高氨基酸代谢介导核苷酸合成关键酶ATIC的表观修饰在肠息肉发生中的机制研究

The Frontier achievements of metabolic research show that amino acids are important signaling molecules that regulate various pathophysiological processes, and their metabolic abnormalities are involved in the occurrence of major serious diseases. The incidence of colonic polyps is high, and the mechanism of their formation and recurrence is unknown. Preliminary evidence indicates that high amino acids metabolism may play an important role in the process. We found that found that high glycine and serine levels in patients with colon polyps, and ATIC has been low methylation. It is suggested that high glycine/serine metabolism leads to the epigenetic modification of ATIC that may involve the formation of polyp. In recent years, numerous studies have found that mTOR signaling pathway is an important amino acid sensing signaling pathway. We found that mTOR signaling was significantly activated in polyp, and its downstream molecules were associated with the ATIC transcription. Based on the above, we hypothesized that high glycine/serine metabolism activate the mTOR signaling to regulate the epigenetic modification of ATIC, then promote the synthesis of nucleotide and largely consumption of methyl donor, led to lower DNA methylation, eventually led to formation and recurrence of polyps. We plan to further explore the role of amino acid metabolism in colorectal polyps in the organoids model of proliferative colorectal polyps, which is first established by our research group. The results of this study are expected to elucidate the mechanism of polyp formation and recurrence from the perspective of amino acid metabolism, so as to provide a new perspective for preventing colorectal polyps.

代谢研究的前沿成果显示氨基酸是重要的信号分子，调控多种病理生理过程，其代谢异常参与人类重大疾病的发生。大肠息肉发病率高，形成及复发机制不明，初步证据显示或与高氨基酸代谢相关。申请人发现，肠息肉患者体内两种参与核苷酸合成的氨基酸，即甘氨酸与丝氨酸水平升高，且核苷酸合成关键酶基因ATIC呈低甲基化，提示高氨基酸代谢导致的ATIC表观修饰异常可能参与息肉的发生。mTOR系已知最重要的氨基酸信号感知通路，申请人发现其下游分子在息肉中明显活化，或与ATIC转录相关。据此提出假说：高甘氨酸/丝氨酸通过mTOR调控ATIC的表观修饰，促进核苷酸的大量合成，进而大量消耗体内甲基供体，导致DNA甲基化水平降低，最终促进息肉形成及复发。进一步研究拟基于申请人建立的具增殖能力的肠黏膜类器官模型验证该假说，探究氨基酸代谢在肠息肉发生中的作用。研究结果有望从代谢角度阐明息肉形成及复发机制，为预防肠息肉提供新视角。

代谢异常参与人类重大疾病发生，大肠息肉复发率高，形成及复发机制不明，本研究拟从代谢角度阐明其机制，为预防及治疗提供新视角。通过构建人肠息肉类器官模型及生物样本库，研究肠息肉的代谢及表观遗传特征，并进行二甲双胍调控糖代谢抑制肠息肉生长的功能及机制研究。研究成果包括：①构建肠息肉类器官生物库，其形态分子特征与体内肠息肉高度一致；②结直肠腺瘤WNT信号通路、花生四烯酸代谢通路、亚油酸代谢通路上调，并发现WNT2在结直肠腺瘤中高表达，可作为结直肠腺瘤的诊断标志物；③结直肠腺癌中CBX2启动子低甲基化，正常黏膜-息肉-癌组织中CBX2表达水平逐渐升高，CBX2可作为肠息肉的诊断标志物；④阐释了二甲双胍调控肠腺瘤糖代谢的机制，二甲双胍通过NOX1影响腺瘤糖酵解活性，从而抑制腺瘤类干性和增殖，并于体内证实了二甲双胍对肠腺瘤的潜在治疗效果。研究意义：通过构建肠息肉类器官生物库，揭示了肠息肉的代谢和表格遗传特征，发现了肠息肉的诊断标志物WNT2和CBX2，同时为肠息肉干预策略提供新视角。