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

基本信息

  • 批准号:
    8213454
  • 负责人:
  • 金额:
    $ 17.21万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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):在美国当代备受关注,以及在其他国家,问题是什么构成了B族维生素叶酸的健康饮食摄入量。虽然足够量的叶酸摄入可以预防结直肠癌,但越来越多的证据表明,在那些患有癌前病变或癌性病变的人中,过量的叶酸摄入可能会导致肿瘤发生的矛盾加速。在美国人的饮食中有很多叶酸的来源,它们补充了食物中天然存在的叶酸量:维生素强化食品,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促癌作用;这是一个严重的问题,已经有来自几项临床前和临床研究的支持性证据。由于伦理和时间的限制,这种困境不能仅仅通过人类研究来解决。与这一现实相一致的是最近一次关于这一主题的国际会议的结论,其中包括高度优先的建议,即需要在适当的动物模型中研究这一问题。因此,本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。这种新的结肠直肠癌发生的动物模型,GEM-1,允许一个监测结肠肿瘤在体内几个月的时间内的发展。这将使我们能够确定关键参数,例如膳食叶酸具有促进作用的剂量阈值,并开发定义这种关系的数学模型。我们建议的研究将:1)表征GEM-1模型对超生理量的膳食叶酸在癌症促进方面的反应,2)定义超生理量的叶酸摄入和肿瘤发生加速之间的剂量-反应关系的定量性质,3)确定递送超生理量的天然形式的维生素5-甲基四氢叶酸,缺乏用合成形式叶酸观察到的促癌作用,和4)提供证据表明过量叶酸驱动致癌作用的分子途径是通过提供大量的DNA合成限速底物胸苷。 公共卫生相关性:在美国和其他国家,关于什么是B族维生素叶酸的健康饮食摄入量存在很大争议,因为许多维生素来源已被引入食物流,并且有越来越多的证据表明,过量的维生素可能会增加结直肠癌的风险。关于可能促进癌症的现有数据是相当模棱两可的,但潜在的影响是非常大的,使这成为一个特别紧迫的公共卫生问题,需要以一定的紧迫性加以解决。本申请中提出的研究将在一种新的特别适合的动物模型中进行,并将提供重要的答案,即帮助优化一部分人群健康的叶酸摄入是否可能对社会的其他部分构成潜在风险。

项目成果

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JOEL B MASON其他文献

JOEL B MASON的其他文献

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{{ truncateString('JOEL B MASON', 18)}}的其他基金

FASEB SRC: The Folate, Vitamin B12, and One-Carbon Metabolism Conference
FASEB SRC:叶酸、维生素 B12 和一碳代谢会议
  • 批准号:
    10539408
  • 财政年份:
    2022
  • 资助金额:
    $ 17.21万
  • 项目类别:
Colorectal tumorigenesis on a cricket powder-based diet versus diets based on more typical protein sources
基于蟋蟀粉的饮食与基于更典型蛋白质来源的饮食的结直肠肿瘤发生
  • 批准号:
    10198460
  • 财政年份:
    2021
  • 资助金额:
    $ 17.21万
  • 项目类别:
Colorectal tumorigenesis on a cricket powder-based diet versus diets based on more typical protein sources
基于蟋蟀粉的饮食与基于更典型蛋白质来源的饮食的结直肠肿瘤发生
  • 批准号:
    10368084
  • 财政年份:
    2021
  • 资助金额:
    $ 17.21万
  • 项目类别:
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:
    8049302
  • 财政年份:
    2011
  • 资助金额:
    $ 17.21万
  • 项目类别:
The MTHFR C677T SNP exerts bipolar effects on colorectal cancer risk through the
MTHFR C677T SNP 通过以下方式对结直肠癌风险产生双极效应:
  • 批准号:
    7713460
  • 财政年份:
    2009
  • 资助金额:
    $ 17.21万
  • 项目类别:
The MTHFR C677T SNP exerts bipolar effects on colorectal cancer risk through the
MTHFR C677T SNP 通过以下方式对结直肠癌风险产生双极效应:
  • 批准号:
    7944033
  • 财政年份:
    2009
  • 资助金额:
    $ 17.21万
  • 项目类别:
The role of the extracellular calcium-sensing receptor in dietary Ca2+ chemopreve
细胞外钙敏感受体在膳食 Ca2 化学预防中的作用
  • 批准号:
    7270119
  • 财政年份:
    2006
  • 资助金额:
    $ 17.21万
  • 项目类别:
One-carbon nutrients in cancer prevention
一碳营养素预防癌症
  • 批准号:
    7114292
  • 财政年份:
    2003
  • 资助金额:
    $ 17.21万
  • 项目类别:
One-carbon nutrients in cancer prevention
一碳营养素预防癌症
  • 批准号:
    6598043
  • 财政年份:
    2003
  • 资助金额:
    $ 17.21万
  • 项目类别:
One-carbon nutrients in cancer prevention
一碳营养素预防癌症
  • 批准号:
    7284838
  • 财政年份:
    2003
  • 资助金额:
    $ 17.21万
  • 项目类别:

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