IDH突变胶质瘤代谢组学变化的调控机制和临床转化研究

胶质瘤致残率、致死率高，预后差，尤其是胶质母细胞瘤综合治疗后效果仍非常差。我们前期研究已证实胶质瘤是一种代谢异常性疾病，80%以上II、III级胶质瘤中都存在IDH突变，IDH突变胶质瘤具有独特临床特点和分子代谢机制，已被广泛应用于分子分型（获2018年教育部科技进步一等奖）。我们通过质谱研究发现IDH突变胶质瘤不仅2-HG特异性增高，还存在着代谢组学的特征性改变，包括proline、fumurate，尤其集中于尿素循环。Fumurate是尿素循环和三羧酸循环的连接点，本研究拟进一步研究IDH突变引起相应代谢组学变化的分子机制，并将尿素循环代谢物应用于MRS，作为术前诊断IDH突变的补充，同时针对尿素循环中的关键酶CPS1，拟通过CHIP研究琥珀酰化对其调控机制，通过同位素标记追踪代谢流方向，通过动物模型探索其抑制胶质瘤效果，实现代谢组学特征变化的临床转化。

Gliomas have high disability rate, lethality rate, and poor prognosis, especially for glioblastomas, GBM, after comprehensive treatment. Our previous studies have confirmed that gliomas are metabolic disorders. Over 80% of grade II and III gliomas have IDH mutations. IDH mutant gliomas have unique clinical characteristics and molecular metabolic mechanisms and have been widely used in molecular subtyping and classification (first prize of 2018 Ministry of Education Science and Technology Progress Award). Through mass spectrometry studies, we found that IDH mutant gliomas not only have a specific increase in 2-HG level, but also have characteristic changes in metabolomics, including proline and fumurate, especially in the urea cycle. Fumarate is the connection point between the urea cycle and the TCA cycle. This study intends to further investigate the molecular mechanism of the corresponding metabolomic changes caused by IDH mutations, and apply urea cycle metabolites to MRS as a supplement to preoperative diagnosis of IDH mutations. For the rate-limiting enzyme CPS1 in the urea cycle, it is planned to study the regulation mechanism of succinylation by CHIP, to track the direction of metabolic flow by isotope labeling, to explore the effect of inhibiting glioma through animal models, and to realize the clinical transformation of metabolomic characteristics.