Folate-Genome Interactions in Colorectal Cancer

描述(由申请人提供)： 这项研究旨在通过专门设计的小鼠模型来阐明叶酸状态受损与结肠癌风险之间的关联的分子机制。叶酸代谢是合成核苷酸(嘌呤和二磷酸腺苷)和S-腺苷蛋氨酸所必需的。维生素缺乏或单核苷酸多态导致的叶酸代谢障碍会影响SAM和DTMP的合成，从而影响DNA甲基化密度和尿嘧啶含量。DNA尿嘧啶含量和甲基化密度都影响DNA的稳定性，DNA甲基化还调节许多基因的表达。目前尚不清楚叶酸与结肠癌风险之间的关联是否源于SAM和/或DTMP合成的改变。最近，我们已经证明细胞质丝氨酸羟甲基转移酶(CSHMT)是一种代谢开关，它引导叶酸激活的一碳单位在DTMP和SAM生物合成途径之间流动，cSHMT的表达和活性受到包括维甲酸、铁/铁蛋白和维生素B6在内的几种膳食成分的调节。因此，eSHMT介导的代谢开关可能参与叶酸相关病理的病因学，并可能成为预防的靶点。在这项建议中，我们将确定eSHMT在调节叶酸代谢、DNA和组蛋白甲基化、DNA稳定性和结肠隐窝基因表达方面的代谢作用，并确定在已建立的小鼠癌症模型中，DTMP或SAM合成的中断是否会增加(或防止)结肠癌的发生。 需要检验的主要假设是： (1)。CSHMT调节结肠隐窝中的叶酸代谢。 (2)。CSHMT在结肠隐窝中的表达受铁蛋白的调节，并影响癌症风险。 (3)。CSHMT的改变影响基因组甲基化、结肠隐窝的表达和稳定性。 该项目的长期目标是： (1)。确定叶酸代谢改变影响癌症风险的机制。

DESCRIPTION (provided by applicant): This research aims to elucidate the molecular mechanisms that account for the associations between impaired folate status and risk for colon cancer using purpose-designed mouse models. Folate metabolism is necessary for the synthesis of nucleotides (purines and dTMP) and S-adenosylmethionine (SAM). Disruption of folate metabolism by vitamin deficiency or single nucleotide polymorphisms can affect SAM and dTMP syntheses and thereby influence DNA methylation density and uracil content. Both DNA uracil content and methylation density affect DNA stability, and DNA methylation also regulates the expression of many genes. It is not known if the associations between folate and colon cancer risk result from altered SAM synthesis and/or dTMP synthesis. Recently, we have demonstrated that the enzyme cytoplasmic serine hydroxymethyltransferase (cSHMT) is a metabolic switch that directs the flux of folate-activated one-carbon units between dTMP and SAM biosynthetic pathways, cSHMT expression and activity is regulated by several dietary components including retinoic acid, iron/ferritin and vitamin B6. Therefore, the eSHMTmediated metabolic switch is likely involved in the etiology of folate-related pathologies and may be a target for prevention. In this proposal, we will determine the metabolic role of eSHMT in regulating folate metabolism, DNA and histone methylation, DNA stability and gene expression in the colonic crypts and determine if disruption of either dTMP or SAM synthesis increases (or protects against) colon cancer incidence in established mouse cancer models. The principle hypotheses to be tested are that: (1). cSHMT regulates folate metabolism in the colonic crypt. (2). cSHMT expression is regulated in the crypts of the colon by ferritin and influences cancer risk. (3). changes in cSHMT influences genomic methylation, expression and stability in the colonic crypt. The long-term goal of this project is: (1). to determine the mechanism whereby alterations in folate metabolism influence cancer risk.