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

描述（由申请方提供）：流行病学研究表明，维生素D代谢物25（OH）D（激素1，25（OH）2D的前体分子）的低血清水平与结直肠肿瘤形成的风险相关，尽管结果不明确，并且对这些生物标志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的抗增殖、促分化和生长抑制作用已在结肠直肠癌细胞系中显示。因此，有令人信服的证据表明，活性维生素D代谢物在降低结直肠肿瘤的风险中发挥作用，但在细胞水平上获得最佳水平的1，25（OH）2D的最佳方法尚不清楚，维生素D受体（VDR）或在组织水平上负责代谢1，25（OH）2D的主要酶的遗传变异的功能影响知之甚少。初步证据表明，VDR中的SNP可能会影响1，25（OH）2D的循环浓度;此外，两种酶CYP 27 B1和CYP 24 A1在该分子的代谢稳态中特别重要。虽然已经有研究的功能和流行病学协会的VDR，有很少的研究，在这两个关键酶的遗传变异的分子或流行病学的影响。此外，维生素D可能发挥其化学预防作用的机制尚不清楚，尽管我们小组和其他人的工作表明APC，b-连环蛋白和1，25（OH）2D-VDR代表了结肠细胞增殖细胞内调节因子的分子“十字路口”。本研究的具体目标是：1）测量结直肠腺瘤复发临床试验参与者的循环25（OH）D和1，25（OH）2D浓度，并评估这些变量与腺瘤复发几率之间的相关性; 2）VDR变异的基因型研究参与者，CYP 27 B1和CYP 24 A1，并评估SNPs与结直肠腺瘤复发几率和维生素D代谢物循环浓度之间的关联; 3）阐明人Caco-2结肠细胞中CYP 27 B1和CYP 24 A1基因中选定多态性的功能影响; 4）研究VDR（和VDR多态性变体）和2-catenin之间的分子串扰，以及APC对这些信号转导通路的功能影响。次要目的包括调查维生素D代谢产物与腺瘤复发和晚期腺瘤之间的性别分层关联，以及评估这些关联是否因结直肠子部位而异。这项工作有可能通过改善维生素D状态为结直肠癌的发生提供一种具有成本效益的预防措施，并阐明维生素D代谢关键酶遗传变异的功能效应的新分子证据，以及阐明可能调节维生素D代谢物和VDR作用的信号通路，包括APC和b-连环蛋白。 公共卫生相关性：拟议的工作有可能通过改善维生素D状态为结直肠癌发生提供具有成本效益的预防措施，并为维生素D途径中关键酶的遗传变异的功能效应提供分子证据，以及维生素D代谢物发挥作用的途径，包括通过APC/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. PUBLIC HEALTH RELEVANCE: The proposed work has the potential to offer a cost-effective preventative measure for colorectal carcinogenesis through improving vitamin D status, as well as providing molecular evidence for the functional effects of genetic variation in key enzymes in the vitamin D pathway, and for the pathways through which vitamin D metabolites are acting, including via APC/B-catenin.