Numbl通过RIP1调节NF-kappa B激活在胶质瘤发生中的作用

Glioma is the most common malignant tumor in the central nervous system, which is characterized by its high invasiveness. Abnormal activation of NFκB pathway is one of the key factors in glioma. Appropriate control of NFκB activity would provide a potential approach for the management of glioma. Together with our previous study and others' reports, we hypothesize that: human Numbl plays an important role in glioma development by inhibiting glioma cell proliferation, migration and invasiveness. During which Numbl regulates NFκB activity by down-regulating RIP1expression, subsequently, regulates mdm2-p53 and PI3K-Akt pathway. Firstly, analyzes the mechanism of the regulation of Numb1 and RIP1 interaction to NFκB, mdm2-p53 and PI3K-Akt pathway in vitro. Secondly, analyzes the clinical relevance of the regulation of Numb1 and RIP1 to NFκB, mdm2-p53 and PI3K-Akt pathway to different grades of gliomas in vivo. Finally, we establish nude mouse model of glioma to verify our above hypothesis. Our data will provide a theoretical basis for the development of novel drug targets for gliomas treatment.

胶质瘤是中枢神经系统最常见的恶性肿瘤，具高度侵袭性生长的特性，NF-κB信号异常激活是其关键影响因素之一，针对这种异常激活开发的药物对治疗胶质瘤有一定疗效。本研究根据课题组前期研究及文献报道提出如下假说：胶质瘤发生、发展过程中，Numbl可能通过抑制RIP1而影响其对下游通路NF-κB的激活，进而影响mdm2-p53及PI3K-Akt的信号转导，从而负性调节胶质瘤的增殖、迁移与侵袭，在胶质瘤发生及发展中发挥负性调节作用。研究拟先在细胞水平分析Numbl与RIP1相互作用对NF-κB、mdm2-p53及PI3K-Akt等信号通路的调节作用机制，及其对胶质瘤细胞增殖、迁移与侵袭等生物学行为的影响；接着在不同类型胶质瘤病理组织中分析Numbl与RIP1的上述调节是否能反映临床胶质瘤的发生及预后；最后以裸鼠脑内胶质瘤模型对上述假设进行验证。实验结果可为开发胶质瘤治疗的新药靶点提供理论依据。

胶质瘤是中枢神经系统最常见的恶性肿瘤，具高度侵袭性生长的特性，NF-κB信号异常激活是其关键影响因素之一，针对这种异常激活开发的药物对治疗胶质瘤有一定疗效。本研究根据课题组前期研究及文献报道提出如下假说：胶质瘤发生、发展过程中，Numbl可能通过抑制RIP1而影响其对下游通路NF-κB的激活，进而影响mdm2-p53及PI3K-Akt的信号转导，从而负性调节胶质瘤的迁移与侵袭，在胶质瘤发生及发展中发挥负性调节作用。研究拟先在细胞水平分析Numbl与RIP1相互作用对NF-κB、mdm2-p53及PI3K-Akt等信号通路的调节作用机制，及其对胶质瘤细胞迁移与侵袭等生物学行为的影响；接着在不同类型胶质瘤病理组织中分析Numbl与RIP1的上述调节是否能反映临床胶质瘤的发生及预后；最后以裸鼠脑内胶质瘤模型对上述假设进行验证。实验结果可为开发胶质瘤治疗的新药靶点提供理论依据。项目实施期间共发表论文9篇，培养硕士研究生4名。