Notch-RBP-J信号通路调控巨噬细胞极化在弥漫大B细胞淋巴瘤微环境中的作用和机制研究

Macrophages are derived from monocytes and have two side roles: enhancing anti-tumor immunity and promoting tumor growth. These two entirely different functions due to monocytes that have influence on tumor microenvironment. It has been reported that Notch pathway is required for the differentiation of monocyte lineage cells, and RBP-J is implicated in monocytes differentiate into tumor-associated macrophages (TAMs). In many human cancers, a high density of tumor-associated macrophages (TAMs) correlates with poor prognosis. And there is few studies of Notch-RBP-J in the field of diffuse large B cell lymphoma (DLBCL). So it is important and necessary to investigate the effect of Notch-RBP-J on lymphomagenesis. Based on establishing direct xenograft NOD-SCID mice model of DLBCL which could passage steady, we will assess: 1. Expression of Notch-RBP-J in the models by Flow Cytometry (FCM) and Western Blot (WB); 2. Potential role of Notch-RBP-J inhibitor in tumor microenvironment and lymphoma growth. Though the experimental study mentioned above, we try to elucidate the mechanism of Notch-RBP-J and TAM in lymphomagenesis and provide the new theoretical basis for targeted therapy for tumor microenvironment.

巨噬细胞具有抗肿瘤免疫和促进肿瘤生长的双重功能，这两种截然相反的效应依赖于机体内环境改变所引起的巨噬细胞极化作用。Notch-RBP-J信号通路被证明与巨噬细胞极化并形成肿瘤相关巨噬细胞（TAM）有关，后者参与了肿瘤发生的过程。鉴于Notch-RBP-J通路已被证实在多个实体肿瘤中具有调控巨噬细胞极化的功能，而在弥漫性大B细胞淋巴瘤（DLBCL）中的研究甚少，因此本研究拟在我们已制备的DLBCL直接异种移植小鼠模型的基础上完成：1.检测模型中巨噬细胞类型及Notch-RBP-J信号通路的表达；2.调控肿瘤细胞和巨噬细胞中Notch基因的表达，观察其对巨噬细胞极化的影响。3.使用Notch通路抑制剂，观察模型中TAM的改变以及成瘤过程和肿瘤微环境的变化。通过上述研究以期阐释Notch-RBP-J通路及TAM在改变DLBCL肿瘤微环境中的作用，为DLBCL微环境靶向治疗提供理论依据。

巨噬细胞具有抗肿瘤免疫和促进肿瘤生长的双重功能，这两种截然相反的效应依赖于机体内环境改变所引起的巨噬细胞极化作用。Notch-RBP-J信号通路被证明与巨噬细胞极化并形成肿瘤相关巨噬细胞（TAM）有关，后者参与了肿瘤发生的过程。鉴于Notch-RBP-J通路已被证实在多个实体肿瘤中具有调控巨噬细胞极化的功能，而在弥漫性大B细胞淋巴瘤（DLBCL）中的研究甚少，因此本研究拟在我们已制备的DLBCL直接异种移植小鼠模型的基础上完成：1.检测模型中巨噬细胞类型及Notch-RBP-J信号通路的表达；2.调控肿瘤细胞和巨噬细胞中Notch基因的表达，观察其对巨噬细胞极化的影响。3.使用Notch通路抑制剂，观察模型中TAM的改变以及成瘤过程和肿瘤微环境的变化。通过上述研究以期阐释Notch-RBP-J通路及TAM在改变DLBCL肿瘤微环境中的作用，为DLBCL微环境靶向治疗提供理论依据。