利用iPS来源的小胶质细胞模拟神经炎症在帕金森病发生中的作用及机制研究

小胶质细胞介导的促炎反应是帕金森病（PD）发病过程中的关键助推因素。我们先前研究证实小胶质细胞响应不同刺激，可以分别极化为促炎性表型（M1型）和抗炎性表型（M2型），并探讨了M2型极化的神经保护作用和表观遗传性机制。LRRK2G2019S是PD常见的致病基因突变，研究发现其与M1型促炎反应密切相关，然而其对M2型极化的影响尚不明确。基于此，本项目将利用PD病人来源的携带LRRK2G2019S的诱导性多能干细胞（iPS）分化为小胶质细胞（iPS-MGs），来模拟M1/M2分型并探讨LRRK2G2019S对M2型极化的作用；进一步通过高通量分析方法，系统的发掘其调控小胶质细胞分型潜在的新靶标和新通路；同时通过细胞移植验证M2型iPS-MGs在PD小鼠中的神经保护作用。本研究将构建PD特异性iPS-MGs模型，对研究具神经保护作用的炎症新机制，改善PD体内促炎微环境具有重要的指导意义。

Microglia-mediated proinflammatory responses is a critical contributor in the pathogenesis of Parkinson’s disease (PD). We previously demonstrated that microglia can be polarized into proinflammatory phenotype (M1) and anti-inflammatory phenotype (M2) respectively upon different stimuli, and we also dissected the neuroprotective effects and epigenetic mechanisms of M2 polarization. As one of the most common pathogenic gene mutations, LRRK2G2019S is reported to be associated with M1 polarization, however, whether it also regulates M2 polarization remains elusive. Therefore, in this project, we propose to differentiate PD patient-derived induced pluripotent stem cells (iPS) harboring LRRK2G2019S into microglia (iPS-MGs), so as to model M1/M2 polarization and meanwhile investigate the functions of LRRK2G2019S in M2 polarization. By virtue of high-throughput technologies, we will further systematically figure out the potential downstream gene targets and novel pathways that may regulate LRRK2G2019S-mediated M1/M2 polarization. We also plan to transplant induced iPS-MGs into PD mice models, and examine the neuroprotective effects of M2 iPS-MGs in PD pathogenesis. This study will generate PD-specific iPS-MGs models, which will provide new insights into dissecting the neuroprotective mechanisms of PD-specific microglia, and is also of great significance to learn how to ameliorate proinflammatory milieu of PD.