EphrinA1/ephA2介导肠胶质-内皮细胞相互作用参与肠血屏障功能调控

Intestinal mucosal barrier dysfunction is an important pathophysiology of inflammation-related intestinal diseases. The latest research has found that the gut-vascular barrier (GVB) is the last gate of the intestinal mucosal barrier. Increased GVB permeability is the key for ectopic colonization of intestinal flora and invasion of enterotoxin into blood which induce and/or aggravate the injury of the important organs of the whole body. Our previous studies have found that the intestinal glial cell and microvascular endothelial cell form an end-foot-like functional unit, which may play a key role in the regulation of GVB function, however, the molecular mechanism is not clear. We further found that ephrinA1/ephA2 was expressed in intestinal glial cells and microvascular endothelial cells respectively, and was significantly up-regulated in inflammatory state, which was positively correlated with the increased GVB permeability. Therefore, we hypothesized that ephrinA1/ephA2 bidirectional signaling may mediate the interaction of intestinal glial-endothelial function unit and play an important role in GVB function regulation. As the starting point, the current project will focus on the role of microvascular endothelial ephA2 mediated positive signal in the regulation of endothelial gap and endothelial fenestrae formation, and the role of the enteric glial ephrinA1 mediated reverse signal in promoting the structural damage of glial end-feet. This study will increase our knowledge of GVB, and provide a theoretical basis and potential target for the prevention and treatment of important organ injuries associated with inflammatory related intestinal diseases.

最新研究发现肠血屏障（Gut-vascular barrier，GVB）是肠黏膜屏障关键的最后一道闸门，其通透性增加才是导致肠道菌群异位、肠源毒素入血诱发和/或加重全身重要脏器损伤的关键。我们前期研究发现肠胶质细胞与微血管内皮细胞间形成终足样功能单位，参与GVB功能调控，但具体分子机制未明。进一步研究发现ephrinA1/ephA2分别表达于肠胶质、内皮细胞，且在炎症时明显上调，与GVB通透性增加呈正相关，因此，我们推测ephrinA1/ephA2双向信号可能介导肠胶质-内皮细胞功能单位相互作用，在GVB功能调控中具有重要作用。以此为切入点，本项目将重点探讨微血管内皮细胞ephA2介导的正向信号在调节内皮间隙增加、内皮窗孔形成，肠胶质细胞ephrinA1介导的反向信号在促进胶质终足破坏中的作用。本研究将增加我们对GVB的认识，为炎症相关肠道疾病诱发肠外重要脏器损伤的防治提供潜在靶点。

本项目旨在研究ephrinA1/ephA2双向信号可能介导肠胶质-内皮细胞功能单位相互作用，在肠血屏障（GVB）功能调控中具有重要作用。项目重点研究和明确了：1）肠血屏障在肠肝互动中的关键重要及调节机制，包括慢性肠炎介导肝损伤的作用及机制，肠炎状态破坏肠道黏膜屏障，引起肝脏持续炎症反应，进而加重肝脏炎症损伤和纤维化过程，这个过程中肠血屏障的完整性起到重要作用；相反，慢性肝病及肝硬化状态下肠血屏障破坏，门脉压力增高介导GVB通透性增加，与压力敏感离子通道Piezo1介导微血管内皮功能异常有关，阻断或沉默微血管内皮细胞Piezo1有效改善GVB通透性，减少肠源性大分子物质入血及细菌移位。2）Ephrin/eph信号通路在调控肠黏膜屏障通透性中具有关键作用，通过Erk/MAPK、PI3K/Akt途径调节紧密连接蛋白及PV1蛋白功能，影响内皮间隙增加、内皮窗孔形成，参与肠血屏障的功能调控，阻断或沉默ephA2受体功能有效降低大分子物质透过性、增加跨膜电阻，改善黏膜屏障即内皮屏障功能；此外，Ephrin/eph信号通路在调控ENS肠胶质细胞生长萌芽和突触可塑性中具有重要作用，通过调节肠神经胶质细胞功能影响GVB的结构和功能稳定，其机制还需进一步的研究和发掘。本研究增加了我们对GVB的认识，明确了维持肠血屏障功能完整的重要意义和可能调控机制，为炎症相关肠道疾病诱发肠外重要脏器损伤（如肠-肝轴、肠-脑轴等）的防治提供潜在靶点和方向。..