Dietary Antioxidants, NF-KappaBeta, and Carcinogenesis

膳食抗氧化剂、NF-KappaBeta 和致癌作用

基本信息

批准号：
6524844
负责人：
HOWARD P GLAUERT
金额：
$ 7.24万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2004-09-29
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant) Dietary antioxidants have been shown to inhibit carcinogenesis in many studies, but the mechanisms by which they do so are unclear. One possibility is that they influence the activation of oxidative stress-sensitive transcription factors, such as NF-kB. NF-kB has been found to be activated by hepatic tumor-promoting agents such as PCBs, phenobarbital, and peroxisome proliferators; the activation by peroxisome proliferators has been found to be mediated, at least in part, by active oxygen. The antioxidant vitamin E inhibits NF-kB activation by peroxisome proliferators, both in vivo and in vitro. Whether the ability of vitamin E to inhibit NF-kB activation is responsible for its anti-carcinogenic effect is unclear, however. The development of a knockout mouse model that is deficient in the p50 subunit of NF-kB will allow the investigators to answer this question. They have found that the cell proliferation-inducing effects of peroxisome proliferators are decreased in this model. In this project, the investigators propose to test the hypothesis that vitamin E and other antioxidants exert their anti- carcinogenic effects at least in part by inhibiting NF-kB activation. The investigators will use the p50 knockout mice to examine if vitamin E-induced changes in hepatic cell proliferation, apoptosis, antioxidant status, and gene expression are mediated by NF-kB. They will then determine if effects on tumor promotion are mediated by NF-kB. These studies will show if the inhibition of NF-kB activation is necessary for the anti-carcinogenic effects of vitamin E and other antioxidants. These results will provide a mechanistic basis for possible dietary recommendations to prevent cancer.

描述（由申请人提供）膳食抗氧化剂已被证明可以抑制许多癌症的发生研究，但其作用机制尚不清楚。一种可能性是它们影响氧化应激敏感的激活转录因子，例如 NF-kB。已发现 NF-kB 被激活促进肝肿瘤的药物，例如 PCB、苯巴比妥和过氧化物酶体扩散者；已发现过氧化物酶体增殖物的激活至少部分是由活性氧介导的。抗氧化剂维生素E 在体内和体内抑制过氧化物酶体增殖剂对 NF-kB 的激活体外。维生素E是否具有抑制NF-kB活化的能力然而，其抗癌作用的具体原因尚不清楚。这开发缺乏p50亚基的敲除小鼠模型 NF-kB 将让研究人员回答这个问题。他们发现过氧化物酶体增殖剂的细胞增殖诱导作用是在这个模型中减少了。在这个项目中，研究人员建议测试维生素 E 和其他抗氧化剂发挥其抗氧化作用的假设致癌作用至少部分是通过抑制 NF-kB 激活而产生的。这研究人员将使用 p50 基因敲除小鼠来检查维生素 E 是否会诱导肝细胞增殖、凋亡、抗氧化状态和基因的变化表达由 NF-kB 介导。然后他们将确定是否会影响肿瘤的促进是由NF-kB介导的。这些研究将表明如果抑制 NF-kB 激活对于抗癌作用是必要的维生素E和其他抗氧化剂。这些结果将提供一个机制为预防癌症的可能饮食建议奠定了基础。