SHP-1通过TRAF6/RIPK1抑制毒性星型胶质细胞减轻脑缺血再灌注炎性损伤的机制研究

小胶质细胞诱导的毒性星型胶质细胞（A1型）的形成被认为是影响脑缺血后神经炎症的重要因素。挖掘调控A1型星型胶质细胞形成的关键分子靶点并阐明其作用机制是改善脑卒中的核心。我们前期发现SHP-1能抑制脑缺血再灌注损伤后的炎症反应，但机制不清。新近研究提示SHP-1参与小胶质细胞诱导的A1型星形胶质细胞形成。结合文献报道及课题组前期研究结果，本项目提出：SHP-1作为小胶质细胞诱导的A1型星形胶质细胞形成的重要负调控因子，可能通过调控TRAF6/RIPK1减少小胶质细胞分泌IL-1α，TNF-α和C1q，最终抑制A1型星形胶质细胞的形成，减轻脑缺血再灌注炎性损伤。本项目通过建立体内外大鼠脑缺血再灌注模型，应用多种分子生物学方法，从多个环节探究SHP-1对小胶质细胞诱导的A1型星形胶质细胞形成的调控作用及其在脑缺血再灌注炎性损伤中的作用机制，为缺血性脑卒中的防治提供新方向和新靶点。

Microglial induced neurotoxic astrocyte (A1) is believed to be a significant factor affecting neuroinflammation after cerebral ischemia. Searching for the key molecular targets regulating the formation of A1 astrocytes and elucidating its mechanism of action is the key of improving stroke. Our preliminary studies showed that SHP-1 can inhibit the inflammatory response after cerebral ischemia/reperfusion injury. However, the mechanism remains unclear. Further studies suggested that SHP-1 is involved in microglia induced A1 astrocyte formation. Combined with the existing literature and the previous research results of our team, this project proposed that SHP -1 as an important negative regulator of the formation of A1 astrocytes induced by microglia may be through regulating TRAF6 / RIPK1 to affect the production of IL-1α，TNF-α and C1q, eventually inhibiting A1 astrocytes formation, alleviating inflammatory injury. This study through the establishment of cerebral ischemia/reperfusion model in vivo and in vitro. Meanwhile, various molecular biology methods were used to investigate the regulatory effect of SHP-1 on microglia induced A1 astrocyte formation and its mechanism in cerebral ischemia/reperfusion inflammatory injury, providing a new direction and a new target for the prevention and treatment of ischemic stroke.