人乳头瘤病毒潜伏整合感染与宫颈癌致病机理研究

It is known that human papillomavirus (HPV) is the leading cause of cervical carcinoma, which is characterized by high HPV infection rate (80%) across the whole population and occasional post-infectious occurrence of carcinoma, but the molecular mechanisms by which HPV induces cervical carcinoma remain unclear at present. It would be hardly affordable to achieve universal coverage of vaccination in a country of the first population. In preliminary studies, we have proved that underlying persistent infection with HPV and integration of viral DNA into human DNA are key steps of the initiation of cervical carcinoma, and that HPV has specific integration sites in host DNA, suggesting that transient infection and underlying persistent infection with HPV must be treated differently in the control of cervical carcinoma. This project is aimed at thoroughly investigating the basic law of HPV integration and the molecular features of malignantly transformed cervical epithelium on the basis of preliminary studies. Paired raft 3-dimensional cell models, zebra fish models and BLT mouse models were established to investigate the essential mechanisms of HPV persistent infection, site-specific integration and malignant transformation by DISP integration site screening, zinc-finger nuclease gene knockout and other key techniques, in order to design HPV targeted therapies and clinical molecule detection. The research results will be beneficial to the formulation of control strategies for cervical carcinoma, maximizing cost savings for national disease prevention.

已知人乳头瘤病毒（HPV）是宫颈癌的首要病因，发病特点是人群HPV的高感染率（80%）和感染后的偶发生率(0.8%)，但HPV如何诱发宫颈癌的分子机制目前尚不清楚，开展全民疫苗接种的预防策略对中国这一人口大国将是难以承受的负担。我们前期研究初步明确HPV潜伏持续感染和病毒DNA整合到人染色体是宫颈癌变的关键步骤，并证明HPV在宿主DNA的整合位点具备特异性，这提示宫颈癌防治应甄别对待HPV一过性感染与潜伏持续感染。本项目将在前期研究基础上深入探索HPV整合的基本规律及整合后宫颈上皮恶性转化的分子特征，通过建立配对筏式三维细胞模型和斑马鱼、BLT鼠模型，采用DISP整合位点筛选、锌指核酶定点敲除等关键技术进一步确定形成HPV潜伏持续感染及定点整合与癌变的根本内涵，进而设计HPV定点整合相关临床分子检测和靶向治疗方案，研究结果将有助于我国制定精确的宫颈癌防治策略，最大限度节约国家疾病防治资金。

本项目经过计划研究内容系统深入的研究，在HPV相关宫颈病变临床资源的收集与管理，HPV持续性感染导致癌前病变的发生机制和靶向治疗，宫颈癌及癌前病变的预警方面做出了卓有成效的工作，发表了以两篇Nature Genetics为代表的SCI论文38篇，合计影响因子达210，申请发明专利5项，授权1项，研究内容“宫颈癌发病新特征及临床诊治新策略应用”获2014年湖北省科技进步一等奖。马丁教授获得2017年“全国创新争先奖状”。项目近五年培养硕士研究生4名，博士研究生4名，博士后2名，项目负责人马丁院士2017年增选为中国工程院院士，大大超过项目预期目标。项目经费严格按照项目预算和华中科技大学同济医学院附属同济财务相关规定执行。