The MTHFR C677T SNP exerts bipolar effects on colorectal cancer risk through the

描述（由申请人提供）：在过去的十年中，已经非常清楚的是，亚甲基四氢叶酸还原酶（MTHFR）基因的高度流行的C677 T多态性赋予了针对发生结肠直肠癌的风险的实质性保护，并且其在这方面的作用是与B族维生素叶酸的营养素-基因相互作用的功能。与叶酸水平相当的野生型个体相比，该变体纯合子和叶酸充足的个体的风险降低了30-70%，叶酸状态不太稳定的个体的保护程度逐渐降低。临床前和临床研究的观察结果表明，当叶酸水平较低时，纯合子具有较高的风险。C677 T变体的这种双极效应，即当叶酸状态充足时提供保护，但当叶酸状态低时提供风险，在所有在确定癌症风险中起作用的多态性中是独特的。我的实验室最近的研究表明，Wnt信号通路在叶酸和其他1-碳微量营养素介导的致癌作用的调节中起着重要作用。拟定动物研究的目的是进行必要的初始步骤，以确定C677 T变体双极效应的机制基础。揭示这种效应的机制基础将具有非常重要的基础和应用功能。首先，了解叶酸-C677 T相互作用的基础将有助于对叶酸的可用性如何调节结直肠癌风险的相关但不完全相同的问题的关键见解。从公共卫生的角度来看，如果工业化社会要明智和安全地实施叶酸强化计划，以及确定适当的个体作为补充计划的目标，可以减少癌症的负担，那么对叶酸和这种多态性如何共同调节致癌作用的基本原则的彻底理解是绝对必要的。为了实现这些目标，将进行两个实验，其共同利用三种遗传工程改造的小鼠品系：一种倾向于肠致癌作用的品系（Apc 1638 N）;一种通过Wnt信号传导级联显示活性的品系（BAT/lacZ）;以及一种含有我们最近自己创建的模拟人类纯合变体的MTHFR基因的cre-lox条件性敲除的品系。第一个实验将确定MTHFR敲除是否以双极方式调节结直肠癌发生的早期阶段，这取决于1-碳营养状态，从而建立该模型与人类的相关性。然后，第二个实验将确定营养素-基因相互作用是否调节Wnt途径及其对细胞周期的下游影响，以重现其对致癌作用的影响。公共卫生相关性：拟议动物研究的目的是确定常见遗传变异C677 T与叶酸和其他相关B族维生素的可用性之间相互作用的机制基础，以确定结肠癌的风险。揭示这种效应的机制基础将具有非常重要的基础和应用功能。首先，了解叶酸-C677 T相互作用的基础将有助于对叶酸的可用性如何调节结直肠癌风险的相关但不完全相同的问题的关键见解。从公共卫生的角度来看，如果工业化社会要明智和安全地实施叶酸强化计划，以及确定适当的个体作为补充计划的目标，可以减少癌症的负担，那么对叶酸和这种多态性如何共同调节致癌作用的基本原则的彻底理解是绝对必要的。

DESCRIPTION (provided by applicant): Over the past decade it has become abundantly clear that the highly prevalent C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene imparts substantial protection against the risk of developing colorectal cancer, and that its effect in this regard is a function of a nutrient-gene interaction with the B-vitamin, folate. Individuals who are homozygous for the variant and who are folate-replete enjoy a reduction in risk of 30-70% compared to wild-type individuals with comparable levels of folate, with diminishing degrees of protection among those whose folate status is less robust. Far less appreciated are the observations from both pre-clinical and clinical studies that indicate that the homozygote possesses an elevated risk when folate status is low. This bipolar effect of the C677T variant, whereby it conveys protection when folate status is adequate but conveys risk when folate status is low, is unique amongst all polymorphisms that play a role in determining cancer risk. Recent studies by my laboratory implicate the Wnt signaling pathway as playing a large role in the modulation of carcinogenesis mediated by folate and the other 1-carbon micronutrients. The purpose of the proposed animal studies is to conduct the initial steps necessary to define the mechanistic basis for this bipolar effect of the C677T variant. Unraveling the mechanistic basis of this effect will serve very important basic and applied functions. First, understanding the basis of the folate-C677T interaction will contribute critical insights into the related, but not identical, issue of how folate availability modulates colorectal cancer risk. From a public health perspective, a thorough appreciation for the underlying principles of how folate and this polymorphism conspire to modulate carcinogenesis is absolutely essential if industrialized societies are to intelligently and safely implement folic acid fortification programs, as well as identify appropriate individuals to target for supplementation programs that can reduce the burden of cancer. To accomplish these goals, two experiments will be conducted that collectively utilize three genetically- engineered strains of mice: one strain that is predisposed to intestinal carcinogenesis (Apc1638N); one strain that displays activity through the Wnt signaling cascade (BAT/lacZ); and one strain containing a cre-lox conditional knockout of the MTHFR gene that we recently created ourselves that models the human homozygous variant. The first experiment will determine whether the MTHFR knockout modulates early stages of colorectal carcinogenesis in a bipolar fashion depending on 1-carbon nutrient status, thereby establishing the relevance of this model to the human. The second experiment will then identify whether the nutrient-gene interaction modulates the Wnt pathway and its downstream effects on the cell cycle in a fashion that recapitulates its effects on carcinogenesis. PUBLIC HEALTH RELEVANCE: The purpose of the proposed animal studies is to define the mechanistic basis for the interaction between the common genetic variant, C677T, and the availability of folate and other related B-vitamins in determining the risk of colon cancer. Unraveling the mechanistic basis of this effect will serve very important basic and applied functions. First, understanding the basis of the folate-C677T interaction will contribute critical insights into the related, but not identical, issue of how folate availability modulates colorectal cancer risk. From a public health perspective, a thorough appreciation for the underlying principles of how folate and this polymorphism conspire to modulate carcinogenesis is absolutely essential if industrialized societies are to intelligently and safely implement folic acid fortification programs, as well as identify appropriate individuals to target for supplementation programs that can reduce the burden of cancer.