Vitamin D Status, Genetic Variation in Vitamin D Signaling and Metabolism, and Ri

描述(由申请人提供)：流行病学调查表明，低水平的维生素D代谢物25(OH)D，激素1，25(OH)2D的前体分子，与大肠肿瘤的风险有关，尽管结果一直是模棱两可的，对于这些生物标记物的性别或结直肠亚部位特异性关系知之甚少。从功能的角度来看，1，25(OH)2D已在结直肠癌细胞系中显示出抗增殖、促分化和生长抑制作用。因此，有令人信服的证据表明，活性维生素D代谢物在降低大肠肿瘤风险方面发挥了作用，但在细胞水平上达到1，25(OH)2D最佳水平的最佳方法尚不清楚，维生素D受体(VDR)或组织水平上负责1，25(OH)2D代谢的主酶基因变异的功能影响也鲜为人知。初步证据表明，VDR中的SNPs可能会影响1，25(OH)2D的循环浓度；此外，两种酶，CYP27B1和CYP24A1，在该分子的代谢动态平衡中具有特别重要的作用。虽然已有研究对VDR的功能和流行病学相关性进行了研究，但很少有人研究这两个关键酶的遗传变异的分子或流行病学影响。此外，维生素D发挥化学预防作用的机制尚不清楚，尽管我们和其他团队的工作表明，APC、b-连环蛋白和1，25(OH)2D-VDR代表了结肠细胞增殖的细胞内调节的分子“十字路口”。这项拟议工作的具体目标是：1)测量结直肠腺瘤复发临床试验参与者循环中25(OH)D和1，25(OH)2D的浓度，并评估这些变量与腺瘤复发几率之间的关系；2)研究VDR、CYP27B1和CYP24A1基因的变异，评估SNPs与结直肠腺瘤复发几率和维生素D代谢物循环浓度的关系；3)阐明在人类Caco-2结肠细胞中，CYP27B1和CYP24A1基因的特定多态对功能的影响；4)研究VDR(和VDR多态变异体)与2-连环蛋白之间的分子串扰，以及APC对这些信号转导途径的功能影响。次要目标包括调查维生素D代谢物与腺瘤和晚期腺瘤复发之间的性别分层关联，以及评估这些关联是否因结直肠亚群而异。这项工作有可能通过改善维生素D的状态为结直肠癌的发生提供经济有效的预防措施，并阐明维生素D代谢关键酶的遗传变异的功能效应的新的分子证据，以及可能调节维生素D代谢物和VDR作用的信号通路，包括APC和b-catenin。

DESCRIPTION (provided by applicant): Epidemiological investigations have demonstrated that low serum levels of the vitamin D metabolite 25(OH)D, the precursor molecule for the hormone 1,25(OH)2D, are associated with risk of colorectal neoplasia, though results have been equivocal, and little is known about sex- or colorectal sub-site-specific relationships for these biomarkers. From a functional standpoint, anti-proliferative, pro-differentiating, and growth inhibitory effects of 1,25(OH)2D have been shown in colorectal cancer cell lines. Thus, there is compelling evidence that active vitamin D metabolites play a role in reducing the risk for colorectal neoplasia, but the best approach for attaining optimal levels of 1,25(OH)2D at the cellular level are not known, and the functional effects of genetic variation in the vitamin D receptor (VDR) or in primary enzymes responsible for metabolism of 1,25(OH)2Dat the tissue level are poorly understood. Preliminary evidence indicates that SNPs in VDR may influence circulating concentrations of 1,25(OH)2D;further, two enzymes, CYP27B1 and CYP24A1, are of particular importance in metabolic homeostasis of this molecule. Although there has been research into the functionality of and epidemiological associations of the VDR, there are few studies of the molecular or epidemiological effects of genetic variation in these two key enzymes. Further, the mechanisms through which vitamin D may exert its chemopreventive effects are unknown, though work by our group as well as others suggests that APC, b-catenin, and 1,25(OH)2D-VDR represent a molecular "crossroads" of intracellular regulators of colonic cell proliferation. The specific aims of the proposed work are to 1) Measure circulating 25(OH)D and 1,25(OH)2D concentrations among participants in clinical trials of colorectal adenoma recurrence, and assess the association between these variables and the odds of adenoma recurrence; 2) Genotype study participants for variation in VDR, CYP27B1 and CYP24A1 and evaluate the association between SNPs and odds for colorectal adenoma recurrence and circulating concentrations of vitamin D metabolites; 3) Elucidate the functional effects of selected polymorphisms in the CYP27B1 and CYP24A1 genes in human Caco-2 colonic cells; 4) Investigate molecular crosstalk between VDR (and VDR polymorphic variants) and 2-catenin, as well as the functional influence of APC on these signal transduction pathways. Secondary aims include investigation of sex-stratified associations between vitamin D metabolites and recurrence of adenomas and advanced adenomas, as well as assessment of whether these associations vary by colorectal sub-site. This work has the potential to offer a cost-effective preventative measure for colorectal carcinogenesis through improving vitamin D status, as well as to illuminate novel molecular evidence for the functional effects of genetic variation in key enzymes of vitamin D metabolism, and for the elucidation of signaling pathways, including APC and b-catenin, that likely modulate the actions of vitamin D metabolites and VDR.