胃癌前病变（GPL）常继发于慢性萎缩性胃炎（CAG），该过程与有氧糖酵解（AEG）相关，而mTOR/HIF-1α/SIRT6是AEG调控关键通路。前期研究发现，GPL大鼠胃黏膜血管损伤导致缺氧、继发缺氧耐受，且HIF-1α、VEGF表达上调，提示AEG活性增强可能促进CAG向GPL转归，而健脾化瘀解毒方（健脾方）可逆转此过程。最新研究显示Atp4a-/-小鼠是CAG向GPL转归的稳定模型，但该小鼠是否存在AEG及所调控mTOR/HIF-1α/SIRT6通路的异常、以及健脾方对其是否有干预效应需深入研究。本项目拟采用Atp4a-/-小鼠模拟CAG向GPL转归，①分析Atp4a-/-小鼠是否存在AEG关键酶、转运蛋白及mTOR/HIF-1α/SIRT6通路的表型变化②探讨健脾方是否可逆转Atp4a-/-小鼠的疾病转归以及是否与AEG调控机制有关。为该方阻断CAG-GPL的临床应用提供实验依据。

Gastric precancerous lesions (GPL) often occurs secondary to chronic atrophic gastritis (CAG). CAG-GPL cascade is closely related to aerobic glycolysis (AEG) which is regulated by key mTOR/HIF-1α/SIRT6 pathway. Our previous studies indicated that vascular injury in gastric epithelium of GPL rats can cause hypoxia, and then result in hypoxia tolerance with a concomitant un-regulated HIF-1α and VEGF expression, suggesting that enhanced AEG activity may promote CAG-GPL progression. A Chinese herbal formula, named Jianpi Huayu Jiedu formula, can reverse the process. Latest studies showed that Atp4a-/- mice can be used as stable CAG-GPL mice model. However, mechanism of mTOR/HIF-1α/SIRT6 pathway-regulated AEG, and interventional mechanism of Jianpi Huayu Jiedu formula in Atp4a-/- mice need to be further studied. In the present study, Atp4a-/- mice is intended to use as CAG-GPL mice model, and then we plan to: ①investigate the phenotypic changes of the key AEG enzymes and transport proteins as well as mTOR/HIF-1α/SIRT6 pathway targets in Atp4a-/- mice; ②mainly explore the AEG-related interventional mechanism of Jianpi Huayu Jiedu formula in CAG-GPL progression of Atp4a-/- mice. The aim is to provide experimental evidence of clinical application of Jianpi Huayu Jiedu formula in blocking CAG-GPL progression.