TIPE3通过P38-ULK1轴调控胶质母细胞瘤自噬及炎性小体激活的作用及机制研究

自噬与炎性小体交互调控在GBM恶性进展中起重要作用。有研究发现P38-ULK1信号轴直接调控自噬抑制炎性小体的过程，但关键分子机制尚不清楚。本课题组前期研究发现促癌蛋白TIPE3能增强GBM自噬，抑制炎症因子IL-1β的产生。TIPE3调控P38-ULK1轴：TIPE3能与P38结合，抑制P38磷酸化及入核，敲低TIPE3可以促进ULK1磷酸化。我们将在此基础上，从临床样本、动物、细胞与分子水平研究TIPE3在GBM自噬与炎性小体中的作用，分析自噬与炎性小体的关系，探讨TIPE3调控P38-ULK1的具体分子机制，特别阐明TIPE3介导的P38磷酸化抑制、P38入核抑制及TIPE3-P38结合作用这三者的关系。本项目的开展将有助于深入了解GBM的发生发展机制，为GBM靶向治疗提供新思路，具有临床转化的潜在价值。

The interactive regulation of autophagy and inflammasome plays an important role in the malignant progress of GBM. Recent studies indicates that P38-ULK1 axis may participate in the process of autophagy inhibiting inflammasome, but the exact mechanism remains unclear. Our preliminary experiment showed that TIPE3 promotes the autophagy of GBM and inhibits IL-1β, and this progress is related to P38-ULK1 axis. TIPE3 interacts with P38, inhibits its phosphorylation and blocks its nuclear translocation; TIPE3 depletion promotes ULK1 phosphorylation. Based above, in the levels of clinical samples, animal models, cells and molecules, we will investigate the role of TIPE3 on GBM autophagy and inflammasome activation, explore the relationship of autophagy and inflammasome, clarify the molecular mechanism which TIPE3 regulates P38-ULK1 axis, especially the relationship of TIPE3-P38 interaction, P38 phosphorylation and P38 translocation. This study will help to investigate the mechanism of GBM progression, provide the theoretical basis for molecular targeted therapy, have a potential value of clinical transformation.