基于TGF-β1介导的ERK1/2、PI3K/Akt信号通路的对话探讨从痰论治CP内环境稳态失衡所致胰腺纤维化形成的机制

Pancreatic fibrosis is the typical pathological manifestation of chronic pancreatitis (CP).The activation of TGF- β1 mediated relevant signaling pathways,which induces CP "homeostasis imbalance",plays an important role in pancreatic fibrosis.The previous study on the treatment of chronic pancreatitis from phlegm showed that the treatment can effectively improve the pancreatic fibrosis, and regulate the expression of related fibrosis protein. The homeostasis imbalance,represented by the activation of abnormal signal pathway and cytokine generation can be attributed to the "phlegm",which participates in the whole process of pancreatic fibrosis.But the specific mechanism is not clear.This project takes the TGF-β1 mediated cross talk between ERK1/2, PI3K/Akt signal pathway as the cut-in point, observing the treatment of Xiaotan Hezhong Recipe on the model of CP rat pancreatic fibrosis formation and intervention effect of TGF-β1 mediated ERK1/2, PI3K/Akt pathway and downstream related fibrosis index;at the same time starting two pathways blocking experiments respectively on pancreatic stellate cells (PSC) in vitro.This study will reveal the cross talk function of two pathways in the formation of pancreatic fibrosis,clarify the role of targets and molecular mechanisms of treated from dispersing phlegm of chronic pancreatitis homeostasis imbalance,confirm the scientific treatment of chronic pancreatitis from dispersing phlegm, provide the experimental basis for the Chinese medicine treatment on chronic pancreatitis.

胰腺纤维化是慢性胰腺炎（CP）典型的病理表现，而TGF-β1介导的相关信号通路活化所致CP"内环境稳态失衡"在胰腺纤维化中起到重要作用。本课题前期研究证实从痰论治CP，能有效改善胰腺纤维化形成，调控相关纤维化蛋白表达，并认为异常信号通路的活化及细胞因子的生成等稳态失衡皆可归因于"痰浊"，其参与胰腺纤维化形成的全过程。但其中具体机制尚不明确。本项目以TGF-β1介导的ERK1/2、PI3K/Akt信号通路的交叉对话为切入点，观察消痰和中方对CP大鼠模型胰腺纤维化形成，TGF-β1介导的ERK1/2、PI3K/Akt通路及下游相关纤维化指标的干预影响；同时体外对胰腺星状细胞（PSC）分别进行两条通路的阻断实验，揭示两条通路的交叉对话在胰腺纤维化形成中的作用，从而阐明从痰论治CP内环境稳态失衡的作用靶点及分子机制，证实从痰论治慢性胰腺炎理论的科学性，为中医药防治慢性胰腺炎提供实验依据。