前列腺素EP4受体激动剂在体内促进小鼠造血干细胞归巢的研究

前列腺素E2(PGE2)促进造血干细胞(HSC)归巢与增殖已获得国外广泛证实，但PGE2有4个承担着不同生理功能的亚受体(EP1～EP4)，PGE2这种效应究竟通过其中哪个亚受体起作用的还不明确。在此前提下，如果将PGE2作为药物直接用于临床患者，在获得HSC归巢与增殖效应的同时，也会产生其它系统的副作用，因此缺乏特异性。近期我们研究发现：人HSC表面EP1和EP3基本不表达，EP2只介导归巢，EP4可同时介导归巢与增殖。但上述结果是通过体外实验获得的，在体内是否具有相同的作用尚不清楚。针对此问题，本课题拟以EP4为研究对象、EP4基因敲除小鼠的克隆干细胞为工具，优先探讨EP4受体激动剂（EP4A）在小鼠体内是否对HSC也有归巢效应。如果实验取得预期结果，课题组将再来探讨EP4A在体内对HSC的增殖效应。这一研究为EP4A最终成为一个新的促进HSC归巢与增殖的特异性靶向药物提供依据。

The study result that ProstaglandinE2 (PGE2) promotes the homing and proliferation on hematopoietic stem cells has been widely confirmed abroad. However, PGE2 has four sub-receptors (EP1~EP4) undertaking different physiologic functions and it is unclear exactly that PGE2 acts through one of the four sub-receptors. Under the premise, PGE2 can brimg about not only homing and proliferation effect but also other systemic side effects if it is used directly as a drug in clinic patients. So the effect of homing and proliferation of PGE2 on human hematopoietic stem cells (hHSCs) is lack of specificity. In our recent studies in vitro, we found that EP1 and EP3 are almost not expressed in hHSCs. EP2 mediates the homing of hHSCs only and EP4 both homing and proliferation. These above results are obtained by experiments in vitro, but not clear in vivo. For this problem, our study objective is to investigate whether EP4 agonist (EP4A) has the same homing effect on HSCs in mice in vivo using EP4 knockout mice as the object of study and cloned stem cells expressed EP4 gene as the tool. If the expected results are obtained, we will investigate the proliferation effect of EP4A on HSC in vivo.This study provides the evidence for EP4A to become a new specific target drug for HSC homing and proliferation.