脑组织中含有大量胆固醇，其主要依赖胶质细胞的从头合成。胆固醇代谢与胶质瘤的发生密切相关，也被认为是胶质瘤治疗的重要靶点。作为胶质瘤最重要的遗传学改变，异柠檬酸脱氢酶（IDH）突变不仅影响表观遗传，同时也直接参与糖脂代谢的重编程。我们最近发现，IDH突变显著增加胶质（瘤）细胞中胆固醇的含量，并上调合成和转运关键分子。此外，抑制胆固醇合成或降低细胞内胆固醇，均能显著抑制IDH突变胶质瘤细胞的生长，但IDH突变对胶质瘤胆固醇代谢的具体影响，及其临床意义尚不清楚。在已有的工作基础上，我们拟利用人胶质瘤组织，探讨IDH突变胶质瘤中胆固醇的代谢特点；利用突变型IDH1敲入小鼠和胶质细胞，确定IDH突变调控胶质瘤胆固醇代谢的具体过程和分子机制，并探讨胆固醇对IDH突变胶质瘤的生物学行为和放化疗敏感性的具体影响。本研究不仅能扩展IDH突变在代谢重编程中的作用，也为探索IDH突变胶质瘤的治疗提供实验基础。

The brain contains large amount of cholesterol, which is derived from local de novo biosynthesis in glia. The dysregulations of cholesterol metabolism are involved in the development of glioma, and targeting cholesterol metabolism is becoming as a new strategy for treating glioma. As the most important genetic change in glioma, the isocitrate dehydrogenase (IDH) mutation not only alters the epigenetics, but also takes part in the metabolic reprogramming of both glucose and lipid. Recently, we found that IDH mutation could reduce the cholesterol levels in both glia and glioma cells. Moreover, the growth of IDH-mutated glioma cells was impeded when the cholesterol biosynthesis was inhibited or the intracellular cholesterol was reduced. These results indicated that the IDH mutation could alter the cholesterol metabolism in glioma, but the details of and clinical significances need to be further investigated. Based on the existing works, we will explore the characteristics of cholesterol metabolism in human IDH-mutated glioma tissues. Furthermore, using tissue-specific mutant IDH1 knock-in mice and the primary glia, the detail metabolic processes and molecular mechanisms will be investigated to explain how the IDH mutation regulates the cholesterol metabolism in glioma. Finally, the biological behaviors and the sensitivity to radiochemotherapy are evaluated in the IDH-mutated glioma after altering the cholesterol metabolism. This study will not only expand the roles of IDH mutation in the tumor metabolic reprogramming, but also provide experimental basis to develop the therapeutic strategies for IDH-mutated gliomas.