IRE1α在低切应力诱导血管内皮细胞功能障碍中的作用及其机制

Prolonged activation of the endoplasmic reticulum (ER) stress pathway can disrupt the normal physiological function of the cells, and even cause cell apoptosis. The ER-localized transmembrane protein IRE1α (inositol-requiring enzyme 1) is a key molecular in ER stress, which is highly expressed in vascular cells. The function and expression of IRE1α in endothelial cells in response to low shear stress remains unclear.The project aims to solve the key scientific issue on the role and mechanism of IRE1α in regulating endothelial cell apoptosis and secretion in response to low shear stress. We aim to employ endothelial cell-specific IRE1α knock-out strategy and in vitro shear stress on endothelial cells to investigate how IRE1alpha regulates the apoptosis and secretion of the endothelial cells. We also attempt to explore the molecular effectors as well as the downstream signaling moleculars of IRE1α action in the control of endothelial homeostasis. These studies will help us elucidate the molecular mechanism of IRE1α in endothelial cells' physiology and pathophysiology, and also provide a new strategy to find the potential molecular target for effectivly treating atherosclerosis, finally provide new clues on how ER stress regulates the occurrence and development atherosclerosis

长期过度的内质网应激反应可以破坏细胞的正常生理功能，甚至引起细胞的凋亡。内质网跨膜蛋白IRE1α是应对内质网应激的关键信号分子，在血管细胞呈高表达，但在低切应力条件下血管内皮细胞（ECs）的IRE1α表达及其功能机制尚不清楚。本项目拟解决的关键科学问题是IRE1α在低切应力诱导ECs凋亡及分泌功能调节中的作用及其力学生物学机制。本项目拟利用血管ECs特异性IRE1α基因敲除的小鼠模型和ECs体外低切应力加载实验，观察低切应力作用下ECs凋亡及分泌功能的变化，探索IRE1α参与的下游效应分子和信号机制，探讨IRE1α通路在ECs响应低切应力刺激中的作用。这些研究不仅有助于我们全面了解IRE1α通路在ECs生理与病理学调控中的作用及其机制，而且能够为寻找有效逆转动脉粥样硬化的干预策略提供潜在的分子靶标，最终为深入解析细胞内质网应激在动脉粥样硬化发生发展中的作用提供新的力学生物学线索。

长期的内质网应激可以破坏细胞的正常生理功能，甚至引起细胞的凋亡。内质网应激信号通路包括三条信号通路：IRE1α-XBP1s，PERK-eIF2α-ATF4及ATF6信号通路。课题组通过巨噬细胞特异性IRE1α敲除小鼠颈动脉结扎模型发现，相对于野生型小鼠，敲除IRE1α后颈总动脉炎症指标明显下降，通过高胆固醇饮食喂养两组小鼠，发现巨噬细胞特异性IRE1α敲除小鼠动脉粥样硬化程度明显轻于野生型小鼠，进一步我们发现内质网应激不仅影响血管，还和脂肪肝关系密切，我们发现和脂肪肝关系密切的蛋白-G0S2受到内质网应激的调控，我们发现G0S2在高脂诱导的脂肪肝模型，它的表达水平明显增高，同时，我们发现内质网应激在脂肪肝中也是发生的。内质网应激三条信号通路，只有一条信号通路PERK-eIF2α-ATF4可以在转录水平调控G0S2的表达。通过我们的研究，对动脉粥样硬化及脂肪肝的治疗提供思路。