CDK5-PBK相互作用介导的双向磷酸化促进垂体腺瘤进袭性发生发展机制的研究

进袭性垂体瘤（aggressive pituitary tumors）发病机制不详，缺乏有效的诊疗手段，面临严峻挑战。在前期研究中，我们率先使用单细胞测序技术，通过对五万个垂体瘤细胞的转录组分析，发现在垂体瘤中有一群 “恶性转化潜能的细胞亚群”，而PDZ结合激酶(PBK)在这群细胞中呈现特征性表达。生物信息分析发现PBK的第9位苏氨酸是细胞周期素依赖激酶5（cyclin dependent kinase 5，CDK5）潜在的特异性磷酸化位点。前期实验表明CDK5和PBK可能存在着双向协同磷酸化并导致下游增殖通路失控性激活，而这有可能是垂体瘤恶性转化的关键节点，本研究拟明确如下内容：1）明确PBK在垂体瘤恶性转化中的作用；2）明确CDK5-PBK的磷酸化位点及协同磷酸化在垂体瘤分子分型和预后判断中的作用。期望能从新的视角揭示垂体瘤的发病机制，为垂体瘤的诊断分型及临床诊疗提供有效的分子靶点。

The diagnosis and treatment of aggressive pituitary tumors are confronted with severe challenges, with unknown pathogenesis and lack of effective diagnosis and treatment. In the study, we pioneered the use of single-cell sequencing technology, through the transcriptome analysis of fifty thousand pituitary adenoma cells, and found that there is a sub-group of “cell subsets with malignant transformation potential”, and PDZ binding kinase (PBK) shows characteristic expression in this group of cells. Bioinformatics analysis revealed that threonine 9 of PBK is a potential specific phosphorylation site for cyclin dependent kinase 5 (CDK5). Preliminary experiments have shown that CDK5 and PBK may have bidirectional synergistic phosphorylation and lead to uncontrolled activation of downstream proliferation pathways, which may be the critical node of pituitary tumor malignant transformation. This study aims to clarify the following contents: 1) To explain the role of PBK in malignant transformation of the pituitary tumor; 2) To explicit CDK5-PBK phosphorylation sites and determine synergy phosphorylation in the role of the molecular classification of pituitary adenoma and prognosis judgment. It is expected to reveal the pathogenesis of pituitary tumors from a new perspective and provide a valid molecular target for the diagnosis and treatment of pituitary adenomas.