ANGPTL8通过LILRB2/NF-κB通路促进造血干细胞老化及机制研究

热量限制(CR)即七分饱饮食是近年来被认为最有效的抗衰措施之一，研究表明CR可改善造血干细胞(HSCs)功能而延缓衰老，但机制未明。新发现的ANGPTL8基因调控能量代谢且在进食后高表达。前期发现敲除ANGPTL8明显延缓小鼠衰老且肝脏中造血分化基因表达改变，ANGPTL8蛋白能与HSCs分化发育相关分子LILRB2存在相互作用并激活NF-κB磷酸化，且使HSCs老化标志物表达上调。因而推测ANGPTL8可能通过LILRB2/NF-κB通路促进HSCs老化加速机体衰老，是CR改善HSCs功能抗衰的关键信号分子之一。因此拟收集不同年龄段人的血清及小鼠的血清和器官组织样本，分析ANGPTL8与衰老的相关性；体内外实验研究该基因对HSCs增殖分化及老化的影响；利用阻断或激活基因表达及免疫共沉淀等方法分析ANGPTL8促进HSCs老化的机制。本项目将为抗衰提供新的靶点。

Calorie restriction (CR) is one of the most effective anti-aging measures recognized in recent years. Studies have shown that CR can improve the function of hematopoietic stem cells (HSCs) and delay aging, but the mechanism remains unclear. ANGPTL8 is a newly discovered gene, which regulates energy metabolism and is highly expressed after eating. Our previous studies found that the knockout of ANGPTL8 gene significantly delayed the aging of mice, and the expression of hematopoietic differentiation genes was altered in the liver. Furthermore, we also found that ANGPTL8 protein could interact with LILRB2 which is a molecule related to HSCs differentiation and development, and ANGPTL8 protein could active NF-κB protein phosphorylation and up-regulate the expression of markers related to HSCs senescence. Therefore, we speculated that ANGPTL8 could promote senescence of HSCs and accelerate the aging of the body through the LILRB2 /NF-κB signaling pathway, and the ANGPTL8 may be play a important role in CR anti-aging. Therefore, we plan to collect serum samples from human and mice of different ages and tissues of various organs from mice to analyze the correlation between ANGPTL8 and aging. The effects of ANGPTL8 on the proliferation, differentiation and senescence of HSCs will be studied in vivo and in vitro. The molecular mechanism of ANGPTL8 promoting HSCs senescence through LILRB2/NF-κB pathway will be analyzed by blocking or activating gene expression and immunoprecipitation. This study will provide a new target for anti-aging.