Generation and analysis of mice lacking the prostanoid receptor

我们构建了与前列腺素受体基因的八个密码子和亚型中的每一个进行同源重组的靶向载体。将载体导入来源于129/OLA小鼠品系的ES细胞。然后将注射ES细胞的囊胚导入假孕ICR小鼠的子宫，产生嵌合体小鼠。将嵌合小鼠与C57BL/6小鼠杂交，产生F1小鼠，随后产生F2小鼠，每个F2小鼠都缺乏前列腺素受体。我们一直试图将每个突变的小鼠回交到C57BL/6，Balb/c和DBA1小鼠，以获得同源小鼠。对这些缺乏前列腺素受体的小鼠的分析揭示了前列腺素在体内的新的生理和病理生理作用。PGI_2具有增加血管通透性、传递炎症中的痛感和抗血栓作用。前列腺素F_2α和孕酮通过诱导黄体退化降低血浆孕酮水平，进而上调足月子宫中催产素受体的表达。前列腺素E_2作用于EP4受体，调节动脉导管的功能，这些结果将有助于开发针对每个前列腺素受体的新药，并为这些药物的应用提供线索。

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.