靶向LMP2特异性多肽的筛选、鉴定及应用基础

EB病毒感染与鼻咽癌（NPC）的发生、发展密切相关，并以潜伏感染状态存在于NPC中，只表达少数基因。其中跨膜蛋白LMP2（2A和2B）表达于大部分NPC，其 N端和C端均位于胞内；LMP2A和2B具有相同的跨膜区，该结构域与其胞内定位密切相关，所以是NPC治疗的理想靶点。前期研究发现LMP2A可诱导NPC细胞发生上皮间质转化，在成瘤和转移中起重要作用；并以LMP2为靶标，采用噬菌体展示技术筛选出多个潜在的LMP2结合多肽。本项目拟进一步检测它们与LMP2的亲和力，鉴定出靶向LMP2并具高特异性和高亲和力的多肽。基于靶向多肽与LMP2结合后，可能随LMP2经代谢通路进入细胞内，为此我们将观察这些LMP2靶向多肽进入细胞后，对鼻咽癌细胞的生物学行为的影响。进而，将这些靶向多肽与肿瘤成像或治疗药物偶联，观察LMP2靶向多肽在鼻咽癌的诊断与治疗中的作用，为研发鼻咽癌的分子诊断和靶向治疗提供新思路。

Nasopharyngeal carcinoma (NPC) is highly associated with EB virus (EBV). EBV exists in the state of latent infection in NPC cells and expresses only a few of genes, in which latent membrane protein 2, LMP2 (LMP2A/LMP2B) expression presents in most of NPC tissues. Both LMP2A/LMP2B are transmembrane proteins in which their N-terminal and C-terminal domains are located intracellularly. LMP2A/2B have the same transmembrane domains, and the function of these domains is closely related to the location of LMP2A/2B, implying that LMP2A/2B is the ideal therapeutic targets for NPC. Our preliminary study found that LMP2A induced epithelial-mesenchymal transition in NPC cells, suggesting an important role of LMP2A in tumor formation and metastasis of NPC. Therefore, we set LMP2 as targets and screened many potential LMP2-bound peptides by phage display technology. We will continue testing the affinity of these peptides to LMP2 and identify the targeting peptides to LMP2 with high affinity. Once these peptides bind LMP2, the compounds of LMP2-peptide will get into cells by the metabolic pathway. Based on these, we will examine the effects of the LMP2-targeted peptides on NPC cells. Furthermore, we will couple these peptides with imaging or labeling agents or tumor therapeutic drugs, these peptides can bring these agents or drugs into LMP2-expressed NPC cells, to achieve the goals of the targeted therapy or molecular image of NPC.