SCR-3在雌激素促巨核细胞分化中的作用及机制研究

项目名称： SCR-3在雌激素促巨核细胞分化中的作用及机制研究

项目编号： No.81500087

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 许杨

作者单位： 中国人民解放军第三军医大学

项目金额： 18万元

中文摘要： 已有研究表明雌激素能够促进巨核细胞分化、血小板生成的作用，但其机制不明。SRC-3是雌激素受体（ER）的重要辅活化因子，SRC-3-/-小鼠其外周血血小板水平显著降低，多倍体受到抑制。生物信息学预测显示ER与巨核细胞成熟分化调控因子GATA-1的启动子区存在得分较高的结合位点，我们前期研究也发现雌激素能够显著上调GATA-1的表达，而SRC-3缺失会阻断雌激素对GATA-1的表达调控作用，提示ER可能通过调控GATA-1的转录而促进巨核细胞分化与成熟，SRC-3在此过程中可能发挥着重要的调节作用。为此，本项目拟采用免疫磁珠分选、IP、ChIP等技术，首先明确SRC-3在雌激素促巨核细胞分化成熟中的作用，然后分析ER是否能够与GATA-1启动子结合并调控其转录，并探讨SRC-3在ER调控GATA-1转录生成的作用，从而深入阐明雌激素调控巨核细胞分化的作用机制，为其临床应用提供理论依据。

中文关键词： 巨核细胞分化；SRC-3；雌激素；转录调控；GATA-1

英文摘要： It has been studied that estrogen can promote megakaryocytes differentiation and platelets production, but its mechanism is still unclear. SRC-3 is an important co-activator of estrogen receptor (ER), and SRC-3-/- mice displayed significantly reduced peripheral blood platelets. Bioinformatics analysis shows that there exists binding sites with higher scores between ER and the promoter regions of GATA-1 which participates in the regulation of differentiation and maturation of megakaryocytes. Meanwhile, our previous study also found that estrogen could significantly increase the expression of GATA-1 in megakaryocytes, while this effect was blocked when SRC-3 was knocked out. These suggest that ER may promote differentiation and maturation of megakaryocytes through regulating the transcription of GATA-1, and SRC-3 may exert an important role in this progress. Therefore, in this study, by application of MACS, flow cytometry, IP and ChIP, we will firstly illustrate the role of SRC-3 in the promotion of megakaryocytes differentiation and maturation by estrogen. Then we plan to explore whether ER can combine with the promoter of GATA-1 to regulate its transcription, and the role of SRC-3 in the transcription regulation of GATA-1 by ER. The aim of this study is to clarify the mechanism of the regulation of megakaryocytes differentiation by estrogen, and to provide theoretical basis for its clinical application as well.

英文关键词： megakaryocyte differentiation;SRC-3;estrogen;transcription regulation;GATA-1