PDGF/PDGFR于原发性血小板增多症发病机制中作用及机理的研究

项目名称： PDGF/PDGFR于原发性血小板增多症发病机制中作用及机理的研究

项目编号： No.81200345

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 叶洁瑜

作者单位： 南方医科大学

项目金额： 23万元

中文摘要： 血小板衍生生长因子（PDGF）及其受体PDGFR被证实与巨核细胞（MK）/血小板关系密切，我们的前期工作表明PDGF显著地促进骨髓抑制小鼠中MK及血小板计数恢复，但此通路在MK及血小板相关疾病，如原发性血小板增多症（ET）中的作用尚不明确。研究表明PDGF在ET患者血清中表达显著增高，提示PDGF的高表达与ET发病有潜在的联系。本项目拟在PDGF超表达的小鼠及体外模型上，观察MK及血小板功能及下游的分子信号通路；并予酪氨酸激酶抑制剂伊马替尼灌饲小鼠，观察MK及血小板功能变化。虽有报道使用伊马替尼治疗BCR/ABL阳性的ET患者，但无一针对PDGFR。通过此研究，我们将首次证实PDGF/PDGFR在ET发病中的作用及机制；确定PDGFR，而非BCR/ABL为伊马替尼治疗ET的分子靶点，并将PDGF血清表达水平作为诊断及评价ET疗效的新指标，使更多的ET患者得到有效的诊疗。

中文关键词： 血小板衍生生长因子；原发性血小板增多症；伊马替尼；细胞信号通路；血小板生成

英文摘要： Platelet-derived growth factor (PDGF) and its receptor (PDGFR) has special affinity with megakaryocytes (MKs) and platelets. Our previous data showed that PDGF potently enhanced the recovery of MK and platlets in the radiation-induced myelosuppression mouse model, and this effect may be induced by the activation of PDGFR and the subsequent PI3K/AKT signal pathway, which lead to a reduction of MK apoptosis. However, the exact role of PDGF/PDGFR in MK/platelets related disease, for example, essential thrombocythemia (ET) was still unknown. Recently, researches demonstrated that the expression level of PDGF increased remarkably in ET patient-derived serum, suggesting a potential relation between the PDGF over expression and ET development. In this study, we'd like to set up the PDGF-overexpression mouse model, from which the proliferative and differentiation function of MK and the amount of peripheral platelets will be determined. We also plan to establish the PDGF-overexpression mesenchymal stromal cell model which will be co-cultured with the CHRF-288-11 MK cells. CHRF cells will then be collected and the phosphorylation level of PI3K/AKT and JAK/STAT on these cells will be detected by flow cytometry and western blot. The tyrosine kinase inhibitor, imatinib mesylate will be given to the mouse model. The MK/plate

英文关键词： platelet-derived growth factor；essential thrombocythemia；imatinib；signaling pathway；thrombopoiesis