EGFR协同丙酮酸激酶M2调控内毒素血症中有氧糖酵解的相关分子机制研究

申请者前期研究发现EGFR抑制剂erlotinib能够显著提高内毒素血症小鼠存活率，证实EGFR在内毒素血症中起到了至关重要的协同作用。以此为基础，我们深入发现erlotinib能够维持内毒素血症中线粒体膜电位水平、NAD+/NADH比值和ATP含量，提示EGFR可能参与调控内毒素血症中的能量代谢。通过代谢组学分析发现，erlotinib能减少糖酵解中间代谢产物和终产物的生成，进一步提示EGFR参与了内毒素血症能量代谢中的有氧糖酵解途径。随后我们又发现，这一效应可能与EGFR调控糖酵解途径的关键酶，丙酮酸激酶M2（PKM2）的磷酸化水平有关。以这些结果为切入点，本课题拟深入探讨EGFR通过PKM2调节内毒素血症有氧糖酵解途径的分子机制以及其他可能相关机制，从而从代谢角度进一步深入分析EGFR对内毒素血症的协同促进作用，为临床上内毒素血症的治疗提供更加有效的靶点。

Our previous studies have found that EGFR inhibitor erlotinib can significantly increase the survival rate of endotoxemic mice and confirmed that EGFR plays a crucial synergistic effect in endotoxemia. Based on these results, we further found that erlotinib can maintain mitochondrial membrane potential, NAD+/NADH ratio and ATP content in endotoxemia, suggesting that EGFR may be involved in the regulation of energy metabolism in endotoxemia. Metabolomics further analysis found that erlotinib can reduce the production of intermediate metabolites and end products of glycolysis, further suggesting that EGFR is involved in the aerobic glycolysis pathway of endotoxemia energy metabolism. we subsequently found that this effect may be related to the phosphorylation level of key pyruvate kinase M2 (PKM2) regulated by EGFR in glycolytic pathway. With these results as the starting point, this project intends to explore in depth the molecular mechanism of EGFR regulating aerobic glycolysis pathway of endotoxemia by PKM2 and other possible related mechanisms, so as to further analyze the synergistic effect of EGFR on endotoxemia from the perspective of metabolism and to provide a more effective target for the clinical treatment of endotoxemia.