Protein S对脑出血的保护作用及机制

脑出血是高致死性和高致残性的脑血管病，凝血酶是导致脑出血后脑水肿及病人死亡的重要原因。Protein S不仅是凝血酶生成的抑制剂，同时也是凝血酶的底物。本项目前期研究结果提示Protein S对脑出血具有保护作用，我们计划进一步明确该作用并探讨其具体作用机制。本项目通过检测Protein S对脑出血后血脑屏障通透性、脑水肿、继发性脑损伤的影响，证明Protein S通过保护血脑屏障减轻脑水肿进而减少脑出血继发性脑损伤。通过检测Protein S对凝血酶生成、活性及下游通路的影响，阐明Protein S不仅通过抑制凝血酶生成，还通过抑制凝血酶剪切激活PAR-1受体抑制血脑屏障组分降解和缩短微血管内皮细胞间隙，起到降低血脑屏障通透性的作用。本项目为发现脑出血的潜在治疗靶点提供科学依据，研究内容具有源头创新性和重要临床意义。

Spontaneous intracerebral hemorrhage (ICH) is a devastating disease with high rate of mortality and disability，thrombin is the leading cause of brain edema and death after intracerebral hemorrhage. Protein S is not only an inhibitor of prothrombinase which transform prothrombin to thrombin, but also the substrate of thrombin. Our preliminary results showed that Protein S was available to attenuate brain delayed injury after intracerebral hemorrhage, We will further explore the underlying mechanism. WE will apply several methods to test the effect of Protein S on blood-brain barrier permeability, brain edema, brain injury volume, degenerating neurons and neurological function, and prove that Protein S reduce brain edema through protecting blood-brain barrier delayed injury, ultimately attenuate delayed brain injury. Subsequently, we will utilize multiple technologies to detect the effect of Protein S on thrombin’s generation and thrombin’s activity, and proved that Protein S inhibits extracellular matrix components degradation and intercellular distance enlargement through suppressing PAR-1's cleavage by thrombin and inactivating downstream path PAR-1-RhoA-MMP-9 and PAR-1-RhoA-ROCK2-MLC, ultimately decreases BBB permeability. We hope that our innovative study would be beneficial for the advancement in prevention, diagnosis and therapy of ICH.