小胶质细胞GPR56在TBI后过度炎症反应及白质损伤中的作用及机制研究

小胶质细胞（MG）介导的过度炎症反应和白质损伤是脑外伤（TBI）后继发性损伤的重要原因，尚无有效治疗。G蛋白偶联受体-56（GPR56）调控外周炎症反应及髓鞘生成，其配体谷氨酰转氨酶-2（TG2）在TBI后显著升高。申请者已证实抗炎治疗促进TBI后MG向M2型极化，改善神经功能，TBI后小胶质细胞GPR56减少，敲除所有细胞的GPR56增加TBI后MG活化，加重白质损伤。鉴于MG高表达GPR56和TG2，故假说小胶质细胞GPR56结合TG2调节MG形态及功能，调控TBI后炎症反应及白质损伤。本研究拟通过MG特异性GPR56敲除小鼠、Gdc13删除M1型小胶质细胞、体外过表达GPR56 MG探明1）小胶质细胞GPR56通过调节M1/M2极化调控TBI后炎症反应及白质损伤；2）TG2能否通过自分泌方式结合小胶质细胞GPR56调节其极化及功能，调控髓鞘再生。有望为TBI治疗提供新的药物干预靶点。

Microglia (MG)-mediated excessive inflammation and white matter injury are important causes of secondary injury after traumatic brain injury (TBI), which lacks effective treatment. G-protein-coupled receptor-56 (GPR56) regulates peripheral inflammation and myelination. Transglutaminase-2 (TG2), the ligand of GPR56, increased significantly after TBI. We have confirmed that anti-inflammatory treatment promotes MG polarization to M2 subtype and improves neurological function after TBI. And microglial GPR56 expression decreases after TBI. Deletion GPR56 in all cell types results in increased MG activation and white matter injury after TBI. Given the high expression of GPR56 and TG2 in MG, we hypothesized that microglial GPR56 binds to TG2 regulating the inflammatory responses and white matter injury after TBI through modulating MG polarization and function. With microglia specific GPR56 knockout mice, deletion of M1-type microglia cells with Gdc13 and in vitro microglial GPR56 overexpression, we are aiming to study:1) Microglia GPR56 regulates the inflammatory responses and white matter injury after TBI by regulating microglia M1/M2 polarization; 2) whether TG2 can regulate MG polarization and function as well as remyelination by binding to microglial GPR56 in an autocrine way. It is expected to provide a new drug target for TBI treatment.