Nrf1/2介导氧化还原信号-代谢-靶基因关联细胞器互作网络差异调控炎症-癌症及其病理转化的机制研究

Nrf2是公认抗氧化转录因子，但其负调控Keap1的不同亚型分子未鉴定。而Nrf1是一个不可或缺的跨膜转录因子，管控细胞氧化还原稳态、内质网-核膜-线粒体稳态、脂糖-蛋白代谢稳态，确保组织器官发育生长，介导抗炎症、抗癌变等过程。该项目集"干湿实验"交叉研究优势，在已建有的模式细胞系和动物平台上，构建Nrf1/2介导氧化还原代谢-靶基因关联细胞器互作的内源性核心网络。1) 明确Nrf1/2-ARE调控抗氧化应答-代谢通路与核呼吸因子α-Pal/NRF1-TFAM-线粒体网络的交互对话，决定从糖酵解为主的增殖状态向氧化性分化状态切换以及肝细胞EMT转化；反之，阐明Nrf1/2缺失导致Warburg效应原理。2) 解析Nrf1/2-介导网络模型对线粒体应激及内质网应激所造成的氧化还原代谢流在炎癌转化与对策性判断预测；3）分子内源性网络动力系统的研究，将提供新概念设计靶点联合化学干预的优化方案。

Nrf2 is commonly accepted as a master antioxidant transcription factor belonging to the CNC-bZIP family, but distinct isoforms of its negative regulator Keap1 have not been identified so far. Nrf1 is an indispensable transmembrane transcription factor, essential for the homeostatic regulation of cellular redox state, the endoplasmic reticulum transported to the nuclear membrane to enter the nucleus before regulating cognate ARE-driven genes, which governs .mitochondrial function and redox metabolisms of glucose, lipid and protein. Importantly, Nrf1 is also required for maintaining the normal development and growth of organs with their integrity, and also mediates anti-inflammatory, anti-apoptosis, anti-aging, anti-cancer and other patho-physiological processes. The proposal project has built on the solid base of our established model cell lines and animal platforms with specific diseases, in combination of the cross-disciplinary advantages of cutting-edge technologies employed in "dry and wet experiments", aiming to construct an endogenous core network of Nrf1/2-mediated redox metabolisms and target genes-regulated organelle interactions. Herein, Nrf1 is hypothesized as a key checkpoint of redox metabolism and antioxidant response. The interactions of membranous organelles is the main research topic, because redox cycling and metabolism are compartmentalized by relevant organelles. For this end, we have proposed to construct this core endogenous network mediated by Nrf1/2 as a hub, which also regulates the composition of membrane-lipids, membrane-proteins and specialized functional proteins within distinct organelles...The objective aims of this project are to: 1) To clarify the cross-talks between Nrf1/2-mediated antioxidant response signalling andα-Pal/NRF1-TFAM-governed mitochondrial network, and to determine the transition from glycolysis-dominated proliferation to oxidative differentiation and the EMT transformation of hepatocytes; on the contrary, the principle of Warburg effect caused by Nrf1/2 deficiency remains to be elucidated. 2) To analyze the prediction of Nrf1/2-mediated network model on the redox metabolic flow caused by oxidative stress, mitochondrial stress or endoplasmic reticulum stress during the transformation of inflammation into carcinogenesis, which facilities to countermeasure the judgment and prediction. 3) This study of molecular endogenous network dynamical system with animal experiments will provide a new concept to design the optimal scheme of combined targets for the optimal chemical intervention from cancer.