对RIP3抑制剂与NF-κB抑制剂联合杀伤白血病细胞的研究

发布时间：2019-05-15 02:18

【摘要】：RIP3抑制剂可抑制RIP3蛋白激酶活性,同时与RIP3蛋白结合并通过驱动RIP3蛋白RHIM结构域募集RIP1蛋白,并成功装配一个Caspase-8-FADD-cFLIP复合体,随后激活Caspase-8造成细胞凋亡。我们在实验中发现,RIP3抑制剂可以诱导ML-2细胞发生凋亡:用GSK‘872处理ML-2细胞两天后,ML-2细胞出现大量凋亡小体,在活细胞内,NF-κB信号的缺失或许可以增加细胞对促凋亡信号敏感性,因此我们使用NF-κB抑制剂BAY11-7082,BAY能有效阻止NF-κB与DNA结合,从而阻断NF-κB信号,希望其与RIP3抑制剂联合使用能产生协同效果;为了使结果更加可靠,我们还将外源性IκBα抑制蛋白在ML-2细胞,THP-1细胞,MM-6细胞,小鼠MLL-AF9细胞中表达,并用不同剂量的GSK’872分别处理这些细胞。令人失望的是,在上述4中细胞中均没有出现协同作用。在用GSK’872与BAY联合处理ML-2,THP-1,Molm-13,RS4;11及SEM等5种细胞时均没有协同作用产生,但我们不能认定RIP3抑制剂与NF-κB抑制剂对白血病细胞一定没有协同作用,更多的白血病细胞需要我们继续去尝试和筛选。
[Abstract]:RIP3 inhibitor can inhibit the activity of RIP3 protein kinase, bind to RIP3 protein and recruit RIP1 protein by driving the RHIM domain of RIP3 protein, and successfully assemble a Caspase-8-FADD-cFLIP complex, and then activate Caspase-8 to induce apoptosis. We found that RIP3 inhibitor could induce apoptosis of ML-2 cells: after ML-2 cells were treated with GSK'872 for two days, a large number of apoptotic bodies appeared in ML-2 cells, in living cells. The deletion of NF- kappa B signal may increase the sensitivity of cells to apoptosis signal, so we can effectively block the binding of NF- kappa B to DNA, thus blocking the NF- kappa B signal by using BAY11-7082,BAY, an inhibitor of NF- kappa B. It is hoped that the combined use of RIP3 inhibitor can produce synergistic effect. In order to make the results more reliable, we also expressed exogenous I kB 伪 inhibitory protein in ML-2 cells, THP-1 cells, MM-6 cells and mouse MLL-AF9 cells, and treated these cells with different doses of GSK'872. It is disappointing that there is no synergistic effect in the above 4 cells. ML-2,THP-1,Molm-13,RS4; is being processed with GSK'872 and BAY. There was no synergistic effect between 11 and SEM, but we could not conclude that RIP3 inhibitor and NF- kappa B inhibitor had no synergistic effect on leukemia cells, and more leukemia cells needed to continue to try and screen.
【学位授予单位】：上海师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R733.7

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