TMEM88调控酒精性肝病中炎症因子分泌的功能和机制研究

Alcoholic liver disease (ALD) is damage to the liver and its function due to alcohol abuse. Activation of Wnt/β-catenin signaling pathway can reduce inflammation, cell injury and apoptosis in ALD model rats. Preliminary experimental results showed that TMEM88 can inhibit the Wnt/β-catenin signaling pathway and its expression was downregulated in ALD model mice. But the specific function and mechanism is unclear. Moreover, miR-708 expression was downregulated in blood of patients with alcoholic liver disease. The software can predict miR-708 targets 3'UTR of TMEM88 mRNA. So we hypothesized that: TMEM88 may inhibit Wnt/β-catenin signaling pathway, regulate the secretion of inflammatory cytokines in the process of alcoholic liver disease, and its upstream regulatory mechanism may be related to miR-708. Therefore, the chronic-binge alcoholic liver disease model and RAW264.7 and THP-1 cells will be used to explore the function role of TMEM88 in the inflammation cytokines secretion of ALD. This study aims to form a new perspective of TMEM88 in modulating inflammation in the process of ALD and its molecular mechanism, providing new targets for clinical prevention and treatment of alcoholic liver disease, and new ideas.

酒精性肝病(ALD)是由饮酒而致的肝脏损害性疾病。Wnt/β-catenin信号通路的激活可减少ALD大鼠中的炎症、细胞损伤和凋亡。预实验结果显示，ALD小鼠中Wnt /β-catenin信号通路的抑制蛋白TMEM88呈明显低表达，但具体功能及机制未明。此外，ALD流行病调查及miRNA筛选结果发现，ALD患者血液中miR-708表达降低。软件预测miR-708可以靶向TMEM88 mRNA的3’UTR。于是假设：TMEM88可能通过抑制Wnt/β-catenin信号通路，进而调节ALD进程中炎症因子的分泌，其上游调控机制可能与miR-708有关。因此，本项目拟采用chronic-binge ALD模型和RAW264.7、THP-1细胞，探索TMEM88 在ALD炎症中的功能，旨在从新的视角阐释TMEM88在ALD过程中调控炎症因子的功能及其分子机制，为临床防治ALD提供新靶点、新思路。

酒精性肝病（ALD）是由饮酒而致的肝脏损害性疾病。本项目采用Gao-Binge ALD模型和RAW264.7、THP-1细胞，探究炎症在ALD中的表达，其次探索TMEM88 在ALD中对炎症调控的功能，旨在从新的视角阐释TMEM88在ALD过程中调控炎症因子的功能及其分子机制。实验结果表明，ALD小鼠中，TMEM88的表达升高，通过YAP信号通路促进炎症因子的分泌。 此外，其上游机制与miR-708有关。同时ALD流行病调查及miRNA筛选结果发现，ALD患者血液中miR-708表达降低。实验结果总体表明，miR-708可以靶向TMEM88通过YAP信号通路进而抑制ALD进程中炎症因子的分泌。因此，该课题结果将为未来临床防治ALD提供潜在的新靶点、新思路。