EFFECTS OF FOLATE-DEFICIENT WESTERN-STYLE ON TRANSGENIC

缺乏叶酸的西式对转基因的影响

• 批准号: 6356777
• 负责人: MARTIN LIPKIN
• 金额: $ 29.36万
• 依托单位: STRANG CANCER PREVENTION CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6356777
• 关键词: DNA damage; DNA methylation; adenomatous polyps; cancer risk; cellular oncology; colorectal neoplasms; disease /disorder model; folate; genetically modified animals; laboratory mouse; neoplastic growth; nutrition aspect of cancer; nutrition related tag; pathogenic diet

Decreased folic acid intake is one of the characteristics of a western diet. Folate acid deficiency is associated with DNA damage, impaired DNA repair and abnormal DNA methylation. Epidemiology suggests that dietary folic acid intake is inversely associated with colorectal cancer risk. Familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) are major contributors to colon cancer in man. Methylation has been proposed as a major modulator of certain HNPCC subtypes. This study focuses on the effects a folate-deficient western diet on genetically-altered transgenic mouse models for colorectal cancer in genetically at-risk humans . Specific objectives are to characterize and establish intermediate biomarkers for four transgenic models mouse models which imitate closely genetic alterations associated with colorectal cancer development in human. These shall include APC 1638 (FAP), MLH1 (HNPCC), and MLH1/APC1638 (HNPCC). Normal mice of the same strain are being used as controls. These studies include treatment of mice with both the western-style diet and the folate-deficient western style diet and the effects of these treatments on tumor development (including colorectal, small intestinal and other cancers), gross and microscopic pathology, cell proliferation, and apoptosis. The studies should demonstrate the efficacy of the test agents against colon cancer and additionally lead to the discovery and application of methylation pathways-specific chemopreventive agents.

减少叶酸摄入量是西方饮食的特点之一。叶酸缺乏与DNA损伤、DNA修复受损和DNA甲基化异常有关。流行病学研究表明，膳食叶酸摄入量与结直肠癌风险呈负相关。家族性腺瘤性息肉病（FAP）和遗传性非息肉病性结肠癌（HNPCC）是人类结肠癌的主要致病因素，甲基化被认为是某些HNPCC亚型的主要调节因子。本研究的重点是叶酸缺乏的西方饮食对基因改变的转基因小鼠模型的影响，在遗传风险的人结直肠癌。具体目标是表征和建立四种转基因模型小鼠模型的中间生物标志物，这些模型密切模仿与人类结直肠癌发展相关的遗传改变。这些应包括APC 1638（FAP）、MLH 1（HNPCC）和MLH 1/APC 1638（HNPCC）。相同品系的正常小鼠用作对照。这些研究包括用西式饮食和叶酸缺乏的西式饮食治疗小鼠，以及这些治疗对肿瘤发展（包括结肠直肠癌、小肠癌和其他癌症）、大体和显微病理学、细胞增殖和凋亡的影响。这些研究应该证明测试试剂对结肠癌的功效，并且另外导致甲基化途径特异性化学预防剂的发现和应用。