胶质母细胞瘤（GBM）血管异常促进肿瘤生长并抑制抗肿瘤治疗。现有抗血管治疗疗效不佳，明确血管异常形成机制有助于开发治疗新方法。前期发现PAK4是促进内皮细胞（EC）间充质转化（EndoMT）导致血管异常的关键激酶，抑制PAK4可逆转血管异常。其具体分子机制是什么？进一步研究发现PAK4上调EndoMT相关转录因子ZEB1表达并与Claudin14表达负相关，而MEF2转录激活且促进ZEB1表达。据此提出假设：GBM EC中PAK4通过MEF2促进ZEB1表达，进而诱导EndoMT并抑制Claudin14表达导致血管异常。本研究拟使用CHIP-qPCR及双荧光素酶报告基因等技术明确PAK4通过MEF2/ZEB1途径促进EndoMT并抑制Claudin14的机制，并用基因编辑小鼠和临床标本进一步明确PAK4及其下游关键基因对血管异常的作用，以期为PAK4作为GBM血管治疗的新靶点提供理论依据。

Glioblastoma (GBM) vascular abnormalities promote tumor growth and inhibit antitumor therapy. Since therapeutic effects of existing anti-vascular treatments are poor, clarifying the mechanism of abnormal blood vessel formation will help develop new effective treatments. We found that PAK4 is a key kinase that promotes endothelial cell (EC) mesenchymal transition (EndoMT) leading to vascular abnormalities, and inhibition of PAK4 can reverse vascular abnormalities. What is its specific molecular mechanism? Further research found that PAK4 up-regulated the expression of EndoMT-related transcription factor ZEB1 and negatively correlated with Claudin14 expression. In addition, MEF2 transcriptional activation increased and promoted ZEB1 expression. Based on this, we propose the hypothesis: In GBM EC, PAK4 promotes ZEB1 expression through MEF2, which in turn induces EndoMT and inhibits Claudin14 expression, leading to vascular abnormalities. In the present study, we intend to use CHIP-qPCR and dual luciferase reporter genes to clarify the mechanism by which PAK4 promotes EndoMT and inhibits Claudin14 and through the MEF2 / ZEB1 pathway. Meanwhile, we will use gene-edited mice and clinical specimens to further clarify the role of PAK4 and its downstream genes on vascular abnormalities. Finally, the present study will provide theoretical basis for PAK4 as a new target for GBM vascular therapy.