GPNMB/ADAM10/TNF-α信号环路在蛛网膜下腔出血后早期脑损伤中的作用及机制研究

蛛网膜下腔出血（SAH）是出血性卒中的一种，其致死率、致残率高，目前无有效治疗手段。SAH的致脑损伤机理不明，近年来国内外学者用早期脑损伤（EBI）解释，炎症反应是EBI最重要的基本病理过程之一。最新的研究表明，GPNMB有抗炎作用，ADAM10有促炎作用，ADAM10还可直接激活TNF-α和GPNMB。本团队前期研究发现，SAH后GPNMB和ADAM10表达显著升高；SAH后1小时给予GPNMB重组蛋白或ADAM10抑制剂能显著改善小鼠神经功能，减轻脑水肿。基于这些，我们提出假说：SAH发生后给予外源性GPNMB或ADAM10抑制剂治疗能使GPNMB/ADAM10/TNF-α信号环路调节的炎症平衡向抗炎方向转化，减轻EBI期炎症反应，改善小鼠预后。本项目通过建立小鼠SAH模型和原代胶质细胞SAH模型，运用多种实验手段验证该假说，为将来临床药物研发提供潜在的靶点。

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke with high mortality and disability rate. Unfortunately, there is no effective treatment currently, and the mechanism of brain injury caused by SAH is still unknown. However, in recent years, many scholars have proposed the concept of early brain injury (EBI) to explain such mechanism, and regarded the inflammation as one of the most important basic pathological processes of EBI. The latest research shows that GPNMB has anti-inflammatory effects, while ADAM10 has pro-inflammatory effects, and ADAM10 can also activate TNF-α and GPNMB directly. Previous studies by our team found that the expression of GPNMB and ADAM10 significantly increased after SAH; the administration of recombinant GPNMB protein or ADAM10 inhibitor 1 h after SAH could significantly improve the neurological function and reduce brain edema after SAH induction in mice. Based on these, we have proposed the hypothesis that the administration of exogenous GPNMB or ADAM10 inhibitor after SAH can drive the inflammatory balance which is regulated by the GPNMB / ADAM10 / TNF-α signaling loop to the direction of anti-inflammatory property, and thus alleviate the inflammation in the EBI phase, and consequently improve the outcomes of mice. By establishing both a mouse model and a primary glial cells model, this project will be conducted in vivo and in vitro, using a variety of methods to confirm our hypothesis, and to provide potential targets for drug development in the future.