GPD1/G3P介导脂代谢重编程调控前列腺癌去势抵抗进程的研究

绝大多数前列腺癌经内分泌治疗后都不可避免地发展为去势抵抗性前列腺癌(CRPC)，CRPC患者10年的死亡率高达25.1%，目前仍缺乏有效的治疗措施。脂代谢重编程是驱动CRPC发生的关键能量代谢特征，但其机制仍然未明。前期研究中我们证明了GPD1高表达的前列腺癌患者预后差，GPD1可通过下游代谢产物G3P生成增多引起肿瘤细胞的脂代谢重编程从而促进肿瘤细胞的恶性进展。进一步预实验显示胞内G3P含量增多或异常增多会影响脂代谢重编程及肿瘤生长。本课题拟通过解决“GPD1/G3P如何调控脂代谢重编程及参与前列腺癌去势抵抗进程”这一关键科学问题来验证我们的科学假说，即“GPD1通过调节胞内代谢产物G3P生成增多从而驱动脂代谢发生重编程，进而影响前列腺癌去势抵抗的发生发展”。本项目主要采用CRPC模型、转录组及靶向脂质组学等方法，为阐明脂代谢重编程新机制和确立G3P作为CRPC新靶点提供科学依据。

The massive majority of prostate cancers inevitably develop into castration-resistant prostate cancer (CRPC) after endocrine therapy. The 10-year mortality rate of CRPC patients is as high as 25.1%, and there is still a lack of effective treatment. Lipid metabolism reprogramming is a critical energy metabolism feature that drives the occurrence of CRPC, and its mechanism is still unclear. In previous studies, we have proved prostate cancer patients with high expression of GPD1 have a poor prognosis, and GPD1 can cause lipid reprogramming by increasing the production of downstream metabolites G3P, thereby promoting the malignant progression of tumor cells. Further pre-experiments have shown that standard increase or abnormal increase of intracellular G3P content can affect lipid reprogramming and tumor growth. This project intends to verify our scientific hypothesis by solving the critical scientific question of "How does GPD1 / G3P regulate lipid metabolism reprogramming and participate in the process of castration resistance of prostate cancer". It means that GPD1 drives the lipid metabolism reprogramming by regulating the increased production of intracellular metabolites G3P, which in turn affects the development of castration resistance in prostate cancer. This project mainly uses CRPC models, transcriptomes, and targeted lipidomics to provide a scientific basis for clarifying new mechanisms of lipid metabolism reprogramming and establishing G3P as a new target for CRPC.