USP22调控癌症代谢重编程的分子机制及生物学功能研究

代谢异常是诱发癌症的关键因素之一，但其发生和时空感应具体分子机制仍是不解之谜。我们前期研究发现，去泛素化酶USP22可扰动癌症代谢重编程，但具体的调控分子机理尚不清楚。因此，揭示USP22去泛素化酶调控癌症代谢重编程及感应新分子机制解析是本研究的核心内容。旨在借助细胞分子生物学、生物化学和高分辨代谢组学、蛋白组学等方法和技术的交叉运用，检测USP22调控的癌症代谢紊乱，鉴定与USP22相互作用并作为底物的癌症代谢通路关键生物分子，解析USP22调控去泛素详细分子机制及作用位点，揭示USP22为核心的调控癌症糖脂代谢网络的蛋白质机器。通过细胞生物学研究USP22调控糖脂代谢通路对细胞恶性生物学行为的影响，阐明生理病理过程中USP22的生物学功能。结合临床病理特征和数据，分析USP22与本研究中新发现糖脂代谢信号通路的相关性，最终为USP22临床转化应用提供科学依据。

Cancer metabolism is one of the critical factors for cancer progression. However, the molecular mechanism for its occurrence is still unknown. Our previous study has detected that the deubiquitinating enzyme USP22 contributes to the reprogramming of cancer metabolism, but the specific molecular mechanism remains unclear. Therefore, this project attempts to reveal the latent mechanism based on a series of biological techniques including molecular cell biology, biochemistry, high resolution metabolomics as well as proteomics. We will detect the USP22 regulated metabolic disorder and identify crucial USP22-interacting substrates which play key roles in cancer metabolic process. Furthermore, the specific deubiquitinating mechanism and the corresponding acting sites will be illustrated. Finally, the protein machinery with USP22 as the core will be revealed which regulates the cancer metabolism. Besides, the influence on the malignant cell biological behaviors, and the biological function of USP22 in physiological and pathological processes will be elucidated. Moreover, combined with clinical pathological features we will investigate the relevance of USP22 and newly-discovered cancer metabolism signaling pathways in this study. Taken together, the proposed study will provide new insights into the role of USP22 in cancer metabolism, and provide scientific rationalities for clinical application of USP22.