Effects of aging and folate on colonic carcinogenesis

衰老和叶酸对结肠癌发生的影响

• 批准号: 7364576
• 负责人: SANG WOON CHOI
• 金额: $ 25.39万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7364576
• 关键词: Address; Affect; Age; Aging; Animal Model; Animals; Appearance; Attenuated; Biochemical; Carbon; Chemoprevention; Chemopreventive Agent; Chromosome abnormality; Chromosomes; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; DNA; DNA Damage; DNA strand break; Development; Diet; Dietary Supplementation; Dietary intake; Elderly; Environment; Enzymes; Epithelium; Exons; Folate; Genes; Genetic Polymorphism; Genetically Engineered Mouse; Genomics; Genus Cola; Goals; Grant; Hereditary Disease; Insulin-Like Growth Factor Binding Protein 3; Intake; Investigation; Laboratories; Malignant Neoplasms; Metabolic; Metabolism; Modality; Molecular; Neoplasms; Nutritional; Pathway interactions; Predisposition; Rate; Research; Research Personnel; Risk; Risk Factors; Rodent; Series; Supplementation; TP53 gene; Thymidine; Transcript; Uracil; age effect; carcinogenesis; dietary supplements; experience; mouse model; normal aging; nucleotide metabolism; prevent; programs; response; success; thymidylate; uridylate

DESCRIPTION (provided by applicant): Elder age and inadequate folate intake are each strongly implicated as important risk factors for colon cancer. In a preliminary study we observed that aging and folate depletion alter one-carbon metabolism in the rodent colon, increasing uracil misincorporation into DMA, thereby creating a predisposition to chromosomal and DNA aberrancy and carcinogenesis. By the same token we observed that dietary folate at supplemental levels prevents the appearance of the abnormal biochemical and molecular effects of aging in the colon. We also found altered expression of several critical genes in response to aging and folate depletion. We, therefore, hypothesize that the increased uracil content in DNA produced by aging and inadequate folate availability increases chromosomal and genomic DNA damage, affects expression of critical genes and consequently enhances colonic carcinogenesis. However, reduction of uracil in colonic DNA will reverse the pro-carcinogenic effects of aging and folate depletion Our long-term goal is to find an effective strategy for the chemoprevention of colon cancer. The studies outlined in this proposal are aimed at defining molecular and cellular mechanisms that determine how aging and folate status affect colonic carcinogenesis. The specific aim of this proposal is to determine whether such molecular anomalies enhance colonic carcinogenesis and whether folate supplementation or any other modalities to reduce uracil misincorporation attenuates such molecular changes and finally prevents cancer development. We propose animal studies using a normal aging mouse model, a mouse model of colon cancer and a genetically-modified mouse model, the latter mimicking a common genetic condition that diverts folate more to nucleotide synthesis. By defining molecular pathways towards cancer modulated by aging and folate, we will have a better understanding of the nutritional circumstances which constitute high risk and thereby will be able to define the precise manner in which folate can be used effectively as chemopreventive agents.

描述（由申请人提供）：老年年龄和叶酸摄入量不足，每个人都被认为是结肠癌的重要危险因素。在一项初步研究中，我们观察到，衰老和叶酸耗竭改变了啮齿动物结肠中的一种碳代谢，从而增加了尿嘧啶的掺入DMA，从而造成了染色体和DNA异常和癌变的倾向。同样，我们观察到，饮食叶酸在补充水平上可以防止衰老中衰老异常的生化和分子作用的出现。我们还发现，响应衰老和叶酸耗竭的响应几个关键基因的表达改变。因此，我们假设通过衰老和叶酸可用性不足产生的DNA中尿素含量增加会增加染色体和基因组DNA损伤，会影响关键基因的表达，从而增强结肠致癌。然而，结肠DNA中尿嘧啶的减少将逆转衰老和叶酸耗竭的促癌作用，我们的长期目标是为结肠癌的化学预防找到有效的策略。该提案中概述的研究旨在定义分子和细胞机制，这些机制决定了衰老和叶酸状况如何影响结肠癌的发生。该提案的具体目的是确定这种分子异常是否会增强结肠癌的发生以及叶酸补充或任何其他减少尿嘧啶失误的模式是否会减轻这种分子变化并最终阻止癌症的发展。我们提出了使用正常衰老小鼠模型，结肠癌的小鼠模型和遗传修饰的小鼠模型的动物研究，后者模仿了一种常见的遗传状况，该遗传条件将叶酸更多地转移到核苷酸合成中。通过定义通过衰老和叶酸调节癌症的分子途径，我们将对构成高风险的营养状况有更好的了解，从而可以定义可以有效地将叶酸用作化学预防剂的精确方式。