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-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.

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。

帕金森病（Parkinson’s disease, PD）是一类由黑质致密部（SNc）多巴胺（dopamine, DA）能神经元的进行性丢失而导致运动功能紊乱为特征的常见神经退行性疾病。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PD的发生发展。小胶质细胞的活化主要分为两种表型即经典激活M1型（神经毒性型）和替代激活M2型（神经保护型）。小胶质细胞表型的变化及其介导的炎症反应是PD的重要病理机制。因此促进小胶质细胞由神经毒性型M1向神经保护型M2转化将是PD治疗的一个新方向。但是调节小胶质细胞表型转化的机制目前尚不清楚。因此，本项目拟应用已制备的Kir6.1敲减鼠和小胶质细胞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通道调节小胶质细胞表型的分子机制。研究发现，小胶质细胞Kir6.1缺失显著加重SNc区DA神经元的丢失及小胶质细胞的活化。进一步发现Kir6.1/K-ATP 通道促进PD进程中小胶质细胞由M1向M2转化，其机制可能是抑制p38-NF-кB信号通路激活及促进Jak-Stat6信号通路激活。抑制M1小胶质细胞转化，显著逆转Kir6.1缺失导致的PD病理损伤的加重。研究结果揭示小胶质细胞Kir6.1/K-ATP通道在PD发生发展中发挥重要的保护作用，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。

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