GADD45与mir-21在燃煤污染型砷中毒基因病理性低甲基化中作用和机制及银杏制剂干预研究

贵州是我国特有的燃煤型地砷病重病区。但砷作为确认的人类致癌物，迄今还没有一个被广泛认可且符合砷生物学效应的致癌机制。基因甲基化水平降低是疾病发生发展中重要的表观遗传学改变之一。Gadd45与miR-21在基因低甲基化发生中可能扮演重要角色。本课题旨在以贵州燃煤型砷中毒病区为现场，通过现况与银杏制剂干预研究，采用环境和人群流行病学与分子毒理学方法，侧重研究砷暴露人群基因组、敏感基因甲基化状况及Gaddd45与miR-21表达情况，并分析其与燃煤型砷中毒发生发展的关系。同时，构建砷中毒细胞模型进行银杏提取物和miR-21模拟物或干扰物干预，在细胞水平对人群研究结果进行补充和验证。通过人群和细胞研究，分析Gadd45及miR-21与基因低甲基化及燃煤型砷中毒的关系，为阐明燃煤型砷中毒分子机理及早期诊断、高危人群的筛查和干预性防治提供科学依据,同时探索性寻找一种天然、经济、有效的砷中毒防治药物。

Guizhou is characteristic endemic areas of coal-burning arsenism in China.But arsenic as a confirmed human carcinogen, so far there is not a widely recognized and consistent with the biological effect of arsenic carcinogenesis.Gene methylation level decreased is one of the important epigenetic changes in disease development.Gadd45 and miR-21 may play an important role in gene hypomethylation.Our study will point at characteristic endemic areas of coal-burning arsenism in Guizhou, using the present situation and intervention study of Ginkgo biloba and environmental and population epidemiology and molecular toxicology methods. Our study will focus on the methylation status of sensitive gene and genome of human exposuring to arsenic and the expression situation of Gadd45 and miR-21, and analyse the relationship between the methylation status and the expression situation told above and the occurrence and development of coal-burning arsenism as well. At the same time,we will construct the cell model of arseniasis and intervent with Ginkgo biloba extract and miR-21 mimetic or disruptors.Our study at the cellular level may supplement and verify the results of population study. Through analysising the relationship between Gadd45 and miR-21 and gene hypomethylation and coal-burning arsenism at population-based studies and cell research level,our study may provide a scientific basis for elucidating the molecular mechanism of coal-burning arsenism and early diagnosis and high-risk groups screening and preventive intervention.Meanwhile, we also try to find a natural, economic and effective drug for the prevention and treatment of arsenism.