p53/E2F7/E2F1通路调控的自噬在砷致肝损伤中的作用及银杏制剂的干预研究

Arsenic pollution was serious harm to people's health and liver damage was one of most outstanding problems in arsenic poisoning. The exact mechanism of arsenic-induced liver damage was still unknown. Because of lacking effective treatments, it was not completely under control yet. The early stage of the research in our research group revealed that p53-mediated apoptosis was related to the development of arsenic-induced liver damage; ginkgo agent could suppress the activation of p53 and thus alleviate hepatocyte apoptosis. However, the specific mechanism of p53 was still unclear. Recent studies showed that autophagy played an important role in the cytotoxic effect of arsenic. Moreover, early studies of applicant demonstrated that E2F7, a downstream molecule of p53, could influence intracellular autophagic activity. Furthermore, it was reported that E2F1, a downstream molecule of E2F7, could also regulate autophagy. On the basis of these finds, a liver cell model of arsenic poisoning would be established to research the mechanism of autophagy regulated by p53/E2F7/E2F1 pathway on liver damage from molecular and cellular level; Then intervened by ginkgo agent and investigate the influence on p53/E2F7/E2F1 pathway and autophagy under arsenic exposure to provide new theoretical and experimental basis to prevent and cure endemic arsenism.

砷污染严重危害人类健康，其中肝损伤已成为地方性砷中毒突出的问题之一。目前砷致肝损伤的确切机制尚不清楚，并缺乏有效的治疗药物，至今尚未完全得到控制。课题组前期研究表明，p53介导的细胞凋亡参与了砷中毒肝损伤的发生发展；银杏制剂可以有效抑制p53的活化，减少肝细胞凋亡。但是，p53在其中的具体作用机制迄今不甚清楚。近年研究显示自噬在砷的毒效应中起重要作用，且申请人前期研究发现，p53下游基因E2F7可以影响细胞自噬水平，而有报道表明E2F7下游基因E2F1可调控细胞自噬。依据课题组前期研究发现并结合国内外最新进展，本研究拟构建砷中毒肝细胞模型，从分子和细胞水平深入探讨p53/E2F7/E2F1通路及其调控的自噬在砷致肝损伤中的作用机制；并采用银杏制剂干预，探讨其在砷暴露下对该通路及自噬的影响，为地方性砷中毒肝损伤的防治提供新的理论和实验依据。

砷污染严重危害人类健康，其中肝损伤已成为地方性砷中毒突出的问题之一。目前砷致肝损伤的确切机制尚不清楚，并缺乏有效的治疗药物，至今尚未完全得到控制。因此，寻找一种有效的干预药物并探究其作用机制十分重要。申请人在该项目中主要通过构建砷中毒肝细胞模型，从分子和细胞水平探讨了p53、E2F7、E2F1在人肝细胞系中的相互调控关系及其调控的自噬在砷致肝损伤中的作用；并采用银杏叶提取物进行干预，探讨其在砷暴露下对自噬的影响及机制。申请人研究结果表明，亚砷酸钠可引起人肝细胞损伤及自噬异常，且p53、E2F7和E2F1介导了亚砷酸钠对人肝细胞的损伤作用。虽然E2F7和E2F1介导了亚砷酸钠对人肝细胞的自噬异常，但p53对细胞自噬没有明显的影响。另外，银杏叶提取物可有效拮抗亚砷酸钠对人肝细胞的损伤作用及自噬异常，其作用可能是通过调控E2F7、E2F1及保护溶酶体所发挥。该项目研究的科学意义在于阐明了E2F7、E2F1对肝细胞自噬的调控作用及其在银杏叶提取物干预砷致肝细胞损伤中的作用及机制，揭示了银杏叶提取物在砷中毒肝损伤防治中的应用价值。