颅脑创伤后血脑屏障继发性损伤机制及干预

Traumatic Brain Injury (TBI) has extremely high disability and mortality. The prevention of the secondary brain injury is crucial for the management of TBI. However the mechanisms responsible for the secondary insult on blood brain barrier (BBB) during TBI remain unknown. It is believed that inflammatory and immune ressponse elicited by TBI play a major role in the compromise of BBB. Based on extensive clinical observations, our group has investigated the inflammatory responses and secondary brain damage. Our recent observations implied that the repair of damaged BBB is closely related with endothelial progenitor cell (EPC), and proinflammatory cytokines, regulatory T cell, vascular endothelial growth inhibitor (VEGI), and vascular endothelial growth factor (VEGF). In this proposal, we will further investigate 1) the relationship between secondary damage of BBB following TBI and the inflammation mediators; 2) the role of VEGI/VEGF imbalance in inducing the secondary damage of BBB; 3) the novel clinical treatment strategy of secondary damage on BBB, such as VEGI and EPC transfected by VEGI. The outcome of this proposal will deepen the knowledge of the mechanism of secondary damage on BBB injury, and pave the way for defining the new clinical strategy of TBI.

创伤性脑损伤（TBI）致残及致死率高。TBI后免疫炎症反应及其所致的血脑屏障（BBB）继发性损伤机制尚不明确，这也是阻断继发性脑损伤救治TBI的关键环节。近年来本课题组在大量临床观察的基础上，对TBI后免疫炎症反应及其所致的继发性脑损伤进行了开创性研究，初步发现调节性T细胞、血管内皮细胞生长抑制因子（VEGI）和血管内皮细胞生长因子（VEGF）等多种免疫炎症相关细胞和细胞因子，以及内皮祖细胞与BBB继发性损伤与修复关系密切。本项目将借助小鼠脑创伤模型、体外BBB模型和临床病例观察进一步研究：1.TBI后BBB继发性损伤与免疫炎症相关因子的关系；2.VEGI/VEGF失衡在BBB继发性损伤中的作用机制及其意义；3.应用VEGI及VEGI转染的内皮祖细胞，探索防治BBB继发性损伤的新策略。通过研究深化对TBI后BBB继发性损伤机制的认识，为建立TBI后继发性脑损伤的临床治疗新方法奠定基础。

脑创伤又称为创伤性脑损伤（Traumatic Brain Injury，TBI）是人类社会的常见病、多发病，其致残及致死率高，是45岁以下青壮年主要死因。TBI后免疫炎症反应及其所致的血脑屏障（BBB）继发性损伤机制尚不明确，这也是阻断继发性脑损伤救治TBI的关键环节。近年来本课题组在大量临床观察的基础上，对TBI后免疫炎症反应及其所致的继发性脑损伤进行了开创性研究，初步发现调节性T细胞、血管内皮细胞生长抑制因子（VEGI）和血管内皮细胞生长因子（VEGF）等多种免疫炎症相关细胞和细胞因子，以及内皮祖细胞与BBB继发性损伤与修复关系密切。本项目借助小鼠脑创伤模型、体外BBB模型和临床病例观察进一步明确了TBI后血脑屏障继发性损伤与一系列免疫炎症反应相关，证实了TBI后继发性血脑屏障损伤的机制与VEGF/VEGI平衡及VEGFR2的磷酸化有关，并在临床TBI患者中验证了VEGF/VEGI平衡与预后的关系；同时还探索了VEGI、microRNA21及Lac蛋白在其中发挥着保护性作用，是TBI治疗的潜在药物。并首次发现TBI后循环系统中脑源性细胞微粒（BDMV)、线粒体微粒（mtMVs）升高，并证实其是导致TBI后凝血功能紊乱、血脑屏障损伤及过度免疫炎症反应的重要因素之一，还证明了TBI后的凝血功能障碍和血脑屏障的开放与VWF-MVs复合物有关,该现象可由LAC蛋白缓解。本项目的结果为脑创伤后继发性血脑屏障损伤的机制探讨和临床治疗药物的开发提供了新的探索方向。