硼替佐米耐药是临床治疗多发性骨髓瘤亟待解决的问题之一。虽然有大量实验证实耐药形成与蛋白酶体功能相关，但其耐药机制尚不清楚。因此,深入研究蛋白酶体在硼替佐米耐药中的分子机制将为寻找逆转硼替佐米耐药的新靶点提供理论依据。我们的前期研究发现，去泛素酶7(USP7)是一种新型的蛋白酶体结合蛋白，并且在多种多发性骨髓瘤细胞系中高表达;进一步通过免疫沉淀证实USP7可与蛋白酶体相互作用，并发现下调USP7可增强硼替佐米对骨髓瘤耐药细胞的杀伤作用，但USP7参与硼替佐米耐药的机制尚未阐明。本课题中，我们计划先通过RNA干扰技术建立稳定下调USP7的骨髓瘤耐药细胞株，再恢复干扰耐药细胞株中USP7的水平，从体内和体外两个层面，探究USP7通过参与蛋白酶体的调控影响硼替佐米耐药的机制。如期完成，我们的研究将阐明USP7在硼替佐米耐药形成中的作用，为临床克服多发性骨髓瘤耐药提供新靶点。

Bortezomib (BTZ)-resistance is an urgent problem to be solved in clinical treatment of multiple myeloma (MM). Although lots of studies have proved that proteasome play a key role in BTZ-resistance,the mechanism of it is still unclear. Therefore, further studing on the mechanism of BTZ-resistance is necessary for overcoming BTZ-resistance. In our previous studies, we identified that ubiquitin-specific protease 7 (USP7) was a new proteasome-interacting protein (PIP), which was upregulated in many MM cells.Futhermore,we found that USP7 knockdown could obviously increase the MM cells sensitivity to BTZ. However, the mechanism of USP7 involved in BTZ-resistance is not elucidated.In this project, we will establish cell strains with USP7 knockdown by stably expressed interfering shRNA through constructs of pLK-shUSP7-GFP using modified lentiviral vectors based transfection system in BTZ-resistance MM cells ，and then rescue the expression level of USP7 in the BTZ-resistance MM (shUSP7) to elucidate the role of USP7 in BTZ-resistance through regulating proteasome in vitro and in vivo. As scheduled, our study will illuminate the function of USP7 in BTZ-resistance，and will provide new targets for MM treatment.