Mertk-Rac1信号通路调控紧密连接蛋白抑制蛛网膜下腔出血后血脑屏障损伤及其机制研究

Subarachnoid hemorrhage (SAH), which leads to high mortality and morbidity in human, is a common cerebral vascular disease in neurosurgery department. Emerging researches have elucidated that the significant increase of blood-brain barrier (BBB) permeability after SAH is highly associated with the occurrence of delayed ischemic neurological deficits (DIND) and poor outcome. Mertk belongs to receptor tyrosine kinase and expresses on endothelial cells in central nerves system (CNS). Recent studies have indicated that the activation of Mertk signaling pathway can effectively regulate the restoration of BBB injury in pathological conditions of CNS. The mechanism might be related to the effect on expression of tight junctions (TJs) by Rac1 which functions downstream of Mertk. We hypothesize that the expression and function of Mertk and its endogenous ligands might have changed under pathophysiological conditions after SAH, and this cause abnormal expression of TJs, which confers to increased permeability of BBB and appearance of DIND. By inducing experimental SAH model in rats, combining with the neurologic score assessment, and the technology of immunofluorescence, qRT-PCR, western blot and other detection on BBB injury, this study is to investigate the role of Mertk on BBB repair and its underlying mechanism, and to provide a potential therapeutic target for SAH.

蛛网膜下腔出血（SAH）是神经外科常见的脑血管病，具有高死亡率和致残率。越来越多的研究表明SAH后血脑屏障（BBB）通透性的显著增加与迟发性缺血性神经功能障碍（DIND）和临床不良预后的发生密切相关。Mertk属于酪氨酸激酶受体，可在中枢神经系统血管内皮细胞上表达。目前已有研究证实，在神经系统病理条件下，Mertk相关信号通路的激活可有效调控BBB损伤的修复，其机制可能与其下游Rac1活性影响紧密连接蛋白（TJs）的表达有关。据此我们推测，在SAH后特定的病理生理条件下可能存在Mertk及其内源性配体表达和功能的改变，使TJs表达异常，从而引起BBB通透性的增加，最终导致DIND的发生。本研究通过建立大鼠SAH模型，结合神经功能评分、免疫荧光、定量PCR、蛋白印迹、BBB损伤相关指标检测等技术观察Mertk的表达及功能改变对BBB修复的作用，并探讨相关机制，以期为SAH的治疗提供新的靶点。

蛛网膜下腔出血（SAH）是神经外科常见的脑血管病，具有高死亡率和致残率。越来越多的研究表明SAH后血脑屏障（BBB）通透性的显著增加与迟发性缺血性神经功能障碍和临床不良预后的发生密切相关。TAM属于酪氨酸激酶受体，可在中枢神经系统血管内皮细胞上表达。目前已有研究证实，在神经系统病理条件下，TAM相关信号通路的激活可有效调控BBB损伤的修复，其机制可能与其下游Rac1活性影响紧密连接蛋白（TJs）的表达有关。因此我们通过检测SAH模型后TAM受体及其内源性配体（Gas6和Pros1）的表达，评价Gas6和Pros1给药后神经功能及BBB的完整性，并通过TAM和Rac1抑制剂的应用，检测下游相关紧密连接蛋白的变化并探讨其中可能潜在的机制，得出以下结论。内源性Gas6和Pros1的表达水平在SAH后24h显著升高，外源性Gas6给药可显著改善SAH后的神经功能缺失，降低SAH后的脑水肿，同时维持SAH后BBB的完整性，而Pros1无此神经保护效果。Gas6通过激活TAM下游Rac-1调控升高TJs从而保护血脑屏障的完整性。本课题为今后SAH的治疗提供了新的思路与靶点。