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Biopharmaceutical Research on Prostaglandin Receptors

前列腺素受体生物制药研究

基本信息

批准号：
12470496
负责人：
ICHIKAWA Atsushi
金额：
$ 10.5万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470496/
关键词：
prostaglandin receptor subtypes cyclic AMP signal transduction colitis platelet aggregation colon cancer gene targeting cyclicAMP プロスタグランジン受容体 Gタンパク質 EP3受容体 EP2受容体トロンボキサン受容体シクロオキシゲナーゼ

项目摘要

(1) The new signal transaction pathway exerted by prostanoid receptor EPS : EP3 has been shown to be coupled to Gi activity, inhibition of adenylate cyclase. EP3 has multiple isoforms that are different in their C-terminal structure and in their agonist-dependent Gi activity. We found that EP3 receptors expressed in COS-7 cells showed augmentation of other receptor-stimulated Gs activity in an agonist-dependent manner. The superactivatipn of Gs by EP3 receptors was not affected by the treatment of pertussis toxin, suggesting that the superactivation is not Gi-mediated. The EP3 agonist-dependent supeactivation of Gs is observed in any type of mouse EPS receptor isoforms, irrespective of C-termnal structure of EP3 receptor. This EP3 signaling may reflect some aspects of the physiological function of PGE2, such as pain sensation.(2) Elucidation of physiological roles of PGE2 by using each receptor subtype-deficient mice : We found that EP2 deficiency attenuated intestinal polyp formation both in number and size in Apc KO mice. We also showed acceleration of COX-2, EP2 and VEGF expression in the intestinal polyps of wild-type mice, but faint expression of COX-2 or VEGF in those of EP2 and Ape double-knockout mice, suggesting that there exists positive feedback regulation between COX-2 and EP2. We introduced dextransulfate (DSS)-induced colitis model into EP-deficient mice. As a result, only EP4-deficient mice showed severe colitis upon 3%DSS treatment that did not induce significant colitisin wild-type mice. EP4 has been shown to promote epithelial regeneration and to inhibit activation ofleukocytes and lymphocytes. We further found that EPS-deficient mice showed increased bleeding tendency and decreased susceptibility to arachidonate-induced thromboembolism compared with wild-type mice. EPS appears to potentiate TP-induced platelet aggregation by increasing intracellular Ca2+ and/or decreasing cAMP level.

(1)前列腺素受体EPS：EP 3所产生的新的信号传递途径已显示与Gi活性、腺苷酸环化酶的抑制偶联。EP 3具有多种同种型，其C-末端结构和激动剂依赖性Gi活性不同。我们发现，在COS-7细胞中表达的EP 3受体表现出增强的其他受体刺激的Gs活性的激动剂依赖性的方式。百日咳毒素处理对EP_3受体对Gs的超激活无影响，提示这种超激活不是Gi介导的。在任何类型的小鼠EPS受体亚型中都观察到Gs的EP 3激动剂依赖性超活化，而与EP 3受体的C-末端结构无关。这种EP 3信号传导可能反映了PGE 2生理功能的某些方面，例如疼痛感觉。(2)通过使用每种受体亚型缺陷小鼠阐明PGE 2的生理作用：我们发现，EP 2缺陷减弱了Apc KO小鼠中肠息肉形成的数量和大小。野生型小鼠肠息肉中考克斯-2、EP 2和VEGF表达增强，而EP 2和Ape双基因敲除小鼠肠息肉中考克斯-2和VEGF表达减弱，提示考克斯-2和EP 2之间存在正反馈调节。我们将葡聚糖硫酸酯（DSS）诱导的结肠炎模型引入EP缺陷小鼠。结果，只有EP 4缺陷小鼠在3%DSS治疗后显示出严重的结肠炎，其在野生型小鼠中不诱导显著的结肠炎。EP 4可促进上皮细胞再生，抑制白细胞和淋巴细胞的活化。我们进一步发现，与野生型小鼠相比，EPS缺陷小鼠表现出出血倾向增加和对花生四烯酸诱导的血栓栓塞的易感性降低。EPS似乎通过增加细胞内Ca 2+和/或降低cAMP水平来增强TP诱导的血小板聚集。