 results)
Research Products
(59 results)
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[Journal Article] Sphingosine-1-phosphate receptor-2 deficiency leads to inhibition of macrophage proinflammatory activities and atherosclerosis in Apoe-deficient mice.2010
Author(s)
Wang F., Okamoto Y., Inoki I., Yoshioka K., Du W., Qi X., Takuwa N., Gonda K., Yamamoto Y., Ohkawa R., Nishiuchi T., Sugimoto N., Yatomi Y., Mitsumori K., Asano M., Kinoshita M., Takuwa Y.
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Journal Title
J Clin Invest. 120
Pages: 3979-3995
NAID
Related Report
Peer Reviewed
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[Journal Article] Sustained delivery of sphingosine-1-phosphate using poly (lactic-co-glycolic acid)-based microparticles stimulates Akt/ERK-eNOS mediated angiogenesis and vascular maturation restoring blood flow in ischemic limbs of mice.2010
Author(s)
Qi X, Okamoto Y, Murakawa T, Wang F, Oyama O, Ohkawa R, Yoshioka K, Du W, Sugimoto N, Yatomi Y, Takuwa N, Takuwa Y.
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Journal Title
Eur J Pharmacol. 634
Pages: 121-131
Related Report
Peer Reviewed
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[Journal Article] S1P_2, the G protein-coupled receptor for sphingosine-1-phosphate, negatively regulates tumor angiogenesis and tumor growth in vivo in mice.2010
Author(s)
Du W, Takuwa N, Yoshioka K, Okamoto Y, Gonda K, Sugihara K, Fukamizu A, Asano M, Takuwa Y.
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Journal Title
Cancer Res. 70
Pages: 772-781
Related Report
Peer Reviewed
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[Journal Article] S1P_3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species.2010
Author(s)
Takuwa N, Ohkura S, Takashima S, Ohtani K, Okamoto Y, Tanaka T, Hirano K, Usui S, Wang F, Du W, Yoshioka K, Banno Y, Sasaki M, Ichi I, Okamura M, Sugimoto N, Mizugishi K, Nakanuma Y, Ishii I, Takamura M, Kaneko S, Kojo S, Satouchi K, Mitumori K, Chun J, Takuwa Y.
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Journal Title
Cardiovasc Res. 85
Pages: 484-493
Related Report
Peer Reviewed
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[Journal Article] Sustained delivery of sphingosine-1-phosphate using poly(lactic-co-glycolic acid)-based microparticles stimulates Akt/ERK-eNOS mediated angiogenesis and vascular maturation restoring blood flow in ischemic limbs of mice.2010
Author(s)
Qi, X., Okamoto, Y., Murakawa, T., Wang, F., Oyama, O., Ohkawa, R., Yoshioka, K., Du, W., Sugimoto, N., Yatomi, Y., Takuwa.N., Takuwa, Y
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Journal Title
Eur J Pharmacol.
Volume: 634
Pages: 121-131
Related Report
Peer Reviewed
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[Journal Article] S1P_2, the G protein-coupled receptor for sphingosine-1-phosphate, negatively regulates tumor angiogenesis andtumor growth in vivo in mice.2010
Author(s)
Du, W, Takuwa.N., Yoshioka, K., Okamoto, Y., Gonda, K., Sugihara, K., Fukamizu, A., Asano, M., Takuwa, Y.
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Journal Title
Cancer Research.
Volume: 70
Pages: 772-81
Related Report
Peer Reviewed
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[Journal Article] Sustained delivery of sphingosine-1-phosphate using poly(lactic-coglycolic acid)-based microparticles stimulates Akt/ERK-eNOS mediated angiogenesis and vascular maturation restoring blood flow in ischemic limbs of mice2010
Author(s)
Qi X, Okamoto Y, Murakawa T, Wang F, Oyama O, Ohkawa R, Yoshioka K, Du W, Sugimoto N, Yatomi Y, Takuwa N, Takuwa Y.
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Journal Title
Eur J Pharmacol. (in press)
Related Report
Peer Reviewed
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[Journal Article] S1P_2, the G protein-coupled receptor for sphingosine-1-phosphate, negatively regulates tumor angiogenesis and tumor growth in vivo in mice2010
Author(s)
Du W, Takuwa N, Yoshioka K, Okamoto Y, Gonda K, Sugihara K, Fukamizu A, Asano M, Takuwa Y.
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Journal Title
Cancer Res. 70(2)
Pages: 772-81
Related Report
Peer Reviewed
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[Journal Article] S1P_3-mediated cardiac fibrosis in sphingosine kinase 1 transgenic mice involves reactive oxygen species2010
Author(s)
Takuwa N, Ohkura S, Takashima S, Ohtani K, Okamoto Y, Tanaka T, Hirano K, Usui S, Wang F, Du W, Yoshioka K, Banno Y, Sasaki M, Ichi I, Okamura M, Sugimoto N, Mizugishi K, Nakanuma Y, Ishii I, Takamura M, Kaneko S, Kojo S, Satouchi K, Mitumori K, Chun J, Takuwa Y.
