HMGB1调节的自噬对多发性骨髓瘤化疗耐药性的影响及机制研究

There was closely relationship with autophagy and tumor cell survival, death, which became the new research hot spot for multiple myeloma (MM).We recently found that high mobility group box 1 (HMGB1) was an important disease genes in MM involved . Moveover suppression of HMGB1 gene significantly inhibited autophagy level of myeloma cells and pathway of PI3K activity,and increased chemotherapy drug resistance in MM cells.Thus, these findings have led us to the rational for the proposed research, which will validate HMGB1 regulation of MM cell autophagy, thereby affecting the MM cell survival and death.MM cell lines and MM patients with primary tumor cells will be tested by Western blot, flow cytometry, laser scanning confocal image analysis and other advanced research measures, (1) Studying the role of autophagy in the resistance of MM induced by HMGB1; (2) Analyzing the role of HMGB1 in regulation of PI3K/Akt/mTOR signaling pathway and mTOR complex components; (3) Investigating the molecular mechanism of endogenous and exogenous HMGB1 regulating autophagy of MM cells deeply..Taken together,successful completion of these studies will therefore form a basis for algorithms to help elucidate mechanism of HMGB1 induced MM cell death and autophagy research, to provide the strategies aimed at laying the foundation for futher clinical studies.

自噬与肿瘤细胞的生存死亡密切相关，成为多发性骨髓瘤(MM)研究的新热点。我们近期发现高迁移率族蛋白1（HMGB1）参与了MM的发病，是重要致病基因，而且HMGB1基因沉默显著抑制骨髓瘤细胞自噬发生，能抑制PI3K的活性，并增加化疗药物的敏感性。本项目在上述研究基础上，提出HMGB1调控MM细胞的自噬，进而影响MM细胞生存和死亡的假说。本项目以MM细胞株和MM患者原代肿瘤细胞为研究对象，采用Western blot、流式细胞技术、激光共聚焦图像分析等先进研究手段，⑴研究自噬在HMGB1诱导的MM细胞耐药性形成中的作用；⑵分析HMGB1对PI3K/Akt/mTOR信号通路及mTOR复合物组分的影响及调控作用；⑶深入系统的探讨内源性和外源性HMGB1调控MM细胞自噬的分子机制。该项目有助于阐明HMGB1诱导MM细胞死亡的具体作用机制，为自噬的研究开辟新的领域，为寻找MM治疗提供了新的思路和线索。

自噬与肿瘤细胞的生存死亡密切相关，成为多发性骨髓瘤(MM)研究的新热点。我们近期发现高迁移率族蛋白 1（HMGB1）参与了 MM 的发病，是重要致病基因，而且 HMGB1基因沉默显著抑制骨髓瘤细胞自噬发生，能抑制 PI3K 的活性，并增加化疗药物的敏感性。本项目以 MM 细胞株和 MM 患者原代肿瘤细胞为研究对象，采用 Western blot、流式细胞技术、激光共聚焦图像分析等先进研究手段，(1)证实了自噬是HMGB1 诱导的 MM 细胞耐药性的重要不可缺的途径;(2) HMGB1调节了PI3K/Akt/mTOR和JNK信号通路并促进了MM耐药性的形成和增强；⑶发现了内源性和外源性 HMGB1 调控 MM 细胞自噬的分子机制。总的来说，HMGB1通过调控 MM 细胞的自噬，进而影响 MM 细胞生存和死亡。该项目阐明了 HMGB1 诱导 MM 细胞死亡的具体作用机制，为自噬的研究开辟新的领域，为寻找 MM 治疗提供了新的思路和线索。