Folate, 1-Carbon Nutrients, Gene Variants & Colon Cancer

叶酸、1-碳营养素、基因变异

• 批准号: 7119203
• 负责人: David John HUNTER
• 金额: $ 151.17万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-18 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7119203
• 关键词: clinical research; colorectal neoplasms; cooperative study; folate; genetic susceptibility; neoplasm /cancer genetics; nutrition related tag

DESCRIPTION (provided by applicant): Most of the over twenty epidemiologic studies that have examined the relationship between dietary folate intake and the risk of developing colorectal neoplasms, have reported that higher folate intakes are associated with lower risk. Animal studies, using either carcinogen-induced or genetically engineered rodent models of colorectal cancer, have indicated an inverse relationship between dietary folate and the risk of colorectal cancer. The folate metabolic pathway influences genomic methylation and the supply of nucleotides for DNA synthesis; these can also be influenced by adequacy of supply of vitamins B12, B6, and B2, all co-factors for critical enzymatic reactions in the pathway. The overall long-term objective of our Team is to establish the role of folate and other nutritional contributors to one-carbon metabolism in colorectal cancer by combining animal, mechanistic, human observational studies and clinical trials. We will accomplish this by establishing a Cooperative Specialized Center for the study of Folate, One carbon nutrients, Gene variants and Colorectal cancer. This Center will be a Collaborative Program between Harvard and Tufts Universities in Boston, Dartmouth University in New Hampshire, the International Agency for Research in Cancer and the University of Bergen in Europe, Variagenics Inc. in Boston, and the Division of Cancer Prevention and the Center for Cancer Research at the NCI. We are organized into three projects, developmental projects, and two cores. Project 1 will pool data from three large prospective cohort studies with 2,700 expected colorectal cancer cases to establish whether higher intake of folic acid reduces risk of colorectal cancer and examine whether this reduced risk is greater among persons with low methionine intake, low plasma folate, vitamins B12, B6, and B2 levels, consumers of more than one alcoholic beverage per day, and homozygotes for the methylenetetrahydrofolatereductase (MTHFR) C677T polymorphism, and compound heterozygotes for the MTHFR A1298C polymorphism. Project 2 will validate mouse models of colon carcinogenesis as systems to examine modification of risk by folate and other contributors to one-carbon metabolism. Project 3 will assess whether the degree of uracil misincorporation and genomic methylation in peripheral blood lymphocytes and distal colon biopsies represent biomarkers of one-carbon nutrient adequacy and colorectal adenoma risk, using data and samples from two randomized clinical trials of folate supplementation. The projects will be supported by innovative Developmental Projects. In initial Developmental Project 1 transgenic mice with the null allele of MTHFR, and the homologous C677T polymorphism; these mice will be available for incorporation into feeding studies in Project 2. In Developmental Project 2 we will explore five folate-metabolism genes for polymorphisms that influence plasma folate and homocysteine levels. All Projects will be supported by the Administrative and Statistical Core (based at the Harvard School of Public Health), and the Measurement Core (based at the Human Nutrition Research Center at Tufts University). These highly interrelated studies will help integrate epidemiologic and mechanistic observations and help provide a basis for public health recommendations on optimal levels of folate and B vitamin intake.

描述（由申请人提供）： 二十多个流行病学研究中，大多数研究了饮食叶酸摄入量与发展结直肠肿瘤风险之间的关系，已报告说，较高的叶酸摄入量与较低的风险有关。使用致癌物诱导的结直肠癌啮齿动物模型的动物研究表明，饮食叶酸与结直肠癌的风险之间存在反比关系。叶酸代谢途径影响基因组甲基化和核苷酸的供应DNA合成。这些也可能受到维生素B12，B6和B2供应的充分性的影响，这是所有用于途径中关键酶促反应的共同因素。我们团队的总体长期目标是通过结合动物，机理，人类观察性研究和临床试验来确定叶酸和其他营养贡献者对结直肠癌中一种碳代谢的作用。我们将通过建立一个合作专业的叶酸，一种碳养分，基因变异和结直肠癌的合作专业中心来实现这一目标。该中心将是波士顿哈佛大学和塔夫茨大学，新罕布什尔州达特茅斯大学，欧洲癌症研究机构和欧洲卑尔根大学，波士顿的Variagenics Inc.，以及NCI癌症预防和癌症研究中心的合作计划。我们组织了三个项目，发展项目和两个核心。 项目1将从三项大型前瞻性队列研究中汇集数据，其中有2,700个预期结直肠癌病例，以确定较高的叶酸摄入是否会降低结直肠癌的风险，并检查这种降低的风险是否更大的蛋氨酸摄入量低，血浆低含量较低的人，维生素B12，B12，B6和B2水平，每天超过一日的饮料，供您使用的消费者。 MTHFR A1298C多态性的甲基苯二氢脱脂酰甲基培养酶（MTHFR）C677T多态性和复合杂合子。 项目2将验证结肠癌的小鼠模型作为系统，以检查叶酸和其他对单碳代谢的贡献者对风险的改变。 项目3将评估外周血淋巴细胞中的尿酸含量和基因组甲基化程度以及远端结肠活检中是否使用来自两种随机的养成含料中补充的随机临床试验的数据和样品，代表了单碳营养充足性和结直肠腺瘤风险的生物标志物。 这些项目将得到创新的发展项目的支持。在最初的发育项目1中，具有MTHFR无效等位基因的转基因小鼠和同源的C677T多态性；这些小鼠将用于项目2中的喂养研究。在发展项目2中，我们将探索五个影响血浆叶酸和同型半胱氨酸水平的多态性的叶酸代谢基因。 所有项目将得到行政和统计核心的支持（位于哈佛公共卫生学院）和测量核心（位于塔夫茨大学的人类营养研究中心）。 这些高度相互关联的研究将有助于整合流行病学和机理观察结果，并有助于为公共卫生的建议提供有关叶酸和B维生素摄入量的最佳水平的基础。