Kir6.1/K-ATP通道对小胶质细胞表型的调控在帕金森病发生发展中的作用

ATP敏感性钾通道(K-ATP 通道)是机体内耦联细胞能量代谢和电活动的独特生物感受器。申请者所在实验室首先提出小胶质细胞表达Kir6.1 构成的 K-ATP 通道（Kir6.1/K-ATP通道），参与帕金森病（PD）的发生发展，我们近期研究发现Kir6.1/K-ATP通道可调节小胶质细胞表型，小胶质细胞不同的激活表型在PD的病理进程中均发挥着关键作用，其中M1小胶质细胞活化介导的神经炎性反应是PD的重要病理机制。因此，本项目拟在原有研究特色的基础上，应用已制备的Kir6.1敲除鼠和小胶质细胞Kir6.1 条件敲除鼠，在整体、细胞和分子水平系统研究Kir6.1/K-ATP通道对小胶质细胞表型的调节作用及其与PD的相关性，揭示小胶质细胞Kir6.1/K-ATP通道在PD发生发展中的作用，阐明Kir6.1/K-ATP 通道是基于小胶质细胞表型调节、研发神经保护剂的新靶标。

ATP-sensitive potassium (K-ATP) channels, which are hetero-octamers composed of pore-forming Kir6.x (6.1 or 6.2) subunits and sulfonylurea receptor (SUR1 or SUR2) regulatory subunits, couple cellular metabolism to electric activity. We first found that Kir6.1-composed K-ATP channels (Kir6.1/K-ATP channels) were highly expressed in microglia and participated in Parkinson's disease. Our recent results suggest that Kir6.1/K-ATP channel may modulate the microglial phenotype. Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either detrimental or beneficial effects in the central nervous system (CNS). Harnessing the beneficial properties of microglia cells by modulating their polarization states provides great potential for the treatment of Parkinson's disease (PD). However, the epigenetic mechanism that regulates microglia polarization remains elusive. Therefore, in the present study, the Kir6.1 knockout mice (Kir6.1-/-) and microglia conditional Kir6.1 knockout mice (Kir6.1loxp/loxp；CD11b cre) were used to investigate the effect of Kir6.1 on microglia phenotype that may contribute to the pathogenesis of PD. Our studies indicate that microglial Kir6.1/K-ATP channel is essential for the epigenetic modulation of microglia phenotypes in pathogenesis of PD. Thus, microglial Kir6.1/K-ATP channel might be a novel prospective target for the treatment of Parkinson's disease.