苯丙氨酸代谢数量性状位点与结直肠癌发生风险的关联及机制研究

结直肠癌发病率高，预后差，严重危害人类的身体健康，但仍缺乏早期预警标志物。苯丙氨酸是人体必需氨基酸，申请人前期通过非靶向检测结直肠癌患者的血清代谢谱，发现苯丙氨酸是结直肠癌潜在的血清标志物。文献及本课题组研究表明，遗传变异（主要是SNPs）可通过调控代谢物而参与疾病的发生发展，但鲜有结直肠癌的相关报道。为此，我们推测遗传变异可靶向调控苯丙氨酸浓度，参与结直肠癌的发生。本项目拟采用分子流行病学方法、靶向定量检测和系统生物学信息分析，明确苯丙氨酸与结直肠癌发病风险的关联及其可能的交互作用，探究苯丙氨酸代谢相关遗传位点（mQLT）与结直肠癌易感性的关联；采用基因编辑、荧光素酶报告基因、染色体构象捕获、细胞表型实验等方法，初步阐明苯丙氨酸及风险位点参与结直肠癌发生的生物学功能及作用机制。该研究的结果可进一步揭示结直肠癌发病机理，明确高危人群，为实现结直肠癌早期风险预警和预防关口前移提供理论依据。

With the high incidence and poor prognosis, colorectal cancer seriously affects national health. However, it is still a lack of early detection biomarkers. Phenylalanine is an essential amino acid for the human body. Previously, we found phenylalanine is a potential serum metabolic marker for colorectal cancer by using a non-targeted metabolic detection method. Several studies and our study have shown that genetic variants (mainly SNPs) can participate in the occurrence and development of diseases by regulating metabolites, but there are few reports on colorectal cancer. For this reason, we suspect that genetic variation can regulate phenylalanine and participate in the occurrence of colorectal cancer. We plan to clarify the relationship of phenylalanine and its related SNP (mQTL) with the risk of colorectal cancer by using molecular epidemiological design, targeted quantitative detection, and system biology information analysis. The methods of gene editing, luciferase reporter gene, chromosome conformation capture, and cell phenotyping experiments will be further used to explore the genetic mechanism of phenylalanine. The results of this study can reveal the pathogenesis of colorectal cancer, identify high-risk groups, and provide a theoretical basis for early detection and prevention of colorectal cancer.