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Journal Title
Cardiovasc Res. 85(3)
Pages: 484-93
Related Report
Peer Reviewed
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[Presentation] Bimodal actions of the cardiac sphingosine-1-phosphate signaling revealed in sphingosine kinase 1 transgenic mice : S1P3-mediated, Rho-and active oxygen-dependent, chronic progression of spontaneous cardiac remodeling and cardioprotection against acutely imposed ischemia/reperfusion injury in sphingosine kinase 1 transgenic mice.2010
Author(s)
Takuwa N, Ohkura S, Takashima S, Ohtani K, Usui S, .Okamoto Y, Wang F, Du W, Yoahioka K, Takuwa Y.
Organizer
第87回日本生理学会大会
Place of Presentation
盛岡
Year and Date
2010-05-19
Related Report
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[Presentation] Bimodal actions of the cardiac sphingosine-1-phosphate signaling revealed in sphingosine kinase 1 transgenic mice : S1P3-mediated, Rho-and active oxygen- dependent, chronic progression of spontaneous cardiac remodeling and cardioprotection against acutely imposed ischemia/reperfusion injury in sphingosine kinase 1 transgenic mice.2010
Author(s)
Takuwa N, Ohkura S, Takashima S, Ohtani K, Usui S, Okamoto Y, Wang F, Du W, Yoahioka K, Takuwa Y
Organizer
第87回日本生理学会大会
Place of Presentation
盛岡
Related Report
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[Presentation] Physiological role of class II PI3K-C2alpha for vascular formation : conditional knockout mouse study.2010
Author(s)
Yoshioka K, Yoshida K, Aki S, Kuntal B, Du W, Qi, X, Wang F, Takuwa N, Okamoto Y, Takuwa Y
Organizer
第87回日本生理学会大会
Place of Presentation
盛岡
Related Report
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[Presentation] Cardiac remodeling and fibrosis in sphingosine kinase 1 transgenic mice through an S1P_3 receptor-mediated, reactive oxygen species-dependent process.2010
Author(s)
Takuwa N., S.Ohkura, S.Takashima, K.Ohtani, Y.Okamoto, S.Usui, K.Yoshioka, M.Takamura, S.Kaneko, Y.Takuwa
Organizer
The 74^<th> Annual Scientific Meeting of the Japanese Circulation Society
Place of Presentation
京都
Related Report
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[Presentation] Cardiac remodeling and fibrosis in sphingosine kinase 1 transgenic mice through an S1P_3 receptor-mediated, reactive oxygen species-dependent process2010
Author(s)
N.Takuwa, S.Ohkura, S.Takashima, K.Ohtani, Y.Okamoto, S.Usui, K.Yoshioka, M.Takamura, S.Kaneko, Y.Takuwa
Organizer
The 74^<th> Annual Scientific Meeting of the Japanese Circulation Society
Place of Presentation
京都
Related Report
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[Presentation] The role of S1P_2, the angiogenesis inhibitory receptor for sphingosine-1-phosphate, in tumor growth and angiogenesis in vivo.2009
Author(s)
Wa Du, 多久和典子, 吉岡和晃, 岡本安雄, Xun Qi, Fei Wang, Hong Cui, Kuntal Biswas, 杉原一司, 浅野雅秀, 多久和陽
Organizer
第82回日本生化学会
Place of Presentation
神戸(招待講演)
Related Report
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[Presentation] The role of S1P_2, the angiogenesis inhibitory receptor for sphingosine-1-phosphate, in tumor growth and angiogenesis in vivo2009
Author(s)
Wa Du, 多久和典子, 吉岡和晃, 岡本安雄, Xun Qi, Fei Wang, Hong Cui, Kuntal Biswas, 杉原一司, 浅野雅秀, 多久和陽
Organizer
第82回日本生化学会
Place of Presentation
神戸
Related Report
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[Presentation] 徐放化SIP製剤による虚血後血管新生の促進2008
Author(s)
戚 〓, 村川智美, 尾山 治, 杉本直俊, 王 飛, 杜 娃, 吉岡和晃, 岡本安雄, 多久和典子, 水岸貴代美, 多久和 陽
Organizer
第50回日本脂質生化学会
Place of Presentation
徳島
Related Report
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[Book] Lysophospholipid Receptors : Signaling and Biochemistry(Role of sphingosine-1-phosphate signaling in atherosclerosis.)(Chun J., Hla T., Spiegel S., Moolenaar W. eds., John Wiley & Sons, Hoboken)2011
Author(s)
Takuwa Y., Wang F., Okamoto Y., Yoshioka K., Takuwa N.
Publisher
New Jersey, U.S.A(in press)
Related Report