ACF7通过GSK3β调控肠上皮细胞粘附动态影响肠粘膜营养吸收效率的机制研究

肠粘膜营养吸收效率与肠绒毛及刷状缘数量及形态有密切联系。微丝交联因子7(ACF7)是交联微丝微管的骨架蛋白，其活化后通过调节微丝微管动力学促进细胞迁移、调控细胞粘附与形态等重要生物学过程。我们前期研究通过构建肠上皮ACF7基因敲除(ACF7 cKO)小鼠发现ACF7缺失导致肠上皮通透性、抗损伤能力、绒毛和刷状缘数量及形态等均发生明显异常。ACF7 cKO小鼠与对照小鼠相比体形明显瘦小、肠粘膜营养吸收效率明显降低。研究显示糖原合成酶激酶-3β(GSK3β)是调控ACF7交联微管活性并调控细胞粘附的主要分子。因此本课题拟利用ACF7 cKO小鼠及ACF7 KO的Caco-2与HIEC细胞，探索ACF7联合GSK3β通过调控微管组装及细胞粘附动态影响肠上皮通透性、绒毛和刷状缘形态及数量进而影响肠粘膜营养吸收效率。对明确ACF7调控肠粘膜营养吸收的具体分子机制，指导临床靶向干预具有重要意义。

The absorption efficiency of nutrients in intestinal mucosa is closely related to the number and morphology of intestinal villi and brush borders. Microfilament cross-linking factor 7 (ACF7) is a cytoskeleton cross-linked protein that connects microfilament and microtubules. After activation, through regulating the dynamics of microfilament and microtubules，it can promote cell migration, regulate cell adhesion and morphology et al. In the previous study, we found that the absence of ACF7 resulted in significant abnormalities in intestinal epithelial permeability, ability to resist damage, the number and morphology of villi and brush borders.ACF7 cKO mice were smaller in size and attenuated nutrient absorption of intestinal mucosal when compared with the control mice. The study showed that GSK3 β was the main molecule to regulate the activity of ACF7 cross-link with microtubules. Therefore, this project intends to use ACF7 cKO mice and ACF7 KO Caco-2 and HIEC cells to explore how ACF7 combined with GSK3β to regulate the permeability of intestinal epithelium and the morphology of villi and brush borders by regulating microtubule assembly and cell adhesion dynamics. And ultimately affect the nutrient absorption of intestinal mucosal. It is significance to clarify the molecular mechanism of ACF7 regulating intestinal mucosal nutrition absorption and guide clinical targeted intervention.