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。

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.