Lp-PLA2：通过修复血脑屏障治疗脑血管疾病的新靶点

血脑屏障(Blood-Brain Barrier，BBB)功能障碍是脑卒中重要病理基础，缺血性损伤激活内皮细胞内信号传导，增加BBB通透性、损伤神经血管单元(Neurovascular unit, NVU)功能。有研究认为BBB损伤可能与阿尔茨海默病(AD)的致病机制相关。抑制BBB通透性损伤能保护NVU功能，可能对多种脑疾病有治疗作用。脂蛋白相关磷脂酶A2(Lipoprotein-associated phospholipase A2, Lp-PLA2)代谢产物损害血管内皮细胞、产生炎症和细胞毒性，可能与BBB损伤相关，但缺少足够证据。本课题拟在大规模临床队列多组学数据库基础上，完成人脑BBB通透性影像学评估，找出适于Lp-PLA2干预的最佳适应症，建立有效病例筛选模式，开发敏感而特异的生物标志物，并通过体外实验探索Lp-PLA2影响BBB功能的机制，为开发改善BBB损伤新药验奠定基础。

Blood-Brain Barrier (BBB) dysfunction is an important pathological basis for stroke. Ischemic injury activates signaling in endothelial cells, increases BBB permeability, and impairs neurovascular unit (NVU) function. BBB injury is also associated with cognitive dysfunction in Alzheimer’s disease (AD). Protecting NVU function through inhibition of BBB deficits represents a new therapeutic strategy for multiple brain diseases. Lipoprotein-associated phospholipase A2 (Lp-PLA2) metabolites can damage vascular endothelial cells, promote inflammation and cytotoxicity, which may be related to BBB damage, but there is lack of sufficient evidence. Based on large-scale cohort study and its multi-omics database, the present study plans to evaluate the effect of altering Lp-PLA2 activity on BBB permeability using PET imaging. We will determine the best-suited brain disease(s) for Lp-PLA2 intervention, its patient seletion strategy, and relevant biomarkers for the disease progression and drug efficacy. Through in vitro experiments we will also explore mechanisms by which Lp-PLA2 regulates BBB function. Our study should provide a solid foundation for developing new medicines based on repairing BBB damage.