ATP-sensitive potassium channels (K-ATP channels) are unique biological receptors linking between cellular energetic and electrical excitability. We recently found that genetic inactivation of Kir6.2-containing K-ATP channels (Kir6.2/K-ATP channels) resulted in a protection of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons in the chronic MPTP and probenecid (MPTP/p) mouse model of Parkinson's disease, while the mechanism is still unclear. Therefore, based on the previous work, the aim of present studies is to investigate the role of Kir6.2/K-ATP channels on DA midbrain neurons in SNc, and the correlation with PD by using Kir6.2/K-ATP channels knockout mice in vivo and in vitro, then clarify the cellular and molecular mechanisms that Kir6.2/K-ATP channels knockout protects the degeneration of SNc DA neurons in midbrain. This study has provided useful ideas for clinical treatment of PD and raised a new target for the development of neuroprotective agents based on Kir6.2/K-ATP channels.
ATP敏感性钾通道(ATP-sensitive potassium channels,K-ATP通道)是机体内偶联细胞能量代谢和电活动的独特生物感受器。申请者前期发现Kir6.2亚基构成的K-ATP通道敲除对MPTP联合丙磺舒所致帕金森病(PD)模型小鼠中脑黑质致密部(SNc)多巴胺(DA)能神经元具有保护作用,但是Kir6.2/K-ATP通道的保护作用机制至今不清楚。本项目拟在前期工作基础上,应用已制备的Kir6.2敲除小鼠,在整体、细胞和分子水平系统研究Kir6.2/K-ATP通道对中脑SNc区DA神经元的调节作用及其与PD发生的相关性,阐明Kir6.2/K-ATP通道敲除对中脑SNc区DA神经元保护作用的细胞与分子机制,为PD临床治疗提供有益的思路,也为发展基于Kir6.2/K-ATP通道的神经保护剂提供新靶标。
帕金森病(PD)的病理特征是黑质致密部(SNc)多巴胺(DA)能神经元进行性丢失,其主要临床特征表现为静止性震颤、肌僵直和行动迟缓。PD病因目前不明,至今仍无一种确切的临床神经保护治疗举措。运用神经干细胞或祖细胞(NSC/NPCs)补充丢失和损伤的DA能神经元是一种很有前景的治疗PD的手段。然而在PD发病中调控NSC/NPCs增殖和分化的分子机制并不清楚。ATP敏感性钾通道(K-ATP通道)是机体内偶联细胞能量代谢和电活动的独特生物感受器,包括Kir6.1和Kir6.2两种亚基,其中Kir6.2亚基参与构成神经元K-ATP通道。我们研究发现Kir6.2亚基构成的K-ATP通道敲除(Kir6.2-/-)对MPTP/p PD模型小鼠在造模早期表现为中脑SNc区DA能神经元损伤加重,造模结束后7d中脑SNc区DA能神经元数目恢复到造模前水平。Kir6.2敲除抑制MPTP/p诱导的小鼠中脑SNc区α-synuclein积聚。另外,Kir6.2敲除增加MPTP/p PD模型小鼠造模后期Nurr1+细胞向TH+神经元分化的程度,促进MPTP/p PD模型小鼠SVZ/SGZ区神经干细胞增殖,抑制MPTP/p诱导的中脑miR-133b表达上调及其靶蛋白Pitx3/GDNF表达下降。说明Kir6.2敲除可以激活内源性的自我修复。我们进一步在体外培养Kir6.2敲除小鼠原代中脑神经元前体细胞,应用MPTP毒性代谢产物MPP+建立PD细胞模型,发现Kir6.2敲除逆转MPP+诱导的中脑NPCs增殖的抑制以及向神经元分化的抑制,Kir6.2敲除通过下调miR-133b来抑制Pitx3和GDNF的表达,上调磷酸化GSK-3β/β-catenin水平,从而促进神经元的分化。本研究揭示Kir6.2/K-ATP通道对中脑SNc区DA神经元的调节作用及其与PD发生的相关性,阐明Kir6.2/K-ATP通道敲除对中脑SNc区DA神经元保护作用的细胞与分子机制,为PD临床治疗提供有益的思路,也为发展基于Kir6.2/K-ATP通道的神经保护剂提供新靶标。
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数据更新时间:2023-05-31
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