Cdc25A调控光感受器细胞核内PKM2 磷酸化的水平促进鼠视网膜瓦格堡效应机制的研究

瓦格堡效应是指肿瘤细胞有氧情况下，主要通过糖酵解途径作为细胞的主要能量来源，此效应也发生在正常视网膜组织中，其机制尚不清楚。我们前期研究表明在作为具有快速代谢以及高能量消耗特点的视网膜细胞中，光感受器中表达的丙酮酸激酶M2(PKM2)可能是视网膜瓦格堡效应关键激酶，并且其磷酸化形式可能发挥重要作用。近期研究显示，增生组织中细胞分裂周期蛋白25 A(Cdc25A)可以与磷酸化PKM2相互作用，促进糖酵解基因相关基因如PKM2表达。由于光感受器细胞的大量膜的更新和盘膜脱落，前期数据提示Cdc25A可能同样表达于视网膜光感受器细胞中, 因此提出机制假设，光感受器细胞表达的Cdc25A可以在细胞核内通过移除底物PKM2磷酸化基团，激活核内PKM2基因表达，调节丙酮酸激酶（PK）活性。本项目拟在鼠模型中，分析Cdc25A调控鼠光感受器细胞核核内PKM2 磷酸化具体机制，为视网膜代谢相关疾病提供理论。

Warburg effect defines proliferating or tumor cell even in the presence of oxygen switches its metabolic pattern to glycolysis pathway and this effect also applies to the normal retina tissue, but the mechanism remains unclear. Our previous research indicated that retinal photoreceptors cells are highly metabolic and its pyruvate kinase M2 (especial in its phosphate form) takes essential role in promoting Warburg effect. In addition, Cell divison clycle 25 has also been proved to interact with phosphate PKM2 in proliferating tissue, thereby accelerating glycolysis related gene such as LDHA expression. Since photoreceptors characterized by membrane disc regeneration, adding to our recent data that also demonstrated that Cdc25A expressed in retinal photoreceptors, we hypothesized that Cdc25A dephosphorlates phosphate-PKM2 thereby activating nuclear PKM2 gene expression and controlling pyruvate kinase activity. This proposal aim to investigate the underlying mechanism by which PKM2 dephosphorylated by Cdc25A and provide theoretical strategy in retinal energy metabolism related disease.