黄蜀葵花总黄酮（TFA）通过AMPK/mTOR信号通路调控自噬治疗克罗恩病肠道纤维化的作用及其机制研究

In Crohn’s disease(CD), one of the two major forms of inflammatory bowel diseases in human beings, persistent and chronic inflammation results in deposition of extracellular matrix (ECM)and promotes fibrotic processes. However, there is no drug that can specifically inhibit or even reverse fibrosis. Researches demonstrated that AMPK/mTOR signaling pathway involved in a variety of tissue organ fibrosis processes through the regulation of autophagy. The corresponding basic research has shown that TFA which is the main component of Abelmoschus mongolicum Flower, can promote CD inflammation and reduce the intestinal fibrous tissue hyperplasia of CD model mice, and the expression of autophagic marker protein LC3、Beclin-1、AMPK in TFA group is higher than that in model group,protein mTOR is lower than that in the model group，suggesting that TFA can significantly activate autophagy. This study intends to establish the rat model of CD and clarify the time-effect relationship during the CD fibrotic processes in order to explore the therapeutic mechanism of TFA on intestinal fibrosis of CD.Besides, the changes of AMPK/mTOR signaling pathway which are involved in regulating autophagy, will be observed in the experimental cells intervented by TFA. We are supposed to interpret the internal mechanism of intestinal epithelial cells autophagy, to find new therapeutic target in intestinal fibrosis of CD，

克罗恩病（CD）是难治性炎症性肠病之一，多因反复慢性透壁性炎症导致肠道纤维化，临床缺乏特异性抑制肠道纤维化的药物。研究表明AMPK/mTOR信号通路通过调控自噬参与多种组织器官纤维化进程。课题组研究证实黄蜀葵花主要成分-黄葵总黄酮（TFA）能够促使CD炎症转归，减轻CD模型小鼠肠道纤维组织增生，使其自噬特异性标志蛋白LC3、Beclin-1在结肠组织中表达显著增高，AMPK表达增高、mTOR表达降低，为此，我们提出以下假说：TFA可能通过AMPK/mTOR信号通路调控自噬治疗肠道纤维化。本研究拟建立CD大鼠模型，进一步明确AMPK/mTOR信号通路及自噬在CD肠纤维化中的作用，诠释TFA通过AMPK/mTOR信号通路调控自噬治疗CD肠纤维化的分子机制。

克罗恩病（CD）是临床难治性疾病之一。研究表明，自噬是细胞新陈代谢的一个重要过程，而通过对自噬通路的调控达到改善CD进程也是目前研究的热点，中医药在CD治疗中有独特疗效，本研究在进一步明确黄蜀葵花总黄酮（TFA）治疗CD疗效的同时，对其治疗机制进行探讨。通过动物实验发现TFA具有减少CD小鼠死亡率，减轻临床症状，改善其肠道炎症程度，降低其结肠组织炎症及纤维化组织评分，并降低CD模型小鼠结肠组织和血清中TNF-α，IFN-γ，IL-6，IL-1β，IL-12和IL-17炎症因子含量，同时能提高CD小鼠结肠组织自噬水平。通过细胞实验，证实TFA通过调控AMPK/mTOR通路，促进肠道成纤维细胞自噬，抑制肠道成纤维细胞合成I型胶原蛋白，进一步证实了TFA改善CD肠道纤维化的作用，为TFA治疗CD肠道纤维化的应用提供了理论支持。