课题组最近研究发现，脑源17β-雌二醇 (BDE2) 合成的关键酶Aromatase (Aro) 在损伤的大脑高表达，且BDE2 可启动天然免疫反应，降低神经元继发性凋亡。因此，揭示BDE2的作用机制、探索诱导BDE2的有效策略对治疗神经退行性疾病至关重要。本研究采用手术绝经大鼠全脑缺血模型，以雌激素膜受体GPR30为切入点，探索其特异激动剂G1上调Aro/BDE2、并协同作用降低神经炎症的分子机制。研究验证以下假设：1)G1通过GPR30上调海马Aro表达及活性，降低神经元迟发性凋亡；2)G1与BDE2协同作用于GPR30降低星形胶质细胞增殖及炎性小体形成，促进抗炎因子表达；3)G1协同BDE2促进小胶质细胞M2表型极化，促进神经元修复；4)AKT/PTEN信号通路是BDE2与G1协同作用降低脑缺血损伤的重要机制。此研究旨在揭示GPR30和BDE2抗脑缺血损伤的新功能，具有医学转化价值。

Our recent studies have shown that aromatase (Aro), the key enzyme to synthetize 17β-estradiol exhibits high expression in the injured brain, and the brain-derived estradiol (BDE2) triggers innate immunity response to protect against secondary neuronal apoptosis. Translationally, an important goal would be to identify mechanisms and potential therapies that can induce BDE2 in the brain so as to provide endogenous CNS protection from secondary apoptosis that occurs in neurodegenerative disorders. In pursuance of this goal, we are going to focus on the membrane estrogen receptor GPR30 that might be an important novel regulator of BDE2 in the brain, and examine the potential synergistic action between GPR30 specific agonist G1 and BDE2 to attenuate inflammatory injury following global cerebral ischemia (GCI) in surgical menopausal rats. The aims of our study would thus test the following hypotheses: 1)G1 replacement upregulates Aro protein expression and activity in the hippocampus through a GPR30-mediated mechanism, which decreases the secondary apoptotic neuron; 2)Synergistic action between G1 and BDE2 targets GPR30 activation to attenuate astrogliosis and inflammasome formation, as well as enhance anti-inflammatory cytokines; 3)Synergism between G1 and BDE2 also promotes microglia polarization from M1 to M2 phenotype, which favors neuronal repair following GCI; and 4)The AKT/PTEN-NFkB rapid signaling pathway induced by GPR30 is an important mechanism to provide neuroprotective and repair roles for synergism between G1 and BDE2 following GCI. If successful, the proposed studies could significantly advance the field by revealing novel functions of GPR30 and BDE2 against cerebral ischemic injury, which could have important translational significance.