酸化对巨噬细胞代谢途径再编程的调控研究

The metabolic reprogramming is required for macrophage differentiation. Resting macrophages depend on glycolysis and oxidative phosphorylation. M1 macrophages are characterized by high aerobic glycolysis. Glycolysis and glucose derived oxidative phosphorylation are required for the early differentiation of M2 macrophages. Extracellular acidosis is a common microenvironmental stress resulted from enhanced metabolism. The effects of acidosis on the function and intracellular metabolism of macrophages are still unknown. We hypothesize that acidosis upregulate the differentiation of M1 macrophages via enhanced aerobic glycolysis affiliated by activated acid-sensing ion channels, and downregulate the early stage differentiation of M2 macrophages via attenuated glucose derived oxidative phosphorylation caused by activated acid-sensing ion channels. We plan to investigate the regulation of acidosis on the metabolic reprogramming of macrophage differentiation using multiple methods including cell biology, molecular biology, mass spectrometry, Seahorse assay and so on.

巨噬细胞分化过程中伴随有获取能量主要来源的代谢途径再编程现象。静息巨噬细胞主要利用糖酵解和氧化磷酸化；M1巨噬细胞则利用有氧糖酵解；增强的糖酵解和葡萄糖来源的氧化磷酸化则为M2巨噬细胞早期分化所必须。酸化是人体生理活动中极为常见、因代谢变化所致的微环境改变，其如何反馈性调节巨噬细胞代谢和功能尚有待深入研究。本课题组推测：酸化通过酸敏感离子通道等上调M1巨噬细胞有氧糖酵解而增强其分化；其亦可因下调线粒体有氧磷酸化而阻碍M2巨噬细胞分化。本项目拟采用细胞生物学、分子生物学、质谱分析和实时检测细胞代谢变化等实验方法，研究酸化对分化过程中巨噬细胞代谢途径再编程的影响及其机制，以期为深入了解微环境变化调控天然免疫细胞代谢和功能提供线索。