PGE2受体特异性激动剂作为促进人造血干细胞归巢与增殖靶向药物的研究

To promote donor haematopoietic stem cells(HSCs) homing and proliferation is one of the crucial measures to prevent graft failure after allo-geneic HSCs transplantation. Recently, some foreign researchers have demonstrated in vitro that prostaglandinE2(PGE2) can not only promotes human CD34+cells homing, but also induces its proliferation.However,it is unknown which subtype receptor is activated eventually by PGE2 since four E-series prostaglandin receptors(EP1～EP4),PGE2 subtype receptors, have been found expressed on the membrane of human CD34+cells. Using the special EP receptor agonists(EPAs) as objects, we recently have found EPA2 and EPA4 could promote CD34+ cells colony formation in vivo.Based on above, taking EP1A and EP3A as control, we are planning to confirm that EP2A AND EP4A could promote human CD34+cells proliferation and homing, and to distinguish their effects. Next,we will screen a more specific and more effective target medicine EPxA, and then desmostrate its mechanism. This study will help us further understand theoretically the extracellular signal pathway promoting human CD34+cells homing and proliferation mediated by PGE2. More importantly, it will provide an evidence to develop EPAx as a new specific target medicine to prevent human CD34+cells graft failure in the future.

促进供者造血干细胞归巢与增殖是防止移植后植入失败的关键措施之一。近年来国外多个研究均证实了前列腺素E2(PGE2)体外可促进人CD34+细胞归巢与增殖。但人CD34+细胞能同时表达4个PGE2亚受体(EP1～EP4)，PGE2究竟通过其中的哪个亚受体起作用还不清楚。近期我们在国内外首次选用这四个亚受体的特异激动剂(EPA)作为研究对象，初步发现EP2A和EP4A在体外可促进人CD34+细胞的增殖。本课题在此基础上，拟以EP1A和EP3A作为对照，详细探讨EP2A和EP4A体外对人的CD34+ 细胞增殖的影响并比较两者影响的效果，进而从中筛选出一个特异性好、作用强的目标EPxA,然后进一步明确其对CD34+ 细胞归巢与增殖的作用机制。这一研究不仅有助于进一步明确PGE2促进人CD34+细胞归巢与增殖的膜外受体途径，更为重要的是为EPxA在将来有可能成为防止植入失败的特异靶向药物提供依据。

造血干细胞的成功植入是异基因造血干细胞移植发挥作用的前提，促进供者造血干细胞成功归巢与增殖是防止移植后植入失败的关键措施之一。近年来，国内外多个研究均已证实了前列腺素E2（PGE2）体外可促进人CD34+细胞归巢与增殖。但人CD34+细胞能同时表达PGE2的四个亚受体(EP1~EP4)，PGE2究竟是通过其中的哪个亚受体发挥作用仍未清楚。前期我们已经证实PGE2体外可促进人CD34+细胞增殖，本课题在此基础上，在国内外首次选用这四个亚受体的特异性激动剂（EPA）作为研究对象，拟详细探讨PGE2四个亚受体的特异性激动剂体外对人CD34+细胞的归巢和增殖的作用，进而从中筛选出一个特异性好、作用强的目标EPXA，然后进一步明确其对人CD34+细胞归巢和增殖的具体作用机制。首先我们初步筛选促进人CD34+细胞归巢和增殖的特异性目标EPXA，发现EP4A体外不仅可促进人CD34+细胞归巢还能促进人CD34+细胞增殖，EP2A体外仅能促进人CD34+细胞归巢，而EP1A和EP3A不起作用。而后进一步明确EP4A在浓度为10umol/L，培养72h的条件下对人CD34+细胞的增殖作用最佳。EP4A主要通过Wnt/β-catenin信号途径促进人CD34+细胞增殖。这一研究不仅有助于进一步明确PGE2促进人CD34+细胞的归巢与增殖膜外受体途径，更为重要的是为EPXA在将来有可能成为防止植入失败的特异性靶向药物提供理论依据。