RecQ家族DNA解旋酶在砷对人肝损伤中的调控研究

Endemic arsenism is one of the prevention and control of endemic diseases in china. Because of the mechanism of endemic arsenism is unclear, hazards have not been controlled totally. Liver is a major target organs impaire by arsenic poisoning. Studies demonstrate that DNA damage and repair is a major factor of liver damage caused by arsenic. Recent study found that RecQ helicase plays an important role in cell metabolism process including DNA replication, repair, recombination and transcription. RecQ helicase may be involved in DNA damage repair process through multiple ways. This project intends to study in the crowd of coal-burning arsenism in Guizhou, along with studies in vitro, by using population epidemiology, molecular toxicology and molecular biology methods, to observe the expressions of RecQ helicase and to analysis the relationship between RecQ helicase and DNA methylation. Moreover, this project also intends to explore the relationship between the activities and functions of RecQ helicase and DNA damage repair in liver damage caused by arsenism. This project will try to illustrate the molecular mechanism of liver damage caused by arsenic from the perspective of RecQ helicase, which will provide a theoretical basis for early detection and targeted therapy of liver damage caused by arsenic.

地方性砷中毒是我国高度重视、持续防控的地方病之一，因其机制至今不清，故危害未完全得到控制。已知肝脏是砷中毒主要靶器官之一，研究表明DNA损伤及修复是砷致肝损害的重要原因，国内外学者新近研究发现RecQ解旋酶在DNA的复制、修复、重组、转录等细胞代谢过程中具有至关重要的作用，RecQ解旋酶能通过多种途径参与DNA损伤修复过程。本项目拟在前期研究的基础上，从人群及细胞两个实验体系，采用人群流行病学、分子毒理学及分子生物学的方法，观察砷致肝损伤患者外周血中RecQ解旋酶表达情况及其DNA甲基化的状况，并分析两者之间的关系；同时探讨在砷致肝损伤过程中RecQ解旋酶活性和功能与DNA损伤修复之间的关系，力图从RecQ解旋酶的角度揭示砷致肝损伤的分子机制，为更好地解决砷中毒肝损伤的早期发现、针对性干预提供理论和实验依据。

砷是一种已知的毒物和人类致癌物。砷中毒是全球范围内严重危害人体健康的疾病。地方性砷中毒导致的肝损伤、肝纤维化、肝硬化及肝癌的防治研究已逐渐成为国内外研究的热点，是目前地方性砷中毒防控丞待解决的问题。本研究从人群及细胞两个实验体系，采用人群流行病学及分子毒理学方法，揭示了RecQ解旋酶DNA 甲基化在砷致肝损伤中的作用及其机制，系统地阐明在砷致肝损伤过程中RecQ解旋酶与DNA损伤修复之间的关系。本项目运用细胞生物学、基因组学、分子生物学、生物信息学等技术研究砷对人正常肝细胞形态、细胞凋亡、DNA损伤、氧化损伤的影响，并揭示砷对RecQ家族解旋酶表达的调控及其分子机制。砷暴露可造成RecQ解旋酶BLM、WRN、RECQL1、RECQL4基因启动子区DNA甲基化水平升高，导致mRNA及其蛋白表达降低，进而抑制了砷致肝细胞DNA损伤修复机制，参与砷致肝损伤发生发展。抑制DNA甲基化可通过恢复RecQ 解旋酶水平，拮抗砷诱导的DNA损伤、氧化损伤和肝细胞活性。燃煤型砷中毒肝损伤患者存在不同程度DNA损伤和氧化损伤，砷中毒肝损伤患者RecQ解旋酶转录表达均降低，BLM、WRN、RECQL1基因启动子区存在不同程度的甲基化。同时发现影响BLM解旋酶生化活性的因素，揭示BLM解旋酶在砷致肝细胞损伤中的作用。本项目系列研究结果表明RecQ解旋酶在砷致肝损伤过程中发挥重要作用，对RecQ解旋酶进行针对性干预可能对有效逆转砷致肝损伤具有重要科学意义及转化应用价值。