TIGAR与NOX调控线粒体自噬和ROS在神经退行性疾病发病机制中的作用

We previously reported that p53 induction contributed to excitotoxic neuronal death through apoptotic and autophagic mechanisms. Recent studies have revealed that TP53-induced glycolysis and apoptosis regulator (TIGAR) was a p53-inducible dual regulator of apoptosis and glycolysis, and played important roles in the pathogenesis of many diseases. However, it remains unknown what the roles and mechanisms of TIGAR signaling pathways in neurodegenerative diseases are. Our recent studies found that the protein expression level of TIGAR increased in KA-induced neuronal excitotoxicity. In addition, we found that inhibition of TIGAR before KA treatmeant could inhibit KA-induced upregulation of NADPH oxidase (NOX) and downregulation of mitochondrial membrane potential, and could ultimately protect neurons. Accordingly, we predicted that TIGAR might regulate neuronal excitotoxicity by NOX. Therefore, this project aims to sduty: (1) The roles of TIGAR and NOX in neuronal excitotoxicity; (2) The roles and mechanisms of TIGAR and NOX in regulation of neuronal energy metabolism and reactive oxygen species (ROS) generation; (3) The regulative roles and mechanisms of TIGAR and NOX in mitophagy, apoptosis, and the pathogenesis of neurodegenerative diseases. These studies will provide a new basis for elucidating the molecular mechanisms of excitotoxicity, and provide new ideas for the prevention and treatment of neurodegenerative diseases.

本课题组以往研究发现p53通过调节细胞凋亡和自噬在神经兴奋性毒性中发挥重要作用。近年研究发现，p53下游基因TIGAR是细胞凋亡和糖酵解的双重调节子，在多种疾病的发病机制中起重要作用。但在神经退行性疾病研究领域，TIGAR信号通路的作用和机制尚无报道。申请人最近工作发现，KA引起的神经兴奋性毒性伴随着TIGAR上调，在损伤神经元之前阻断TIGAR，可抑制KA引起的NADPH氧化酶 (NOX)上调、线粒体膜电位下降和神经元死亡，据此我们认为TIGAR可能通过NOX调节神经兴奋性毒性。本项目旨在研究：(1)TIGAR与NOX的表达在神经兴奋性毒性中的作用；(2)TIGAR与NOX调节神经元能量代谢和活性氧族(ROS)的分子机制；(3)TIGAR与NOX对线粒体自噬和凋亡通路的调节机制及其在神经退行性疾病发病机制中的作用。这些研究将为阐明神经兴奋性毒性的分子机制提供新依据，为防治神经退行性疾病提供新思路。

近年研究发现p53下游基因TP53诱导的糖酵解和凋亡调控因子（TP53-induced glycolysis and apoptosis regulator gene, TIGAR）是细胞凋亡和糖酵解的双重调节子，在多种疾病的发病机制中起重要作用。但在神经退行性疾病研究领域，TIGAR信号通路的作用和机制尚无报道。本研究发现，过表达TIGAR可逆转神经兴奋性毒素介导的动物运动功能障碍、神经元损伤和炎症因子的释放。NADPH氧化酶（NADPH oxidase, NOX）的失调激活被认为是自由基生成和炎症反应的主要调节因子。本研究构建了体内外神经兴奋性毒性模型，通过动物行为学、生物化学和细胞分子生物学等方法，对NOX参与调控TIGAR和神经兴奋性毒性进程中自噬和线粒体功能的分子机制进行了探究。结果显示NOX抑制剂夹竹桃麻素（Apocynin, Apo）和氯化二亚苯基碘鎓（Diphenyleneiodonium chloride, DPI）显著改善神经元生存率和神经行为学评分；抑制NOX可逆转神经兴奋性毒素介导的TIGAR下调、线粒体膜电位下降、超氧化物增多、能量生成减少和自噬激活。本研究为探讨TIGAR和NOX在神经退行性疾病中的作用奠定了基础，对认识TIGAR和NOX与线粒体功能之间的关系提供了新思路。

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