Folate Deficiency and Susceptibility to GI Disease

叶酸缺乏和胃肠道疾病易感性

• 批准号: 6533219
• 负责人: AHMAD R HEYDARI
• 金额: $ 14.9万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6533219
• 关键词: DNA damage; DNA repair; biomarker; cancer risk; carcinogenesis; colon neoplasms; folate deficiency; gene targeting; genetic susceptibility; genetically modified animals; laboratory mouse; liver neoplasms; neoplasm /cancer genetics; nutrient interaction; nutrition related neoplasm /cancer; nutrition related tag

DESCRIPTION (provided by applicant): This exploratory research grant in the area of digestive diseases and nutrition has an overriding aim to identify a gene/nutrient interaction that will predispose animals to disease, cancer. The goal of this research grant is to elucidate the molecular mechanism by which folate deficiency increases tumorigenicity, i.e., we will determine whether genes in the DNA repair cascade, in particular base excision repair (BER), are involved in susceptibility to diseases of the colon and liver as a result of folate deficiency. Folate deficiency causes massive incorporation of uracil into DNA and also results in increased levels of DNA single strand breaks and chromosomal aberrations. These strand breaks could reflect incomplete DNA repair of uracil as a result of saturation of the BER pathway and stalling at the rate-limiting step of BER. By using an animal with a diminished BER capacity, we can directly test whether the genotoxic effects of folate deficiency and the synergy between folate deficiency and carcinogen exposure are due to impairment in BER capacity. In folate deficiency, we suggest that the ability of the BER pathway to process the massive amount of DNA damage is exceeded, and that any additional stress presented to the system is poorly handled. Our central hypothesis is that oxidizing and alkylating agents are more damaging in the face of folate deficiency as a result of saturation of the base excision repair pathway, and that a synergism between folate deficiency and inefficient BER will predispose to diseases of the colon and/or liver. The model of BER deficiency used in these studies is the DNA polymerase Beta heterozygous knockout mouse. The specific aims of the research described in this proposal are as follows: (1) To determine the sensitivity of a BER deficient animal to folate deficiency: the incidence of DNA damage and mutation frequency in response to folate deficiency in a BER compromised environment will be measured. (2) To determine whether folate deficiency within the context of BER deficiency will result in greater accumulation of biomarkers of disease in the dimethylhydrazine model of colon carcinogenesis. (3) To determine whether folate deficiency within the context of BER deficiency will result in greater accumulation of biomarkers of disease in the 2-nitropropane model of hepatocarcinogenesis. Achieving these objectives will provide molecular insights into the synergy between nutritional deficiency and genetic polymorphisms resulting in mutation induction and will further elucidate the relationship between diet and environmental carcinogens.

描述（由申请人提供）：消化疾病和营养领域的探索性研究赠款的旨在识别一种基因/营养相互作用，该基因/营养相互作用将使动物易患疾病，癌症。这项研究赠款的目的是阐明叶酸缺乏增加肿瘤性的分子机制，即，我们将确定DNA修复级联中的基因（特别是碱基切除修复（BER））是否涉及因叶酸降低而对结肠和肝脏疾病的易感性。叶酸缺乏会导致将尿嘧啶大量掺入DNA中，并导致DNA单链断裂和染色体畸变的水平增加。这些链断裂可能反映出由于BER途径饱和并在BER的限制步骤下停滞的结果，可能反映尿嘧啶的不完全DNA修复。通过使用ber能力降低的动物，我们可以直接测试叶酸缺乏症的遗传毒性作用以及叶酸缺乏和致癌物暴露之间的协同作用是否归因于BER的损害。在叶酸缺乏症中，我们建议BER途径处理大量DNA损伤的能力，并且对系统中呈现的任何其他应力都处理不当。我们的中心假设是，面对叶酸缺乏，氧化和烷基化剂由于碱性切除修复途径的饱和而更具破坏性，并且叶酸缺乏和效率低下的BER之间的协同作用将使结肠和/或肝脏的疾病易感性。这些研究中使用的BER缺乏模型是DNA聚合酶β杂合基因敲除小鼠。本提案中描述的研究的具体目的如下：（1）确定ber不足动物对叶酸缺乏的敏感性：DNA损伤和突变频率在响应BER受损的环境中响应叶酸缺乏的发生率。 （2）确定在BER缺乏症中的叶酸缺乏是否会导致疾病的生物标志物在结肠癌发生的二甲基氢氮杂模型中的积累。 （3）确定在BER缺乏症中的叶酸缺乏是否会导致肝癌的2-硝基丙烷模型中疾病的生物标志物的积累。实现这些目标将为营养缺乏症与遗传多态性之间的协同作用提供分子见解，从而导致突变诱导，并将进一步阐明饮食与环境致癌物之间的关系。