IDH1突变在胶质瘤支链氨基酸代谢重编程中的作用和机制研究

Isocitrate dehydrogenase (IDH) mutation is the most important genetic alteration in lower-grade glioma (LGG). Recent researches suggested that IDH muation might contribute to the metabolic reprogramming in tumors, which was the critical step in the tumorigenesis of glioma. Recently, we found that: ① wildtype IDH1 promoted the transaminatin and gluconeogenesis of amino acids in liver; ② the levels of branched chain amino acids (BCAA) were significantly elevated in the brains of glia-specific IDH(R132H) knockin mice, and the expression of BCAT1 was lowered; ③ the catabolic rate of BCAA in the primary glia with mutant IDH1 was significantly reduced. The BCAA metabolism in brain is very active, and we believed that IDH1 mutation was involved in BCAA metabolic reprogramming in glioma, but the mechanism and biological significances need to be further explored . Based on our previous studies, we will analyze the IDH1(R132H) knockin mice and primary glia, to clarify the roles and mechanism of IDH mutation in reprogramming BCAA metabolism in glioma. Furthermore, combining with the genetic alterations of LGG, we will further explore the biological significances of BCAA metabolic reprogramming in the tumorigenesis of IDH-mutant glioma. This study is not only helpful for us understanding the tumorigenesis of glioma, but also provide research foundation for developing new therapeutic strategy.

异柠檬酸脱氢酶（IDH）突变是较低级别胶质瘤最重要的遗传学改变。最新研究认为，IDH突变直接参与肿瘤代谢重编程，并可能是肿瘤发生的重要环节。我们最近发现：① 野生型IDH1能够促进肝脏氨基酸的转氨作用；② 胶质细胞IDH1（R132H）敲入小鼠脑组织内支链氨基酸（BCAA）含量显著升高，且BCAT1表达降低；③IDH1突变的原代胶质细胞中BCAA分解代谢速度显著降低。由于BCAA在脑组织代谢活跃，我们认为IDH1突变直接参与胶质细胞BCAA代谢重编程，但具体机制和生物学意义仍有待深入。本研究在已有的工作基础上，利用IDH1（R132H）敲入小鼠和原代胶质细胞等，在体内外明确IDH1突变调控胶质细胞BCAA代谢中的具体作用和机制，并结合较低级别胶质瘤的遗传特点，确定IDH1突变导致的BCAA代谢重编程在胶质瘤发生中的作用。本研究不仅有助于认识胶质瘤的发生，也为探索新的治疗手段提供研究基础。

IDH1/2突变是胶质瘤中的重要的遗传学改变，支链氨基酸代谢是胶质瘤中重要的代谢过程。我们在本课题研究中发现IDH突变导致小鼠脑发育异常，脑组织代谢异常，特别是支链氨基酸（BCAAs）以及与其密切相关的谷氨酸，三羧酸循环代谢过程。进一步，在原代胶质细胞以及U87胶质瘤细胞的基础上，我们发现IDH突变导致TCA循环和支链氨基酸代谢都发生了改变。IDH突变的细胞中BCAAs分解代谢降低，谷氨酰胺谷氨酸脱氨作用增强，而α-KG作为支链氨基酸转氨酶（BCAT）催化的重要底物，对BCAT的活性具有重要的调节作用，我们的研究结果证实：在IDH突变的胶质（瘤）细胞中，BCAT催化的支链氨基酸分解代谢与谷氨酸以及三羧酸循环代谢偶联发挥代谢调节作用，并且其催化活性具有显著的底物依赖特性。本研究对深入理解IDH1突变胶质瘤支链氨基酸代谢重编程提供了重要的数据和理论支持。