多角度、多目标靶向防治HPV16阳性子宫颈癌及相关机制探讨

人乳头瘤病毒（HPV）相关的宫颈疾病严重危害着妇女的健康，而HPV逃逸免疫攻击得以持续感染是宫颈癌（CC）发生的必要条件，探索能多角度同时预防与治疗CC的"良方"一直是相关研究的焦点。我们前期研究证实HPV16/18 E5在CC发生发展中有重要生物学作用。由此，本课题开创性的多目标同时靶向HPV16E5E6E7三个关键致病因素（治疗CC靶点），利用生物信息学筛选针对人类主要HLA型别的抗原表位；结合我们前期关于L1（预防CC靶点）的研究，引入昆虫细胞-杆状病毒表达系统； 特别的，联合腺相关病毒（AAV）做载体，制备L1-E5E6E7(短效)+AAV-L1-E5E6E7(长效) 免疫制剂共同阻遏CC；依托筏式三维细胞模型和BLT人源动物模型，体内外同时探索L1、E5、E6、E7 致癌机制及其作为靶点防治CC的可行性；并通过短效制剂启动免疫+长效制剂增强免疫等方法探讨疫苗最佳配伍和免疫方式。

Human papillomavirus (HPV) related cervical diseases is severely impaired women's health, however HPV escapes immune attack to persistent infection is the necessary requirements of cervical cancer (CC), and exploring a "good recipe" to prevention and treatment CC from multi-angle at the same time is always the focus of related research. Our pre-research proved that the HPV16/18E5 had important biologic function during the development of CC. Thus, in this research, we creatively simultaneously targeted multi-objective HPV16E5E6E7 the three key pathogenic factors (treatment targets of CC), analyzed the antigenic epitopes of human leukocyte antigen (HLA) with bio-informatics；combined with our former research of L1 (prevention targets of CC), used the insect-baculovirus expression system； especially united the adeno-associated virus (AAV) vectors, constructed L1-E5E6E7 (short-effect preparation)+AAV-L1-E5E6E7(long-effect preparation) to rescue CC; we relied on the three-dimensional cell model and bone/liver/thymus (BLT) humanization animal model, researched the carcinogenesis of L1、E5、E6、E7 in vitro and in vivo, and tested their possibility of prevention and treatment of CC；meanwhile, explored the optimal compatibility and immune method by priming immunity with short-effect preparation and booming with long-effect preparation.