探索能量代谢异常的分子机制是当前肿瘤研究热点之一。晚期糖基化终产物受体（RAGE）是高迁移率族蛋白1（HMGB1）的受体，与肿瘤发生密切相关。自噬是一种保守的代谢信号通路，对能量代谢调节至关重要。项目组在《Leukemia》、《Autophagy》等期刊上首次报道HMGB1调节白血病细胞自噬的形成。申请者在此基础之上进一步提出"RAGE促进线粒体自噬、调控线粒体质量，以维持白血病细胞能量代谢和生长需求"的科学假说，并拟采用突变体构建、免疫共沉淀、电镜、共聚焦显微镜、实时生物能量代谢测定等研究手段，在分子、细胞和整体动物水平，探讨白血病细胞生长和应激时RAGE的亚细胞定位改变机制及其功能意义，其中RAGE如何调控能量产生以及线粒体自噬是研究重点。开展本项目可望揭示RAGE在肿瘤中的作用新机制，为能量代谢的研究开辟新的领域，为白血病的靶向治疗提供新的思路与实验线索，具有重要的转化医学意义。

Exploring the molecular mechanism of energy metabolism is one of the hot topic in cancer research. RAGE is a multiligand receptor that binds structurally diverse molecules, including not only HMGB1, but also S100 family members and amyloid-beta. HMGB1-RAGE pathway plays an important role in cancer development. Tumor cells activate autophagy in response to cellular stress and/or increased metabolic demands related to rapid cell proliferation. We have demonstrated that HMGB1 is an important autophagy regulator in leukemia cells. We hypothesize that RAGE promotes mitophagy and regulates mitochondrial quality to maintain metabolic demands related to rapid cell proliferation. To explore the structure, function and subcellular localization of RAGE in leukemia at the molecular, cellular and whole animal level, we will use several methods and tools including constructing mutants, co-immunoprecipitation, western blot, electron microscopy, confocal microscopy, and real-time biological energy metabolism determination. We hope to reveal a new function of RAGE in tumors, and provide new ideas and experimental clues for targeted therapy of leukemia, which is important for translational medicine.