LncRNA HOXA-AS2调控帕金森病小胶质细胞极化的机制研究

小胶质细胞极化状态失衡介导的神经炎症反应在PD发病过程中有着重要作用，但调控机制还不清楚。我们前期发现炎症过程中PGC-1α表达受到抑制，并参与小胶质细胞极化；PD患者外周血中PGC-1α表达降低。为了明确小胶质细胞极化过程中PGC-1α表达降低的机制，前期预实验表明：1）lncRNAHOXA-AS2在PD患者和细胞炎症模型中表达增多；2）抑制lncRNAHOXA-AS2可以增加PGC-1α表达，减轻炎症反应。但lncRNAHOXA-AS2调控PGC-1α的机制及其在小胶质细胞极化中的作用尚不清楚。基于此，我们提出：小胶质细胞极化过程中，lncRNAHOXA-AS2一方面可能调控PGC-1α组蛋白甲基化水平，另一方面可能直接作用于PGC-1α，调控PGC-1α转录，在小胶质细胞极化中发挥作用。本课题拟探究与PD小胶质细胞极化相关的lncRNA及其作用机制，为PD的治疗提供新的策略和靶点。

Neuroinflammation mediated by imbalance of microglia polarization plays an important role in the pathogenesis of Parkinson’s disease (PD), however, the mechanism is still unclear. Our previous work found PGC-1α was down-regulated in conditions of neuroinflammatory injury and PGC-1α played a role in the regulation of microglia M1/M2 polarization. We also found PGC-1α was decreased in peripheral blood leukocytes of PD patients. To characterize the underlying mechanism of PGC-1α abnormalities in microglia polarization, our previous studies found that 1) LncRNA HOXA-AS2 was upregulated in PD patients and M1-polarized microglia. 2) LncRNA HOXA-AS2 interference in microglia promoted PGC-1α expression and alleviated LPS-induced inflammatory response. Therefore, we present a hypothesis that lncRNA HOXA-AS2 may regulate microglia polarization via histone modifcation of PGC-1α or bind to PGC-1α directly to modulate the transcription of PGC-1α. We intend to explore this issue by investigating the lncRNA involved in PD microglia polarization and its mechanism. This research may shed light on the potential treatment of PD.