缺氧诱导的BPGM调控脑胶质细胞糖酵解的机制研究

Acute hypoxia in high altitude can cause abnormal change of function, energy metabolism and structure of brain tissues, and lead to high altitude brain edema and even death. The cellular energy metabolism reprogamming of brain cells is the phathophysilogical basis for these chagnes. Recent study reported that increased lactate produced by hypoxic brain gliacyte through glycolysis, could be uptaked by neuron cells and used as important substrates for TCA cycle and improve their fucntions. Our primary study found that 2, 3 diphosphoglycerate mutase (BPGM) displayed significanly higher levels under hypoxia compared with normoxia. Moreover, knock down of BPGM expression in hypoxic gliacyte could inhibit glycolysis and the product of BPGM, 2,3-DPG could induce HIF-1a expression and promote glycolysis phenotype. Based on the previous work, we conclude that hypoxia could up-regulate BPGM expression, and increase 2,3-DPG content and promote glycolysis by HIF-1a. And the increased lactate could be used by neurons as enery substrates. This study aims to investigate the hypothesis above in cells and animals to provide theorical basis for clarifying brain damage-protection mechanism and seeking effective theapeutic measurements.

急性高原缺氧可引起脑组织功能、代谢和结构异常改变，严重时发生高原脑水肿，甚至死亡，脑细胞能量代谢异常改变是其病理生理学基础。新近研究发现，缺氧时由脑胶质细胞糖酵解增强、产生增多的乳酸可被神经元摄取进入三羧酸循环，是缺氧神经元的重要能源底物。我们的初步研究提示，急性缺氧时脑胶质细胞中2, 3二磷酸甘油酸变位酶(2, 3-bisphospho-glycerate mutase，BPGM)表达显著升高、糖酵解增强，敲低BPGM后，糖酵解受到抑制；外源性增加BPGM的产物2,3-DPG可以诱导HIF1α的表达增加和糖酵解增强。我们推测，缺氧可能通过上调BPGM，使2,3-DPG生成增多进而通过HIF通路促进糖酵解，乳酸生成增多，为神经元提供能源底物。本项目拟在前期工作基础上，在细胞和动物水平，深入研究上述假说，为阐明缺氧脑损伤-保护的机制、寻找有效的防护措施提供理论依据。

急性高原缺氧可引起脑组织功能、代谢和结构异常改变，严重时发生高原脑水肿，甚至死亡，脑细胞能量代谢异常改变是其病理生理学基础。新近研究发现，缺氧时由脑胶质细胞糖酵解增强、产生增多的乳酸可被神经元摄取进入三羧酸循环，是缺氧神经元的重要能源底物。BPGM主要在红细胞中表达，介导1,3-DPG到2,3-DPG的关键酶，而2,3-DPG是红细胞中血红蛋白氧结合亲和力的负变构调节因子。本研究发现人星形胶质细胞（HEB细胞）缺氧后，糖酵解增强，同时BPGM表达上调，其代谢产物2,3-DPG增多。但是当敲低BPGM表达后，HEB细胞的糖酵解继续增强。过表达BPGM或者培养基中加入2,3-DPG后，糖酵解受到抑制。进一步研究显示，敲低BPGM可以上调HIF-1a和TET2，下调FIH-1；过表达BPGM或者加入2,3-DPG处理时，则改变相反。此外，缺氧的HEB细胞敲低BPGM后，ROS增加；加入2,3-DPG后，LDH降低。我们的研究提示上调的BPGM/2,3-DPG通路可以改善缺氧星形胶质细胞的缺氧损伤，其主要机制是通过抑制HIF-1a和TER2继而导致的抑制糖酵解效应。本工作揭示了缺氧星形胶质细胞代谢重编程的新机制，并为保护缺氧的神经元提供了新途径。