PPARγ/p300介导的表观遗传调控促进小胶质细胞M2极化缓解脑出血后继发性脑损伤的作用机制

小胶质细胞在脑出血（ICH）后继发性脑损害的发生发展中发挥重要作用。我们前期研究发现，罗格列酮（RSG）激活PPARγ可增加小胶质细胞的吞噬能力并减轻继发性脑损害；既往研究表明，RSG激活PPARγ可促进小胶质细胞向M2极化，但机制有待阐明。PPARγ在IL-4反复刺激后可募集表观遗传调控复合物p300、RAD21并抑制信号转导和转录激活蛋白的活化，阻断相关炎症因子的产生。因此推测，RSG激活PPARγ治疗继发性脑损伤的机制可能是通过募集 p300、RAD21从而促进小胶质细胞M2极化而实现的。本研究拟在细胞水平及动物模型水平观察RSG促进小胶质细胞M2极化的分子机制；预期结果为RSG激活 PPARγ可募集p300、RAD21到小胶质细胞M2启动子区域，促进小胶质细胞M2极化，产生神经保护因子、减少炎症因子，从而减轻继发性脑损害。该项目的完成有望对脑出血的治疗提供新的策略。

Microglia plays important roles in the development of the secondary brain injury following intracerebral hemorrhage (ICH). Our previous studies demonstrated that activation of the PPARγ by administering rosiglitazone (RSG) could increase the phagacytosis of the microglia and decrease the secondary brain injury. The previously published studies showed that activating PPARγ by using RSG might promote the microglia to M2 polarization, but the mechanisms underlying the PPARγ-induced M2 polarization of the microglia are to be elucidated. Under recurrent stimulation of IL-4, the PPARγ could recruit epigenetic complexes p300、RAD21 to inhibit the activation of the signal transducer and activator of transcription protein 1(STAT1),and block the production of the STAT-associated inflammatory cytokines. So we postulate that the mechanism of activating PPARγ by using RSG for the treatment of secondary brain injury following ICH may be achieved by recruiting p300 and RAD21 to the promoter of the M2 area of the microgila and promoting the microglia M2 polarization. The present study takes the neurological function of the ICH model and microglia M1/M2 polarization associated cytokines as indicators, by regulating PPARγ, p300 and RAD21, observing the mechanisms underlying the RSG activates the PPARγ and promote the microglia M2 polarization and the protective effects of the RSG on neurons at the cellular level and the animal model level. The expected results are that the RSG could activate and promote the PPARγ to recruit the p300 and RAD21 to the promoter area of the microglia, promoting the microglia M2 polarization, producing neuroprotective cytokines and anti-inflammatory factors, and reducing inflammatory cytokines, thus reducing the secondary brain damage following ICH. The completion of this project is expected to provide new strategies for the treatment of ICH.