益髓颗粒调控DNA甲基化治疗骨髓增生异常综合征分子机制研究

项目名称： 益髓颗粒调控DNA甲基化治疗骨髓增生异常综合征分子机制研究

项目编号： No.81503575

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： 王婧

作者单位： 北京中医药大学

项目金额： 18万元

中文摘要： 目前国际上公认，DNA甲基化异常是骨髓增生异常综合征（MDS）的重要发病机制。Wnt通路与MDS发病密切相关，其关键基因甲基化异常直接影响MDS预后。我们既往临床观察发现，“气阴两虚、血瘀内阻”是MDS临床主要病机，具有“益气养阴活血”功效的院内制剂“益髓颗粒”能够延缓MDS转化为白血病时间、提高患者生活质量与生存期，并有改善骨髓病态造血（抑制增殖、促进分化）、调节Wnt通路等作用。同时，益髓颗粒治疗有效的MDS患者DNA甲基转移酶（DNMTs）水平下调，表明益髓颗粒治疗MDS获效机制可能与去甲基化有关。因此，本课题将构建MDS大鼠模型，以益髓颗粒为干预药物，通过观察血象与骨髓缓解情况，检测DNMTs表达水平、DNA甲基化水平、Wnt通路关键基因Wnt3a、FZD、β-catenin、TCF、SFRP表达及甲基化水平，从DNA甲基化角度探讨益髓颗粒治疗MDS疗效机制。

中文关键词： 骨髓增生异常综合征；益髓颗粒；DNA甲基化；Wnt信号通路；表观遗传学

英文摘要： Aberrant DNA methylation is currently known as an important pathogenetic mechanism of myelodysplastic syndrome (MDS) worldwide.Wnt signaling plays an essential role during the onset of MDS, and the aberrant DNA methylations of its key genes are prognostic factors of MDS. Our previous studies confirmed that qi and yin deficiency, combined with blood stasis was the major clinical syndrome of MDS patients. Yi Sui Granules (YSG), manufactured by our hospital, have the function of supplementing qi, nourishing yin and promoting blood circulation by removing blood stasis according to traditional Chinese medicine. Clinically, YSG was proved safe and effective in treating patients with MDS, delaying progresses into AML, improving quality of life and prolonging overall survival. Basic research also showed YSG had the effects of improving dysplasia by inhibiting proliferation and promoting differentiation, and regulating Wnt signaling. Our preliminary studies indicated that the DNMTs mRNA level was reduced in patients benefiting from YSG treatment, which indicated demethylation might be the mechanism of YSG’s efficacy in treating MDS. Therefore, in this project the rat model of MDS will be established, YSG will be administered, peripheral and bone marrow smears will be observed, and the expression and DNA methylation level of the key genes(including Wnt3a, FZD, β-catenin, TCF, SFRP) in canonical Wnt signaling will be detected in order to explore, from a DNA methylation point of view, the mechanism of YSG in treating MDS.

英文关键词： myelodysplastic syndrome;Yi Sui Granules;DNA methylation;Wnt signaling;epigenetic disease