ANKRD22/PHLPP促进Akt线粒体转位和ROS产生致炎症性肠病肠黏膜屏障损伤的分子作用机制研究

Impaired intestinal mucosal barrier is closely associated with inflammatory bowel disease (IBD). Excessive reactive oxygen species (ROS) play an important role in the pathophysiology of intestinal mucosal barrier damage. However, the molecular mechanism is unclear. Our previous studies have shown that the anchored-repeat protein ANKRD22 expresses significantly higher in intestinal mucosa of IBD patients compared with normal controls and inflammatory factors promte the expression of ANKRD22. ANKRD22 is located in the mitochondria and recruits PHLPP to transport into mitochondria. ANKRD22 and PHLPP collaboratively drive phosphorylated Akt to mitochondria. Therefore, we speculate that all three proteins may interact with each other in the inflammatory microenvironment and lead IECs to apoptosis and further intestinal mucosal barrier damage by increasing ROS production. To test our hypothesis, first we will explore the role of ANKRD22/PHLPP in regulating Akt mitochondrial transposition and ROS production by virtue of ANKRD22 knock-out mice, dextran sodium sulfate-induced mice colitis and the culture of primary epithelial cells. Then illuminate the molecular mechanism that how ANKRD22/PHLPP/mitochondrial Akt/ROS pathway impairs the function of intestinal mucosa barrier in IBD. In all, our research can help us to find new key therapeutic targets in IBD.

肠黏膜屏障损伤与炎症性肠病（IBD）发病密切相关，线粒体产生过多活性氧自由基即ROS是肠黏膜屏障损伤的重要病理生理学因素，但其分子机制尚不明了。我们前期研究发现IBD患者肠黏膜中锚定重复蛋白ANKRD22表达明显增加，炎症因子促进其表达；ANKRD22定位于线粒体且招募磷酸酶PHLPP转位于线粒体，二者共同作用进一步促进磷酸化Akt向线粒体转位。据此我们推测三者在炎症微环境下相互作用，通过增加线粒体ROS的产生，导致肠上皮细胞凋亡及进一步肠黏膜屏障损伤。本研究拟在先前研究基础上，借助ANKRD22基因敲除小鼠、葡聚糖硫酸钠诱导的小鼠结肠炎模型和原代肠上皮细胞培养，探讨炎症状态下ANKRD22/PHLPP调控Akt线粒体转位和ROS生成的作用，阐明ANKRD22/PHLPP/线粒体Akt/ROS通路对损伤IBD肠黏膜屏障的分子作用机制，为寻找关键性IBD治疗靶点提供新的思路。

肠黏膜屏障损伤与炎症性肠病（IBD）发病密切相关，线粒体产生过多活性氧自由基（ROS）是肠黏膜屏障损伤的重要病理生理学因素，但其分子机制尚不明了。我们研究发现IBD患者肠黏膜锚定重复蛋白ANKRD22表达明显增加，炎症因子促进ANKRD22的表达；ANKRD22定位于线粒体，能够促进磷酸化Akt向线粒体转位。炎症微环境下，ANKRD22通过增加线粒体ROS的产生，导致肠上皮细胞凋亡及进一步肠黏膜屏障损伤。本研究借助ANKRD22基因敲除小鼠、葡聚糖硫酸钠诱导的小鼠结肠炎模型，炎症状态下ANKRD22通过调控Akt线粒体转位和ROS生成的作用，导致IBD肠黏膜屏障损伤，而敲除ANKRD22后可以阻断这种影响，可能可以成为一种新的肠黏膜保护剂。