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.

我们检查了细胞外鞘氨醇1-磷酸盐（S1P）和溶血磷脂酸（LPA）及其身体作用的调节。 （1）S1P作为血管细胞中脂蛋白作用的介质：我们在HDL-S1P和HDL-胆固醇之间显示出良好的相关性。为了鉴定血管内皮细胞中与HDL和S1P作用相关的受体亚型，我们使用抗体乙酰氨基核苷酸或siRNA特异性S1P受体亚型，并证明细胞的存活主要由S1P1介导，主要由S1P1和S1P-IS-iSp3 tnf-inder od thf-indimandimantime抑制。 S1P1。在血管平滑肌细胞中，S1P2受体介导了cAMP的积累和细胞迁移的抑制作用。这些结果表明，S1P受体是血管疾病的有用治疗靶标。 （2）表征LPA受体拮抗剂及其应用：我们将KI16425表征为LPA受体拮抗剂，并表明该药物有效抑制胰腺癌细胞和胶质瘤细胞等癌细胞的运动性。 （3）脂质介体在中枢神经系统中的作用：我们确定自身蛋白酶（一种溶血磷脂酶D）是脑脊液中的神经磷脂缩回因子。 （4）溶血脂受体的新功能：我们证明TDAG8已被证明是脂质分子心理的受体，会感觉到细胞外质子或pH值，从而激活腺苷酸环酶。我们还使用siRNA技术证明了细胞外酸性pH值可诱导前列腺素的产生和cAMP通过OGR1（在人血管SMC中具有与TDAG8相似的基本结构的GPCR）的OGR1积累。那就是OGR1家族GPCR是用于传感细胞外pH的功能受体。

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

Effects of interleukin-1beta and prostaglandin E2 on prostaglandin D synthase production in cultivated rat leptomenigeal cells.

IL-1β 和前列腺素 E2 对培养大鼠软脑膜细胞中前列腺素 D 合酶产生的影响。

• 发表时间: 2004
• 期刊: J Cereb Blood Flow Metab. 24
• 作者: Muraki T;Fujimori K;Ishizaka M;Ohe Y;Urade Y;Okajima F;Ishikawa K.
• 通讯作者: Ishikawa K.

Kim HS, Okajima F, Im DS: "Analysis of vasopressin-induced Ca2+ increase in rat hepatocytes."Arch Pharm Res. 26. 64-69 (2003)

Kim HS、Okajima F、Im DS：“加压素诱导的大鼠肝细胞 Ca2+ 增加的分析。”Arch Pharm Res。

Analysis of vasopressin-induced Ca2+ increase in rat hepatocytes

加压素诱导大鼠肝细胞 Ca2+ 增加的分析

• 发表时间: 2003
• 期刊: Arch Pharm Res 26
• 作者: Wang;JQ.;Kon;J.;Mogi;C.;Tobo;M.;Damirin;A.;Sato;K.;Komachi;M.;Malchinkhuu;E.;Murata;N.;Kimura;T.;Kuwabara;A.;Wakamatsu;K.;Koizumi;T.;Uede;T.;Tsujimoto;G.;Kurose;H.;Sato;T.;Harada;A.;Misawa;N.;Tomura;H.;Okajima;F.;Malchinkhuu E;Kim HS
• 通讯作者: Kim HS