目前多发性骨髓瘤（MM）治疗面临的最大障碍就是耐药的产生。申请人之前的结果发现骨髓基质细胞分泌的外泌体（exosomes）能够通过调控JNK、p38、p53等信号通路来诱导MM细胞对万珂的耐药，但是其中引起耐药的具体分子还不清楚。由于外泌体可以通过表面分子接触或者传递miRNAs来影响靶细胞的功能，因此我们猜想骨髓基质细胞外泌体可以通过其表面分子与MM细胞受体结合来调控MM细胞内信号通路变化并传递内含的miRNAs来改变相应靶蛋白的表达，最终诱导MM细胞耐药的产生。本项目拟利用受体蛋白抗体芯片技术、Small RNA测序、流式细胞术、细胞转染等实验方法，对外泌体诱导MM细胞耐药的具体表面分子和内含miRNAs进行鉴定，并确认它们各自所影响的通路或者靶蛋白，从而详细地阐明外泌体诱导MM细胞耐药的分子机理，为发展出针对外泌体的靶向策略来克服MM耐药和改善MM治疗提供更充分的科学依据。

The biggest challenge for successful multiple myeloma (MM) treatment is frequent occurrence of drug resistance. Our previous results found that bone marrow stromal cell-derived exosomes, a class of nanometric extracellular vesicles, also facilitate MM drug resistance to Bortezomib though regulating JNK, p38, and p53 signaling pathways. However, detailed exosomal molecules that induced drug resistance have not been identified. Exosomes can affect the function of target cells through their membrane molecules and delivering microRNAs. Therefore, bone marrow stromal cell-derived exosomes may also induce MM drug resistance through regulating signaling pathways in MM cells after binding of exosomal membrane molecules with MM cell receptors and through exosomal miRNA-mediated regulation on target proteins, finally inducing drug resistance. Based on our previous findings, we seek to identify the specific exosomal membrane molecules and cargos which are responsible for exosomes-induced MM drug resistance, and determine the changes of signaling pathways and target proteins using several comprehensive methods, such as receptor antibody array, Small RNA sequencing, flow cytometry, and cell transfection. Our study will favor the development of novel therapeutic strategies by targeting exosomes for overcoming drug resistance, thus improving the MM treatment and prognosis.