HPV逃逸机体TLRs介导的天然免疫应答反应的分子机制

Persistent infection of high-risk type HPV (HR - HPV) and the failure of the body's immune system monitoring is initiating factors in cervical lesion development and carcinogenic process. TLRs as sentry receptors to be the first line of defence constitute the body's innate immune system, play an important role in recognition and clearing HPV. At present, it was considered that HR HPV - mainly through the integration of encoding cancer-causing protein E6 and E7, caused key moleculars expression abnormaliy of cervical epithelial cells in the upstream and downstream of innate immune signaling pathways, forming a tumor escape immune surveillance "environment", i . e . the immune escape. This study in view of the different stages of cervical lesions in the HR group 16 / 18 positive cervical tissue samples, meanwhile, establishing HPV16 E6 / E7 transgenic mouse model, will use PCR Arrays gene expression profiles technology to analyze the expression differences of key target genes and the effect molecules in the upstream and downstream of TLR mediated innate and adaptive immune response signal pathways, as well as the correlation of the HR - HPV infection, viral load, and E6 / E7. Exquisitely and accurateiy distinguishing the key genes, will aid to interpretate the mechanism of HPV escape TLRs mediated the body's innate immune response regulation , to reveal the biological essence of pathogenesis and carcinogenesis in HPV infection and out of control in innate immune response, which has important significance for us to enrich the early warning system and the "therapeutic window"of cervical cancer.

高危型HPV(HR-HPV)持续感染和机体免疫监视失败是宫颈病变进程发展致癌的始动因素。TLRs作为哨兵受体构成机体天然免疫的第一道防线，在HPV的识别与清除中扮演重要角色。目前认为HPV主要通过编码致癌蛋白E6和E7的整合，导致宫颈上皮细胞中天然免疫信号通路上下游的关键分子表达异常，构成一个肿瘤逃避机体免疫监视的"微环境"形成免疫逃逸。本研究针对不同宫颈病变阶段HPV16/18阳性的宫颈组织标本，同时建立HPV16 E6/E7转基因小鼠模型，运用基因表达谱筛查技术分析TLR信号通路以及天然免疫与适应性免疫应答关键靶基因和上下游效应分子的表达差异，以及与HR-HPV感染、病毒载量以及E6/E7的相关性，精巧准确全面地对关键基因进行分辨定格，阐释HPV逃逸机体TLR介导的天然免疫反应的分子调控机制，对揭示天然免疫应答失败以及HPV致病和致癌的生物学本质，丰富宫颈癌预警体系和治疗窗都有重大意义