IDH1/2突变是胶质瘤最重要的遗传学改变之一。突变型IDH1/2能够催化α-酮戊二酸（α-KG）转变为癌代谢物2-羟基戊二酸（2-HG），而2-HG与肿瘤表观遗传学改变密切相关。我们最近研究发现，IDH1突变胶质瘤细胞的生长依赖培养液中谷氨酰胺（Gln）水平，且IDH1突变肿瘤细胞和胶质细胞对Gln缺乏均更加敏感。此外，IDH1突变原代胶质细胞的Gln消耗速度增加，且Gln代谢相关分子表达水平明显改变。这些结果表明，IDH1突变能够增强胶质瘤的谷氨酰胺依赖（Addiction），但尚不清楚其在胶质瘤发生中的作用，以及产生的主要机制。本研究将分析IDH1突变增强胶质瘤谷氨酰胺依赖的程度和关键步骤，阐明发生的代谢机制，并研究干预谷氨酰胺代谢能否应用于IDH1突变胶质瘤的治疗。本研究对认识IDH1/2突变在胶质瘤发生中的作用具有重要意义，也为IDH1突变胶质瘤的治疗提供的靶途径和靶分子。

Isocitrate dehydrogenase 1/2 (IDH1/2) mutation is one of the most frequent genetic changes in Grade II and III glioma. Mutant IDH1/2 gains a new enzymatic activity, and reduces α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2HG) instead of converting isocitrate to α-KG. This competitive inhibition of α-KG by 2-HG causes widespread epigenetic changes, suggesting that 2-HG may function as an oncometabolite. Our recent results showed that IDH1(R132H) mutant colon cancer cells and IDH1(R132H) overexpressing glioma cells were more sensitive to the deprivation of glutamine compared to control cells. Moreover, the primary glial cells with IDH1(R132H) mutation consumed more glutamine, and also become more sensitive to the deprivation of glutamine, and these enzymes involved in glutamine metabolism were changed. These data indicated that IDH1 mutation could enhance the glutamine addiction. However, the details and roles of glutamine addiction enhanced by mutant IDH1 are still unknown, and the metabolic mechanism should also be clarified. Using IDH1 mutant glioma, IDH1(R132H) knock-in mouse and glioma cells with overexpressed IDH1(R132H), we will determine the degree and critical processes of glutamine addiction induced by DH1 mutation, and illuminate how IDH1 mutation enhance the glutamine addiction in glioma, and discuss whether intervention of glutamine metabolism could be used in the therapy of IDH1 mutant glioma. These results should be helpful for us to clarify the significance of IDH1/2 mutation in glioma, and to identify new metabolic targets for the therapy of IDH1 mutant glioma.