小胶质细胞的极性转化是脑卒中重要的病理机制之一。髓系细胞触发受体-2（triggering receptor expressed on myeloid cells 2，TREM2）是表达在小胶质细胞的免疫球蛋白受体，可能通过调节脑内免疫反应稳态而参与神经损伤病理过程。本项目拟在前期工作基础上，应用小胶质细胞条件性敲除TREM2、过表达TREM2-R47H等技术，从在体、离体和临床水平研究TREM2对小胶质细胞极化的动态调节在脑卒中进程和转归中的作用；阐明TREM2调节小胶质细胞极化的作用和机制。基于发现1-磷酸鞘氨醇（sphingosine-1-phosphate，S1P）可能通过与TREM2结合而调节其功能，研究、揭示S1P是TREM2的内源性配体，并以S1P为先导物合成、筛选靶向TREM2的调节剂。预期结果将为揭示脑卒中的病理机制及其防治提供新思路，为神经免疫调控剂的研发提供新靶标。

The polarization shift of microglia plays a key role in the pathogenesis of stroke. Triggering receptor expressed on myeloid cells 2 (TREM2) is a member of the immunoglobulin superfamily expressed on microglia in the brain. TREM2-mediated signaling pathways may participate in the pathological process of neural injury via regulating the immune response homeostasis in the brain. Based on our preliminary works that TREM2 could regulate microglial M1-to-M2 shift in the brain of ischemic mouse, the present study will use various research methods including conditional knockout of TREM2 in microglial cells, over-expressing TREM2-R47H, and establishing stroke models in in vivo and in vitro, to reveal the roles of TREM2 in dynamically regulating microglial polarization in the pathological process of stroke; to clarify the involved mechanisms of TREM2-mediated M1-to-M2 polarization of microglia. Based on our findings that sphingosine-1-phosphate (S1P) may regulate TREM2 function by binding with TREM2, we will further investigate whether S1P is an endogenous ligand for TREM2, and then use S1P as the precursor to synthesize the regulators targeting on TREM2. The expected results will provide new ideas and strategies for the prevention and treatment of stroke, and provide a new target for developing neuroimmunomodulators.