Function of erythropoietin and control of its expression in reproductive organs

促红细胞生成一直被认为是促红细胞生成素（EPO）唯一的生理功能。但我们证明了促生成素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。EPO治疗脑卒中脑损伤的临床试验已取得成功。此外，我们已经证明EPO也在子宫中产生，EPO作为子宫内膜周期性生长的血管生成因子。子宫内促生成素的产生是缺氧诱导的，就像它在肾脏和大脑中一样。本项目主要旨在探讨EPO在男性生殖器官中的表达，并发现EPO在这些器官中的重要性。培养小鼠睾丸和附睾，检测培养上清中EPO的含量。两个器官都产生促生成素，但附睾产生的促生成素比睾丸多得多。EPO的信使RNA在附睾也高于睾丸。性成熟（3 ~ 7周）伴附睾EPO mRNA显著升高（增加120倍）。EPO可能参与了精子获得生育能力的过程，因为这一过程发生在精子从睾丸被运送到附睾的地方。同时，研究表明，从色氨酸到NAD代谢途径中的代谢中间体喹啉酸酯（QA）可抑制EPO的产生。当我们能够积累QA从而抑制EPO的产生时，我们可能能够发现EPO在生殖器官中的作用。我们决定破坏负责QA代谢的喹啉酸磷酸核糖基转移酶基因，但该项目尚未完成。邻苯二甲酸酯被发现积累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.