Defining the promoting effect of folate on colorectal cancer in a novel animal mo

在新型动物模型中确定叶酸对结直肠癌的促进作用

• 批准号: 8213454
• 负责人: JOEL B MASON
• 金额: $ 17.21万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213454
• 关键词: Acceleration; Address; Adult; American; Animal Model; Animals; Automobile Driving; Biochemical; Cancerous; Cells; Clinical Research; Colonic Neoplasms; Colorectal; Colorectal Cancer; Country; DNA biosynthesis; Data; Development; Diet; Dietary intake; Distal; Dose; Elderly; Epithelium; Ethics; Europe; European; Folate; Folic Acid; Food; Food Safety; Fortified Food; General Population; Goals; Health; Health Policy; Human; Human Experimentation; Individual; Intake; International; Knock-out; Lesion; Malignant Neoplasms; Measures; Metric; Modeling; Molecular; Monitor; Mucous Membrane; Mus; Nature; Neoplasms; North America; Pathway interactions; Plasma; Population; Public Health; Recommendation; Resolution; Risk; Seminal; Societies; Source; Stream; Supplementation; Testing; Thymidine; Time; Tumorigenicity; United States National Institutes of Health; Vitamin B Complex; Vitamins; authority; base; cancer risk; carcinogenesis; dietary supplements; fortification; in vivo; innovation; knockout gene; mathematical model; meetings; neoplastic cell; novel; pre-clinical; public health relevance; research study; response; sound; symposium; thymidylate; tool; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Of great contemporary concern in the U.S., as well as in other countries, is the question of what constitutes a healthful dietary intake of the B-vitamin, folate. Although adequate amounts of folate intake protect against colorectal cancer, accumulating evidence indicates that overly abundant quantities among those who harbor pre-cancerous or cancerous lesions may produce a paradoxical acceleration of tumorigenesis. There are many sources of folic acid in the american diet that supplement the quantities naturally present in foods: voluntarily-fortified foods, vitamin supplements and mandatory fortification. The seminal question is whether these sources are collectively sufficient to produce the cancer-promoting effect of folate; a grave concern for which there is already supportive evidence from several pre-clinical and clinical studies. Due to ethical and chronological constraints, this dilemma cannot be resolved by human studies alone. Consistent with this reality are the conclusions of a recent international conference on the topic, which included among the high priority recommendations the need to pursue the issue in appropriate animal models. The overall goal of this proposal, therefore, is to answer these questions within the context of a highly innovative and powerful animal model. This novel animal model of colorectal carcinogenesis, GEM-1, allows one to monitor development of colonic neoplasms in vivo over a period of several months. This will enable us to determine critical parameters such as the threshold of dose at which dietary folate has a promotional effect and to develop a mathematical model that defines the relationship. Our proposed studies will: 1) characterize the GEM-1 model's response to supraphysiological quantities of dietary folic acid in regard to cancer promotion, 2) define the quantitative nature of the dose-response relationship between supraphysiological folic acid intake and acceleration of tumorigenesis, 3) determine whether delivery of supraphysiological quantities of a natural form of the vitamin, 5-methyltetrahydrofolate, lacks the cancer-promoting effects observed with the synthetic form, folic acid, and 4) provide evidence that the molecular pathway by which excess folic acid is driving carcinogenesis is by providing abundant quantities of the rate-limiting substrate for DNA synthesis, thymidine. PUBLIC HEALTH RELEVANCE: There is great debate in the U.S. and in other countries as to what constitutes a healthful dietary intake of the B-vitamin, folate, because many sources of the vitamin have been introduced into the food stream and there is accumulating evidence to suggest that overly abundant quantities of the vitamin may promote the risk of colorectal cancer. The existing data concerning the possible promotion of cancer is rather equivocal, and yet the potential ramifications are very great, making this a particularly pressing public health issue that needs to be addressed with some urgency. The studies proposed in this application will be conducted in a novel and particularly well-suited animal model and will provide important answers as to whether the intake of folate that is helping optimize health for one segment of the population might be presenting potential risks to other segments of the society.

描述（由申请人提供）：在美国以及其他国家的当代关注点是什么构成B-Vitamin的健康饮食摄入的问题。尽管足够量的叶酸摄入量可以预防结直肠癌，但积累的证据表明，含有癌前或癌变的患者中过多的数量可能会产生肿瘤发生的矛盾加速。美国饮食中有许多叶酸来源补充食物中天然存在的数量：自愿食品，维生素补充剂和强制性强化。开创性的问题是这些来源是否足以产生叶酸的癌症促进作用。一个严重的关注点已经有一些临床前和临床研究的支持证据。由于道德和按时间顺序的限制，仅通过人类研究就无法解决这一困境。与这一现实一致的是该主题的最新国际会议的结论，其中包括在高优先级建议中需要在适当的动物模型中追求该问题。因此，该提案的总体目标是在高度创新和强大的动物模型的背景下回答这些问题。这种新型的结直肠癌发生的动物模型GEM-1使人们可以在几个月内监测体内结肠肿瘤的发展。这将使我们能够确定关键参数，例如饮食叶酸具有促销作用的剂量阈值，并开发定义关系的数学模型。我们提出的研究将：1）表征GEM-1模型对癌症促进饮食叶酸超生理量的反应，2）定义剂量反应关系的定量性质，在造影剂叶酸的摄入量和超级酸的加速度之间的剂量反应关系和肿瘤的加速之间，3）确定是否缺乏自然的量化量的自然量，是否是自然的量化。用合成形式，叶酸和4）观察到的癌症促进作用提供了证据，表明多余叶酸驱动致癌的分子途径是通过提供大量的DNA合成速率限制底物（胸腺胺）。 公共卫生相关性：在美国和其他国家存在激烈的辩论，即构成B-Vitamin的健康饮食摄入叶酸，因为许多维生素的来源已被引入食物流中，并且有积累的证据表明，过量量的维生素可能会促进结肠直肠癌的风险。关于癌症可能促进的现有数据相当模棱两可，但潜在的后果非常好，这使得这是一个特别紧迫的公共卫生问题，需要在某种程度上紧迫地解决。本应用中提出的研究将以新颖的，特别是精心挑选的动物模型进行，并将为叶酸的摄入是否有助于优化一部分人群的健康，可能会给社会的其他领域带来潜在的风险。