Pathophysiological roles of the sphingosine-1-phosphate signaling system in vivo

1-磷酸鞘氨醇信号系统在体内的病理生理作用

• 批准号: 20590288
• 负责人: TAKUWA Noriko
• 金额: $ 3.08万
• 依托单位: Ishikawa Prefectural Nursing University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20590288/
• 关键词: 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

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.

鞘氨醇-1-磷酸(S1P)是一种血脂介质，由红细胞中的鞘氨醇激酶1(SphK1)产生，通过G蛋白偶联的S1P受体亚型中的5个成员介导不同的生物学活性。我们先前克隆了孤儿G蛋白偶联受体S1PR2，并确定S1P为其生理配体。事实上，S1PR2被证明是第一个负向调节细胞迁移的G蛋白偶联受体。在本研究中，我们建立了SphK1转基因小鼠和S1PR2基因敲除小鼠，以研究S1P信号系统在体内的作用。我们发现SphK1转基因小鼠表现出对急性心肌缺血的抵抗，而它们通过参与S1PR3和转化生长因子β信号通路的反式激活以及活性氧依赖过程而发生自发性心脏重构和纤维化。我们还发现S1PR2的缺失导致了肿瘤血管生成和肿瘤生长的增强。肺内皮细胞培养和骨髓移植实验表明，S1PR2在血管内皮细胞和骨髓来源的髓系细胞上协同表达，抑制肿瘤血管生成，从而抑制肿瘤进展，为S1PR2选择性激动剂抗血管生成肿瘤治疗提供了分子基础。

项目成果

Tumor-suppressive sphingosine-1-phosphate receptor-2 counteracting tumor-promoting sphingosine-1-phosphate receptor-1 and sphingosine kinase 1 - Jekyll Hidden behind Hyde.

• 发表时间: 2011
• 期刊: American journal of cancer research
• 影响因子: 5.3
• 作者: N. Takuwa;Wa Du;E. Kaneko;Y. Okamoto;K. Yoshioka;Y. Takuwa

The role of vascular Ca^<2+>-PI3KC2alpha-Rho axis in hypertension of spontaneously hypertensive rats.

血管Ca^2-PI3KC2α-Rho轴在自发性高血压大鼠高血压中的作用。

• 发表时间: 2010
• 作者: Okamoto Y;Seok Y-M;Azam MA;Sato A;Yoshioka K;Wang F;Hong C;Takuwa N;Takuwa Y
• 通讯作者: Takuwa Y

脂質メディエーターS1PによるS1P2受容体を介した腫瘍血管新生の抑制

脂质介质 S1P 抑制 S1P2 受体介导的肿瘤血管生成

• 发表时间: 2009
• 作者: 杜娃、多久和典子、吉岡和晃、岡本安雄;多久和陽
• 通讯作者: 多久和陽

The role of S1P_2, the angiogenesis inhibitory receptor for sphingosine-1-phosphate, in tumor growth and angiogenesis in vivo

1-磷酸鞘氨醇血管生成抑制受体S1P_2在体内肿瘤生长和血管生成中的作用

• 发表时间: 2009
• 作者: 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
• 通讯作者: 多久和陽

Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis

• DOI: 10.3390/ph4010117
• 发表时间: 2011-01-04
• 期刊: Pharmaceuticals
• 影响因子: 4.6
• 作者: Okamoto Y;Wang F;Yoshioka K;Takuwa N;Takuwa Y
• 通讯作者: Takuwa Y