基于转化生长因子β通路的酒精性肝纤维化的细胞对话机制及调肝理脾方的干预

Alcoholic liver fibrosis, four major effector cells to liver cells, kupffer cells, hepatic stellate cells and sinus endothelial cells, in the stage of alcoholic liver injury, these cells secrete inflammatory factor and medium decide the process of fibrosis.One (1) liver cell damage and kupffer cells start to hepatic stellate cell phenotype transformation and activation, hepatic sinus endothelial cell endocytosis, as a classic transmission path.(2) liver cells dialogue hepatic stellate cells.(3) kupffer cells dialogue hepatic stellate cells.Hepatic stellate cells (4) the hepatic sinus endothelial cells dialogue for this project research center link.This topic proposed in alcoholic liver fibrosis animal and cell models, in order to maintain the/paracrine pathogenic/resistance factor balance for clues, through main cytokines in precise measurement path TGF beta and the change of the upstream and downstream factor value, discusses the dynamic connotation.By using the methods of cluster analysis, find out potential biomarkers, and through the secondary mass spectrometry, accurate methods such as mass number carries on the appraisal, analyzes the liver spleen intervention effect of the formulas and efficacy with its target protein in a target genes.Looking for and explain the interaction between cells dialogue relations.Clarify its possible positive and negative regulatory factors mutual influence the secretion of concentration and the safety threshold value range, to show start alcoholic liver fibrosis mechanism and regulation of the formulas.

酒精性肝纤维化四种主要效应细胞为肝细胞、枯否细胞、肝星状细胞和窦内皮细胞，在酒精性肝损伤阶段，上述细胞分泌的炎症因子和介质决定纤维化的进程。其中①肝细胞损伤→枯否细胞启动→肝星状细胞表型转化与激活→肝窦内皮细胞内吞，其为经典传递路径。②肝细胞对话肝星状细胞。③枯否细胞对话肝星状细胞。④肝窦内皮细胞对话肝星状细胞为本项目研究中心环节。本课题拟在酒精性肝纤维化动物和细胞模型上，以维持自/旁分泌的致病/抗病因子平衡为线索，通过精确计量路径中主要细胞因子TGFβ及其上下游因子的变化值，探讨其动态内涵。利用聚类分析等方法，找到可能的生物标记物，并通过二级质谱，准确质量数等方法对其进行鉴定，分析调肝理脾方药干预的影响和药效的靶基因与靶蛋白。寻找与解释细胞对话之间的相互作用关系。明确其可能出现的正负调控因子相互影响的分泌浓度和安全阈值范围，以说明启动酒精性肝纤维化的机制及方药的调控环节。

酒精性肝纤维化四种主要效应细胞为肝细胞、枯否细胞、肝星状细胞和窦内皮细胞，在酒精性肝损伤阶段，上述细胞分泌的炎症因子和介质决定纤维化的进程。其中1肝细胞损伤→枯 否细胞启动→肝星状细胞表型转化与激活→肝窦内皮细胞内吞，其为经典传递路径。2肝细胞对话肝星状细胞。3枯否细胞对话肝星状细胞。4肝窦内皮细胞对话肝星状细胞为本项目研究 中心环节。本课题拟在酒精性肝纤维化动物和细胞模型上，以维持自/旁分泌的致病/抗病因子平衡为线索，通过精确计量路径中主要细胞因子TGFβ及其上下游因子的变化值，探讨其动 内涵。利用聚类分析等方法，找到可能的生物标记物，并通过二级质谱，准确质量数等方法对其进行鉴定，分析调肝理脾方药干预的影响和药效的靶基因与靶蛋白。寻找与解释细胞对话之 间的相互作用关系。明确其可能出现的正负调控因子相互影响的分泌浓度和安全阈值范围，以说明启动酒精性肝纤维化的机制及方药的调控环节。实验结果表明，TGFβ/Smad是酒精性肝纤维化发生发展中的关键信号通路。酒精性肝纤维化发生时，TGFβ信号启动，导致效应细胞内Smad2、Smad3等关键分子表达上调，直接与肝细胞的凋亡；肝星状细胞激活转分化，过度合成胶原、层粘连蛋白等胞外基质，；促进肝内巨噬细胞极性转化，释放大量细胞因子启动肝内炎症反应相关。调肝理脾方对酒精性肝纤维化具有明显的保护作用，其作用机制可能与抑制TGFβ/Smad信号通路激活有关。