LRG1调控脂质代谢重编程介导脑缺血后血管内皮紧密连接损伤的机制研究

脑缺血因其高发病、高复发、高致残率，成为中国国民第一位死亡病因。血管内皮紧密连接是调节脑缺血后血脑屏障通透性的核心结构。申请人前期针对血管内皮紧密连接蛋白的直接调控已有丰富研究，进一步研究发现内皮细胞脂质组分的变化，是导致脑缺血后血管内皮紧密连接损伤的根本原因。前期基础提示富亮氨酸α2糖蛋白LRG1分子在缺血脑组织中表达异常升高并致细胞凋亡，干预LRG1可使内皮细胞脂质组分发生变化，然而LRG1与内皮细胞紧密连接损伤的机制尚不明确。据此我们提出科学假说“脑缺血后LRG1介导内皮细胞脂质代谢重编程，致血管内皮紧密连接损伤”。研究拟探索脑缺血后内皮细胞脂质代谢重编程的变化规律，LRG1调控脂质重编程对血管内皮损伤的影响，以及LRG1与miR-20a、SREBP间上下游调控参与脂质代谢重编程致内皮紧密连接损伤的机制。本研究期望从脂质代谢重编程角度，为阐释脑缺血后血管内皮损伤新机制奠定科学基础。

Cerebral ischemia ranked first disease in China due to its high incidence, high recurrence, and high disability rate. Endothelial tight junction is the central link of blood brain barrier permeability stimulated by cerebral ischemia. Previous studies has got adequate experimental foundations on the direct regulation mechanism of endothelial tight junction proteins. Further studies have found that the change of lipid components of endothelial cells was the fundamental cause of vascular endothelial tight junction injury after cerebral ischemia. Previous studies indicated that leucine-rich α2-glycoprotein LRG1 was abnormally elevated in ischemia brain tissues and led to cellular apoptosis, while the intervention of LRG1 could carry the lipid composition change to endothelial cells. However, the mechanism between the LRG1 and endothelial cellular tight junction injury remained unclear. Based on these, we proposed the scientific hypothesis that LRG1 mediated lipid metabolism reprogramming of vascular endothelial cells, resulting in vascular endothelial tight junction injury after cerebral ischemia. This study attempted to explore the change law of lipid metabolism reprogramming of vascular endothelial cells after cerebral ischemia, and to study the effects of LRG1 in regulating lipid metabolism reprogramming on vascular endothelial tight junction injury, and to investigate the upstream and downstream regulation mechanism of LRG1, miR-20a, and SREBP on endothelial tight junction injury induced by lipid metabolism reprogramming. This study was desirable to lay the scientific foundation for explaining the new mechanism of vascular endothelial injury after cerebral ischemia from the perspective of lipid metabolism reprogramming.