bantam对Dpp信号通路的调节影响神经胶质细胞及前体干细胞的增殖

Malignant gliomas are the most common malignant tumors that develop in the central nervous system and are essentially incurable. Understanding the biology of the disease is the pivotal way leading to the effective treatment. microRNAs are the newly identified, endogenous, small non-coding RNAs, which participate in developing gliomas by its negative regulation on target genes. Our previous finding shows that evolutionarily conserved microRNA bantam is critical for the proliferation of glial cells and glial precursor cells in Drosophila optic lobe. Human homologs of bantam showed the similar function as bantam that they can stimulate the proliferation of the U87 glioblastoma cells. And Mad, the Dpp signaling transduction molecule, is the target of bantam. Based on these findings, we hypothesize that bantam stimulates the proliferation of glial cells and glial precursor cells through its inhibitory effect on Mad. And this might be the conserved mechanism that affects the proliferation of the human glioblastoma cells. We will use the tools from genetics and molecular and cellular biology to test our hypothesis in both Drosophila animal and the human glioblastoma cell line. Our results will certainly shed light on the new clues to the effective treatment of gliomas.

脑胶质瘤是中枢神经系统最常见的恶性肿瘤，了解其发生发展的机制是有效治疗的关键，microRNAs是内源性非编码小RNA，通过负性调节靶基因参与脑胶质瘤的发生发展。本课题组前期研究发现：在生物进化过程中高保守果蝇microRNA bantam是视觉中枢内神经胶质细胞及前体干细胞增殖的重要促进因子；bantam人同源体miRNAs具有相似促进胶质瘤细胞增殖的功能；体内体外实验证实bantam能靶向作用Dpp信号通路的关键信号传递分子Mad。基于此，我们提出科学假设：在中枢神经系统内神经胶质细胞及前体干细胞中，bantam能通过其靶向作用Mad从而负性调节Dpp信号通路的强度，从而调控细胞增殖，并且这种调节在进化上具有保守性，是影响人脑胶质瘤细胞增殖的重要机制。我们将以遗传学与分子细胞生物学相结合的方法，利用果蝇模式生物和人胶质瘤细胞模型开展课题研究，课题结果将为临床治疗胶质瘤提供新的科学依据。

脑胶质瘤是中枢神经系统最常见的恶性肿瘤，了解其发生发展的机制是有效治疗的关键，microRNAs是内源性非编码小RNA，通过负性调节靶基因参与脑胶质瘤的发生发展。基于本课题组前期研究发现，我们提出科学假说：生物进化过程中高保守果蝇microRNA bantam在生物发育过程中与Dpp/BMP信号通路之间存在调节作用关系，并且这种调节机制在在进化上具有保守性，bantam人同源体小RNA将影响人脑胶质瘤干细胞活性与化疗药物敏感性。本课题以遗传学与分子细胞生物学相结合的方法，研究发现在果蝇内，过表达bantam能特异性降低Dpp信号通路传导分子Mad的磷酸化水平，并负性影响Dpp信号通路靶基因的表达。反之在bantam基因删除型纯合子突变体克隆中，Dpp负向调控基因brk的表达降低。同时Dpp信号通路能影响bantam的表达，Dpp基因突变称为单倍体剂量不足拯救实验发现Mad 3’UTR上的bantam结合位点能够影响Dpp信号通路强弱，我们的研究支持在果蝇中，bantam是Dpp信号通路的调节因子，同时Dpp能反馈性调节bantam的表达。本课题对bantam人同源体RNA的研究发现，hsa-miR-542-5p在胶质瘤干细胞中特异性高表达，并且其表达受BMP信号通路调节。hsa-miR-542-5p能促进胶质瘤干细胞U87S的细胞活性，并影响U87S细胞对化疗药物TMZ的敏感性。本课题结果将为临床治疗胶质瘤提供新的科学依据。