Generation and analysis of mice lacking the prostanoid receptor

缺乏前列腺素受体的小鼠的产生和分析

• 批准号: 07557175
• 负责人: USHIKUBI Fumitaka
• 金额: $ 9.92万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07557175/
• 关键词: prostanoid; prostaglandin; thromboxane; prostanoid receptor; knockout mouse; 受容体; 遺伝子ノックアウトマウス; ES細胞; C57BL; 6; プロスタグラジン; トロンボキサンA_2

We constructed the targeting vectors for homologous recombination with each of the eight rypes and subtypes of the prostanoid receptor genes. The vectors were introduced into the ES cells originating from the mouse strain of 129/ola. The blastcystes injected with the ES cells were then intoduced into the uterus of pseudo-pregnant ICR mice, and the chimeric mice were generated. The chimeric mice were crossed with C57BL/6 mice, and the F1 mice were generated followed by F2 mice lacking each of the prostanoid receptor. We have been trying to back-cross each of the mutant mice to C57BL/6, balb/c and DBA1 mice to get the congenic mice.Analyzes of these mice lacking each of the prostanoid receptors have revealed the novel physiological and pathophysiological roles of prstanoids in the body. PGI_2 has roles in increased vascular permiability and transmission of pain sensation in inflammation as well as antithrombotic role. PGF_<2alpha> decreases the plasma progesterone level by inducing the regression of corpus luteum, which then upregulates the expression of the oxytosin receptors in the uterus at term. PGE_2 acts on the EP4 receptor and regulates the function of the ductus arteriosus.These results would contribute to the development of new drugs acting specifically on each prostanoid receptors, and would also present the clues to the application of these drugs.

我们构建了与前列腺素受体基因的八个RYP和亚型中的每一个同源重组的靶向载体。将载体引入源自129/OLA小鼠应变的ES细胞中。然后将注入ES细胞的爆炸性分子插入伪孕的ICR小鼠的子宫中，并产生嵌合小鼠。将嵌合小鼠与C57BL/6小鼠交叉，并产生F1小鼠，然后是缺少每种前列腺素受体的F2小鼠。我们一直在试图将每只突变小鼠的每只突变小鼠反向C57BL/6，BALB/C和DBA1小鼠，以使其具有相似小鼠。这些小鼠缺乏每种前列腺素受体的小鼠已经揭示了prstanoids在体内的新型生理和病理生理学作用。 PGI_2在炎症和抗血栓形成作用中疼痛感觉的增加和疼痛感觉的传播中具有作用。 PGF_ <2alpha>通过诱导Luteum的回归来降低血浆孕酮水平，然后在期间上调子宫中氧胞质受体的表达。 PGE_2作用于EP4受体，并调节导管动脉的功能。这些结果将有助于专门针对每个前列腺素受体作用的新药物的发展，并且还将为这些药物的应用提供线索。

项目成果

Hirata, M., et al.: "Molecular Biology of the Arachidonate Cascade.(分担執筆)" Elsevier Science., 393-404 (1995)

Hirata, M. 等人：“花生四烯酸级联的分子生物学。（贡献者）”Elsevier Science.，393-404 (1995)

Yukihiko Sugimoto: "Failure of parturition in mice lacking the prostaglandin F receptor." Science. 277. 681-683 (1997)

Yukihiko Sugimoto：“缺乏前列腺素 F 受体的小鼠分娩失败。”

Kishi,K.,et al.: "G_q-coupled receptors transmit the signal for GLUT4 translocation via an insulin-independent pathway." J.Biol.Chem.271. 26561-26568 (1996)

Kishi,K.,et al.：“G_q 偶联受体通过不依赖于胰岛素的途径传递 GLUT4 易位信号。”

Eri Segi: "Patent ductus arteriosus and neonatal death in prostaglandin receptor EP4-deficient mice." Biochemical and Biophysical Research Communications. 246. 7-12 (1998)

Eri Segi：“前列腺素受体 EP4 缺陷小鼠的动脉导管未闭和新生儿死亡。”

Takako Hirata: "Two thromboxane A_2 receptor isoforms in human platelets : opposite coupling to adenylyl cyclase with different sensitivity to Arg^<60> to Leu mutation." Journal of Clinical Investigation. 97. 949-956 (1996)

Takako Hirata：“人血小板中的两种血栓素 A_2 受体亚型：与腺苷酸环化酶相反偶联，对 Arg^<60> 和 Leu 突变具有不同的敏感性。”