Regulation of distribution of extracellular Edg receptor family ligands and their physiological roles

细胞外Edg受体家族配体分布的调控及其生理作用

• 批准号: 15370051
• 负责人: OKAJIMA Fumikazu
• 金额: $ 9.66万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15370051/
• 关键词: sphingosine 1-phosphate; lysophosphatidic acid; lipid mediator; G-protein-coupled receptor; lipoprotein; vascular endothelial cell; vascular smooth muscle cell; proton-sensing receptor; サイコシン; OGR1; 高密度リポ蛋白; 動脈硬化; TDAG8; 神経突起退縮; オートタキシン; アス

We examined the regulation of distribution of extracellular sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA), and their physiological roles. (1) S1P as a mediator of lipoprotein actions in vascular cells : We showed a good correlation between HDL-S1P and HDL-cholesterol. In order to identify the receptor subtypes involved in HDL and S1P actions in vascular endothelial cells, we used antis enseoligonucleotides or siRNA specific S1P receptor subtypes and demonstrated that cell survival is mainly mediated by S1P1, cell migration is by both S1P1 and S1P3, and inhibition of TNF-α-induced adhesion molecule expression is by mainly S1P1. In vascular smooth muscle cells, it was shown that S1P2 receptor mediates cAMP accumulation and inhibition of cell migration. These results suggest that S1P receptors are useful therapeutic targets for vascular diseases. (2) Characterization of an LPA receptor antagonist and its application : We characterized Ki16425 as an LPA receptor antagonist and showed that this drug is effective for inhibiting motility of cancer cells such as pancreatic cancer cells and glioma cells. (3) Role of lipid mediator in central nervous system : We identified autotaxin, a lysophospholipase D, as a neurite retraction factor in cerebrospinal fluid. (4) A novel function of lysolipid receptors : We demonstrated that TDAG8, which has been shown to be a receptor for lipid molecule psychosine, senses extracellular proton or pH, resulting in activation of adenylyl cyclase. We also demonstrated by using siRNA techniques that extracellular acidic pH induces prostaglandin production and cAMP accumulation through OGR1, one of GPCRs with a similar primary structure to TDAG8, in human vascular SMC. Thus, OGR1 family GPCRs are functional receptors for sensing extracellular pH.

我们研究了细胞外1-磷酸鞘氨醇（S1 P）和溶血磷脂酸（LPA）的分布调节，以及它们的生理作用。(1)S1 P作为血管细胞中脂蛋白作用的介质：我们显示HDL-S1 P和HDL-胆固醇之间具有良好的相关性。为了鉴定血管内皮细胞中参与HDL和S1 P作用的受体亚型，我们使用反义寡核苷酸或siRNA特异性S1 P受体亚型，证明细胞存活主要由S1 P1介导，细胞迁移主要由S1 P1和S1 P3共同介导，并且主要由S1 P1抑制TNF-α诱导的粘附分子表达。在血管平滑肌细胞中，显示S1 P2受体介导cAMP积累和细胞迁移的抑制。这些结果表明，S1 P受体是血管疾病的有用的治疗靶点。(2)LPA受体拮抗剂的表征及其应用：我们将Ki 16425表征为LPA受体拮抗剂，并表明该药物可有效抑制癌细胞如胰腺癌细胞和神经胶质瘤细胞的运动。(3)脂质介质在中枢神经系统中的作用：我们确定了自分泌运动因子，溶血磷脂酶D，作为脑脊液中的神经突起收缩因子。(4)溶血脂质受体的一种新功能：我们证明了TDAG 8，它已被证明是脂质分子psychosine的受体，传感细胞外质子或pH值，导致腺苷酸环化酶的激活。我们还证明，通过使用siRNA技术，细胞外酸性pH诱导前列腺素的生产和cAMP的积累，通过OGR 1，与TDAG 8的一级结构相似的GPCR之一，在人血管SMC。因此，OGR 1家族GPCR是用于感测细胞外pH的功能性受体。

项目成果

Sphingosylphosphorylcholine Antagonizes Proton-Sensing OGR1-Mediated Inositol Phosphate Production and cAMP Accumulation

鞘氨醇磷酸胆碱拮抗质子感应 OGR1 介导的磷酸肌醇产生和 cAMP 积累

• 发表时间: 2005
• 期刊: J. Pharmacol. Sci 99
• 作者: Mogi;C
• 通讯作者: C

動脈硬化予防物質とその利用法

动脉硬化预防物质及其用途

• 发表时间: 2004

TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor

• DOI: 10.1074/jbc.m406966200
• 发表时间: 2004-10-29
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Wang, JQ;Kon, J;Okajima, F
• 通讯作者: Okajima, F

Sphingosine 1-phosphate receptors mediate the lipid-induced cAMP accumulation through cyclooxygenase-2/prostaglandin I2 pathway in human coronary artery smooth muscle cells

• DOI: 10.1124/mol.104.004317
• 发表时间: 2005-04-01
• 期刊: MOLECULAR PHARMACOLOGY
• 影响因子: 3.6
• 作者: Damirin, A;Tomura, H;Okajima, F
• 通讯作者: Okajima, F

Correlation of high density lipoprotein (HDL)-associated sphingosine 1-phosphate with serum levels of HDL-cholesterol and apolipoproteins.

• DOI: 10.1016/j.atherosclerosis.2004.08.024
• 发表时间: 2005
• 期刊: Atherosclerosis
• 影响因子: 5.3
• 作者: Bo Zhang;H. Tomura;A. Kuwabara;Takao Kimura;Shin-Ichiro Miura;Keita Noda;F. Okajima;K. Saku