MAPKs调控TGF-β1/Smads信号通路在砷致肝纤维化中的作用机制及竹荪干预

Arsenic pollution is a global problem threatening human health, hepatic fibrosis is the key pathological process of chronic arsenic poisoning death caused by Arsenic poisoning. TGF-beta1/Smad signals is one of key system in the process of hepatic fibrosis. MAPK signaling pathway is one of the important regulatory factors in the hepatic fibrosis cause by arsenic.But it is importance to explore the mechanism of them in the hepatic fibrosis.Dictyophora is one of important fungus resources of Guizhou, Our previous research indicated that polysaccharides from dictyophora indusiata ameliorated apoptosis of hepatic cell induced by arsenic involving in MAPKs signal.The project is to establish the hepatic fibrosis experimental animal and cell model of by arsenic. Used the MAPK and TGF-β1 specific inhibitors, Research on the TGF-beta1/Smad and MAPK signaling pathway Crosstalk regulate and control mechanism,Expound the MAPK and TGF-beta1/Smad signaling pathways mechanism in the process of arsenic to liver damage.The MAPK and TGF-β1/Smad regulation crosstalk will be confirmed in arsenic induced hepatic injury which will provide the key target and novel theroetical guide for prevention and reversion hepatic injury,and further explore the new drug preventing arsenic poision and provide the theroetical guide and experimental basic for research and advance of Guizhou regional characteristics natural resources.

环境砷污染是威胁人类健康的全球性问题，砷中毒所致肝纤维化是慢性砷中毒致死的关键病理过程。TGF-β1/Smad信号在肝纤维发生的关键信号系统，近期的研究证实MAPKs激活是砷致肝纤维化的重要调控因子，但是二者之间在砷致肝纤维化的机制亟待探讨。竹荪为贵州区域特色重要真菌资源，前期研究发现竹荪多糖干预MAPKs信号对砷所致肝细胞凋亡具有保护作用。本项目建立砷致肝纤维化的实验动物与细胞模型，采用MAPK和TGF-β1特异性的抑制剂，研究MAPK对TGF-β1/Smad信号通路Crosstalk调控作用机制，阐明MAPK和TGF-β1/Smad信号通路在砷致肝损伤过程中作用机制，为防治/逆转肝纤维化提供关键靶位和理论指导，为民族药竹荪提供新的药理作用及作用机制，为贵州区域特色资源的深层次开发与利用提供新理论依据与实验基础。

慢性砷暴露是威胁人类健康的全球性公共卫生挑战，而砷中毒所致肝纤维化是慢性砷中毒致死的关键病理过程，但目前其致病机制尚不清楚，且无有效防治措施。本项目在前期研究的基础之上，从动物和细胞两个水平侧重探讨了砷致肝纤维化的探讨了TGF-1/Smad信号通路在砷致肝损伤中的作用以及MAPK对TGF-1/Smad信号通路的调控作用机制；同时采用贵州特色食药资源竹荪多糖进行了针对性干预研究探索。经过四年的项目实施，获得了一系列研究成果：① 从细胞、动物两个水平阐明了MAPK与TGF-β1/Smad 信号通路Crosstalk调控作用机制在砷致肝损伤中的作用及关键调控靶点作用靶点PAI-1、Smad7、Smad3，为防治和逆转砷所致肝纤维化提供了靶向依据。② 基于MAPK、TGF-β1/Smad和Nrf2信号通路，探讨了贵州特色食药资源竹荪多糖对砷致肝损伤的潜在治疗价值，为民族药竹荪提供了新的药理作用及作用机制，亦为贵州区域特色资源的深层次开发与利用提供新理论依据与实验基础。本项目的系列研究成果系统阐释了砷中毒所致肝纤维化的MAPK与TGF-1/Smad信号通路Crosstalk调控作用机制，为新时期针对性防治砷中毒健康损害及优化新的干预策略提供了科学依据。