SIRT1营养感应的新关键调控因子及其在糖脂代谢稳态调控中的作用和机制研究

SIRT1作为营养感应蛋白在糖脂代谢的稳态调控中起重要作用。但SIRT1营养感应信号通路及其在疾病中的作用机制还有待进一步阐明，特别是SIRT1上游营养感应的新关键调控因子及其作用机制还有待研究和探索。本项目拟利用高通量测序技术对营养正常、缺乏和过剩状态下的小鼠肝脏组织和原代肝细胞的lncRNA表达谱和mRNA表达谱进行检测、差异分析和实验验证；接着从中筛选可以影响细胞内SIRT1去乙酰化酶活性，并可调节SIRT1蛋白水平、SIRT1体外酶活性或NAD+水平的营养感应lncRNA和蛋白；进而在细胞和动物水平深入研究候选的营养感应lncRNA和蛋白对糖脂稳态的调控作用，并探讨其是否通过SIRT1的相关机制发挥其调控作用。本项目的顺利实施将揭示SIRT1营养感应信号通路的新关键调控因子及其在糖脂代谢稳态调控中的作用和机制，并为营养感应相关疾病的预防和干预提供新的思路和线索。

SIRT1 plays an important role in regulating glucose and lipid homeostasis as a nutrient-sensing protein. However, the nutrient-sensing signal pathway of SIRT1 and its role and related mechanisms in the development of related diseases are still largely unknown. Especially some key regulators of the nutrient-sensing signal pathway of SIRT1 are yet to be investigated. This project aims to screen nutrient-sensing lncRNA and mRNA by high throughput sequencing with RNA samples from mouse liver and primary hepatocytes under normal, nutrient deficient and over-nutritional status. The differentially expressed lncRNA and mRNA will be validated by quantitative PCR, and subsequently will be applied to screen nutrient-sensing lncRNA and mRNA which affect the in vivo enzyme activity of SIRT1 accompanied with the change of SIRT1 protein level, in vitro enzyme activity of SIRT1, or inracellular NAD+ level. Then the effect of the candidate lncRNA and protein on glucose and lipid homeostasis will be investigated in vitro and in vivo, and whether SIRT1-related mechanisms are involved will also be investigated. This project will identify some novel key regulators of SIRT1 nutrient-sensing signal pathway, reveal their roles in glucose and lipid homeostasis, and elucidate the related molecular mechanisms, which will provide new clues for the prevention and intervention of nutrient-sensing related diseases.