FGF21调控小胶质细胞介导的神经免疫炎症促进2型糖尿病缺血性脑卒中后神经功能的修复

缺血性脑卒中是糖尿病的严重并发症之一，大约30%的脑缺血患者伴有糖尿病且90%为2型糖尿病（T2D）。T2D脑缺血患者脑损伤加重，具有较高的死亡率和严重致残率，其病理的一个主要特点是加重脑神经组织炎症反应，目前尚无有效的治疗药物。成纤维细胞生长因子21（FGF21）是新近发现的一个强效安全的糖脂代谢调节因子，具有强大的抗炎和组织修复功能。前期发现在小鼠T2D脑缺血模型中，重组人FGF21能抑制促炎性小胶质细胞激活，减少其脑梗死面积，促进神经功能恢复。本项目拟从体内和体外水平上验证：FGF21在改善T2D脑缺血后代谢异常的同时，通过激活小胶质细胞中FGFR1/β-klotho复合物，促进细胞核中PPARγ的活性和抑制NFκB的活性，对T2D脑缺血后小胶质细胞表型和功能进行调控，来维护免疫炎症微环境的稳态、修复神经元和突触的可塑性，从而促进脑功能的修复，为T2D脑卒中的治疗提供新的药物靶点。

Ischemic stroke is one of the most serious complications of diabetes, and about 30% of patients with cerebral ischemia are associated with type 2 diabetes mellitus (T2D). T2D ischemic stroke has severe brain damage, higher mortality and severe long-term disability rate. One of the main characteristics of cerebral ischemia in T2D is that the brain tissue is aggravated by pro-inflammatory reaction. Fibroblast growth factor 21 (FGF21) is a potent regulator of glucose and lipid metabolism, and it also has potent anti-pro-inflammatory and tissue repair functions. Our previous studies have shown that recombinant human FGF21 can inhibit the activation of microglia, reduce the area of cerebral infarction, and promote the recovery of neurological function of T2D stroke in mice. In this project, we will combine in vitro and in vivo experimental systems to test our hypothesis: after T2D cerebral ischemia, recombinant human FGF21(rhFGF21) functions in modulating abnormal metabolisms, while rhFGF21 activates FGFR1/ beta -klotho complexes in microglial cells, resulting in promoting cell nucleus PPAR gamma activity and inhibiting NFkB activity, consequently modulating microglia cell phenotype and function, in order to maintain the immune inflammatory microenvironment homeostasis, which benefits neuron repair and synapses plasticity, and finally leads to better neurological function recovery. This project will shed light on the key role of FGF21 in the regulation of synaptic plasticity and repair of neurological function through the regulation of microglial activation, and provide new drug targets for the treatment of T2D stroke.