NEDD4-1调控巨噬细胞极化介导多发性骨髓瘤耐药的作用及机制研究

多发性骨髓瘤（MM）是浆细胞异常增生的恶性肿瘤，耐药是MM治疗中的最大障碍。已证实骨髓微环境中的骨髓瘤相关巨噬细胞（mMΦs）可极化为促肿瘤M2型而具备保护MM细胞诱导耐药的能力。我们最新研究发现与MM细胞共培养后的mMΦs在极化为M2型同时有E3泛素连接酶NEDD4-1表达明显下调；干扰沉默mMΦs中的NEDD4-1后可诱导其向M2型极化并增强对MM细胞的保护作用，提示决定泛素-蛋白酶体途径特异性的E3泛素连接酶NEDD4-1可能通过调节mMΦs的极化参与骨髓微环境介导的耐药。本项目拟在前期工作基础上继续探讨NEDD4-1对mMΦs表型和功能的调控，深入研究NEDD4-1通过泛素化调节mMΦs胞内底物重编程其极化类型的作用机制，进一步探究调控NEDD4-1-蛋白底物的交互作用从而增强抗MM效应的有效手段，为探索MM耐药机制及治疗靶点提供新的理论依据。

Multiple myeloma (MM) is a malignancy characterized by the proliferation of plasma cells. Drug resistance is the biggest obstacle in the management of MM. It has been demonstrated that myeloma-associated macrophages (mMΦs) in the bone marrow microenvironment prefered to be the tumor-promoting M2 type and could protect MM cells from drug induced apoptosis. Our study showed that NEDD4-1 expression was significantly down-regulated in mMΦs co-cultured with MM cells. RNAi silencing of NEDD4-1 induced the polarization of mMΦs toward M2 and enhanced the protective effect on MM cells, suggesting that ubiquitin ligase E3 NEDD4-1 which determine the specificity of ubiquitin-proteasome pathway might be involved in bone marrow microenvironment-mediated resistance by modulating the polarization of mMΦs. This project is aimed to clarify the regulation of the phenotype and function of mMΦs by NEDD4-1, explore how NEDD4-1 ubiquitinates intracellular key protein substrates in mMΦs to reprogram their polarization, further elucidate effective means to regulate the NEDD4-1-protein substrate interaction to enhance anti-MM drug effect, and develop a new theoretical basis and ideas for exploring the mechanism of MM resistance and therapeutic targets.