肾透明细胞癌（ccRCC）转移率高、治疗耐药、预后差，被认为是细胞代谢性疾病，揭示其发生及耐药机制是ccRCC研究的关键。前期代谢组、蛋白质组、转录组联合分析显示，ccRCC谷氨酰胺（Gln）存在代谢重编程现象，并异于其他肿瘤，其来源、功能及分子机制值得深入探讨。本课题将通过临床标本检测、细胞及动物模型建立，阐明尿素循环失调是否为Gln积累的主要原因，以及Gln代谢是否具有中和乳酸、抵抗ROS并降低药物敏感性的功能。通过分子生物学检测，确定TGFβ1是否为ccRCC乳酸积累感受器，并通过“乳酸→HDACi→TGFβ1信号激活→ASS1表达降低及尿素循环失调→Gln代谢重编程→负反馈抑制乳酸过度堆积”方式协调有氧糖酵解与尿素循环，从而维持ccRCC代谢稳态并促进其恶性转化。本项目以多组学层面的代谢重编程为切入点，是代谢物感知与基因调控回路相结合的研究新视角，将为ccRCC有效诊疗提供新线索。

Renal clear cell carcinoma (ccRCC) is regarded as a disease of cell metabolism with high metastasis rate, drug resistance and poor prognosis. Therefore, the elucidation of mechanisms underlying ccRCC tumorigenesis and drug resistance is the core of ccRCC researches. In the preliminary conjoint analyses of metabolome, proteome and transcriptome data, we found that ccRCC might exhibit glutamine (Gln) metabolic reprogramming, which was different from most other tumors. Hence, the source, function and molecular mechanism of glutamine is potential for more profound investigation. In the present study, we attempt to unravel whether the urea cycle dysregulation is the main source of glutamine abnormal cumulation through detection of clinical specimens and the establishment of cell and animal models. Moreover, we plan to clarify the possible function of glutamine metabolic reprogramming on neutralizing lactate and reducing drug sensitivity by resisting ROS production. Additionally, we will determine whether TGFβ1 is the sensor of lactate accumulation in ccRCC, which coordinates aerobic glycolysis and urea cycle according the following mode: “Lactate→HDACi→aberrant TGFβ1 activation→ASS1 declination and urea cycle dysregulation→Gln metabolic reprogramming→inhibiting lactate excessive accumulation by a negative feedback loop”. This procedure maintains ccRCC metabolic homeostasis and promotes malignant transformation. Taken together, our project is based upon the systematic multi-omics analysis for metabolic reprogramming, which is a new perspective for researches on the combination of metabolite sensing and gene regulation. The results and achievements of this study will provide new clues for the effective diagnosis and treatment of ccRCC.