CUEDC2分子在微囊藻毒素致肝细胞氧化损伤中的作用研究

Microcystins（ MCs) is the most serious toxins of the algal species when blue-geen algae happens.In order to develop protective drugs and reduce the hazard of MCs on human beings, profiling the mechanism toxicity of MCs plays a significant role. Previous research found that Adda loop can be covalent bonding PP1 and PP2A activity center in Ser/Thr site, deactivates the PP2A collaborating with a few inflammatory factors such as TNF alpha make IKK phosphorylation to activate the NF-κB signaling pathways.Based on these theories, we assume that the CUEDC2 get dysfunction through inhibiting dephosphorylation of phosphorylated IKK by recruiting dephosphorylated PP1 which lost the regulatory function to the NF-κB signaling pathways. The project aims to clarify the molecular mechanism of the role of CUEDC2 in the signal pathway that how MCs induces oxidative damage to liver cells, and comprehensive discussion how could CUEDC2 mediate the interaction between dead cells through a pathway which can't pass though checkpoint. All of the work will provide a theoretical basis to reveal the molecular mechanisms on cell malignant transformation for the future.

微囊藻毒素（Microcysins，MCs）是蓝藻水华污染中危害最严重的一类藻毒素，研究MCs毒性分子机制对研究保护性药物，减轻它对人群健康危害具有重要意义。前期研究发现MCs基团中特有的Adda环可共价结合于PP1和PP2A活性中心Ser/Thr位点，失活的PP2A协同TNF-α等炎性因子使IKK磷酸化，激活NF-κB信号通路。我们推测CUEDC2无法通过招募失活的PP1抑制磷酸化IKK脱磷酸，从而丧失对NF-κB信号通路的调节作用。本项目旨在通过建立MCs染毒肝细胞时效、量效模型，从动物、细胞和分子水平全面探讨CUEDC2复合物在MCs诱导肝细胞氧化损伤信号通路中的分子机制；初步探索CUEDC2如何介导无法通过checkpoint的细胞死亡方式间的交互作用，为日后揭示MCs致细胞恶性转化的分子机制提供理论依据。

本研究的目的是揭示CUEDC2分子调控的NF-κB信号通路调控在微囊藻毒素-LR（MC-LR）诱导肝细胞氧化损伤中的作用。研究通过建立MC-LR致肝细胞损伤的体内、外模型检测了MC-LR对肝细胞造成的损伤，结果证实，MC-LR可以诱导肝细胞发生坏死、凋亡、细胞周期阻滞、细胞早衰、氧化损伤（ROS活性氧升高、抗氧化酶表达增加）等多种损伤，甚至发生恶性转化。进而分析了CUEDC2分子及其介导的NF-κB信号通路在MC-LR诱导肝细胞损伤模型中的表达水平。发现MC-LR可以抑制受损肝细胞的CUEDC2分子表达，诱导NF-κB信号通路系列关键基因如Gankyrin蛋白表达增加。为下一步揭示MC-LR致细胞恶性转化的分子机制提供了理论依据。