EFFECTS OF FOLATE-DEFICIENT WESTERN-STYLE ON TRANSGENIC

减少叶酸的摄入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）和遗传性非息肉性结肠癌（HNPCC）是男性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，这些小鼠模型具有遗传风险的人类结直肠癌。具体目的是表征和建立四种转基因模型的中间生物标志物，这些模型模仿人类结直肠癌发生相关的遗传改变。这些应包括APC1638 （FAP）、MLH1 （HNPCC）和MLH1/APC1638 （HNPCC）。同一品系的正常小鼠被用作对照。这些研究包括以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（包括结直肠癌、小肠和其他癌症）、肉眼和显微镜病理、细胞增殖和凋亡的影响。这些研究应该能够证明试验制剂对结肠癌的疗效，并进一步发现和应用甲基化途径特异性化学预防制剂。

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.