Function of erythropoietin and control of its expression in reproductive organs

促红细胞生成素(EPO)被认为是其唯一的生理功能。但我们证明了EPO在大脑中起着重要作用；EPO在中枢神经系统中发挥神经保护作用。其他实验室也支持这一发现。促红细胞生成素对中风引起的脑损伤的临床试验已经成功。此外，我们还发现EPO也是在子宫中产生的，EPO在子宫内膜的周期性生长中起着血管生成因子的作用。EPO在子宫中的产生是低氧诱导的，就像在肾脏和大脑中一样。本课题主要研究EPO在雄性生殖器官中的表达，探讨EPO在生殖器官中的重要作用。两个器官都产生EPO，但附睾产生EPO的量比睾丸多得多。附精中EPO的信使RNA含量也高于睾丸。附睾性成熟(3~7周)伴随着附睾部EPO mRNA的显著增加(增加120倍)。EPO可能参与了精子获得生育能力的过程，因为这一事件发生在附睾处，精子从睾丸运输到精子的地方。同时，研究表明，喹啉(QA)是从色氨酸到NAD代谢途径中的代谢中间产物，抑制EPO的产生。当我们可以积累QA从而抑制EPO的产生时，我们或许能够找到EPO在生殖器官中的作用。我们已经决定销毁负责QA代谢的喹啉酸盐磷酸核糖基转移酶基因，但这个项目尚未完成。邻苯二甲酸盐被发现积累了QA，因此我们可能能够阐明EPO在生殖器官中的作用。

It has been believed that stimulation of erythropoiesis is a sole physiological function of erythropoietin (EPO). But we demonstrated that EPO plays an important role in brain ; EPO exerts neuroprotective function in the central nervous system. Other laboratories have supported this finding. Clinical trial of EPO has been successful for brain damage caused by stroke. In addition we have shown that EPO is also produced in the uterus where EPO acts as an angiogenic factor for periodical growth of uterine endometrial layer. EPO production in the uterus is hypoxia-inducible as it is in the kidney and brain. This project is mainly aimed to explore expression of EPO in the male reproductive organs and to find importance of EPO in these organs.Testis and epididymis from mice were cultured and EPO in the culture supernatant was assayed. Both organs produced EPO but epididymis produced EPO in much larger amount than testis did. Messenger RNA of EPO was also higher in epididymis than that in testis. Sexual maturation (from 3 weeks to 7 weeks) accompanied remarkable increase of EPO mRNA (120-fold increase) in epididymis. It is possible that EPO is involved in the process by which sperms gain fertility capability, because this event occurs in the epididymis to where sperms are transported from testis.In the meantime, it was shown that quinolinate (QA), a metabolic intermediate in the metabolic pathway from tryptophan to NAD, inhibits EPO production. When we can accumulate QA and thereby EPO production depressed, we may be able to find a role EPO in the reproductive organs. We have decided to destroy quinolinate phosphoribosyltransferase gene that is responsible for QA metabolism but this project has not yet completed. Phthalate was found to accumulate QA and therefore we may be able to elucidate a role of EPO in the reproductive organs.