BMP2-BMSCs对胶质瘤干细胞增殖和分化的调控作用及机制

项目名称： BMP2-BMSCs对胶质瘤干细胞增殖和分化的调控作用及机制

项目编号： No.81502568

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： 李加美

作者单位： 山东大学

项目金额： 18万元

中文摘要： 多形性胶质母细胞瘤（GBM）的生长和维持需依赖胶质瘤干细胞（GSCs），后者是导致GBM放、化疗失败及复发的主要原因，靶向GSCs的治疗可有效延长GBM患者生存时间。研究发现，BMP2可抑制GSCs增殖并诱导其分化，但其分子机制及信号通路尚未阐明。我们的前期研究发现，BMP2在胶质瘤中的表达与WHO分级、预后及复发密切相关，并可抑制GSCs增殖，激活AMPK，同时下调HIF-1α的表达。本项目拟通过骨髓间充质干细胞（BMSCs）介导BMP2作用于GSCs，采用免疫组化、脑内移植、小动物磁共振活体成像及分子生物学等实验技术在细胞及动物水平，观察BMP2-BMSCs对GSCs增殖及分化的调控作用，并进一步探讨AMPK/mTOR信号通路在抑制GSCs增殖中的作用及AMPK介导的自噬在GSCs分化中的作用，以期为临床治疗GBM提供新的靶点和实验依据。

中文关键词： C15_脑；中枢神经系统肿瘤；胶质瘤干细胞；多形性胶质母细胞瘤；骨髓间充质干细胞；骨形成蛋白2

英文摘要： Glioblastoma multiform (GBM), is the most malignant brain tumor, in which its growth and persistence depend on glioma stem cells (GSCs) that also induces recurrence and resists current chemo- and radiotherapies. GBM patients obtain a significant survival benefit from GSCs targeted therapy. Some studies found BMP2 inhibited glioma proliferation and induced GSCs differentiation. However, the molecular mechanism and signal pathway still unknown. Our previous study found that the expression level of BMP2 was closely related to the WHO grade, prognosis and recurence. And BMP2-BMSCs treatment significantly inhibited GSCs proliferation, increased AMPK expression, and inhibited HIF-1α expression. Using immunochemistry, intracerebral transplantation, small animal imaging and molecular biology, we intend to obersve the regulated effects and mechanism of BMP2-BMSCs on proliferation and differentiation human glioma stem cells, and further clarify the effect of AMPK/mTOR signal pathway on GSCs proliferation and the effect of autophagy on GSCs differentiation. We hope to provide new insights and experimental basis for GBM therapy.

英文关键词： tumor of brain and central nervous system;glioma stem cells;Glioblastoma multiforme;Mesenchymal stem cells ;BMP2