DIETARY INTERACTIONS WITH APC MUTATION IN COLON CANCER

这个应用程序是三个小组合作开发和 利用一种独特的小鼠模型，在这种模型中，遗传学的相互作用 而饮食在结肠癌发生中的作用可以定义。我们中的一个人 通过在APC 1638小鼠中插入靶向突变 APC基因。这产生了一种截短的APC蛋白，类似于主要的 导致人类家族性息肉病的突变。这些小鼠发育成 早期多发性肠道肿瘤，但与 以前报道的Min小鼠，其中不同的突变是随机的 在APC基因中产生的APC 1638小鼠产生的肠道较少 肿瘤，因此寿命更长，在这个模型中，我们有 发现饮食对结肠癌的发病率有显著影响。 营养紧张的饮食在早期就会导致肿瘤的大量增加 在这些动物的舞台上。这种饮食是根据以下原则制定的 模拟人类主要营养危险因素的营养密度 西式饮食--脂肪和磷酸盐增加，钙和维生素减少 D. 拟议中的实验的目的是利用这一独特的系统 用于研究胃肠道癌症的病因、发病机制和 预防。首先，该模型将在以下方面得到更好的表征 肿瘤形成动力学与形态计量学参数的关系 和病理学。第二，基因座的突变、缺失和扩增 与结肠癌的发生和发展有关的机制 -APC、DCC、P53、Ki-ras、c-myc-将在肿瘤中表现为 它们的出现，并与病理和病因密切相关 因素(即针对APC突变、营养成分，或两者兼而有之)。这 目前还没有关于闽鼠或其他啮齿动物模型的报告。 第三，结肠内正常细胞分化的改变，包括 增殖细胞的数量和位置、凋亡细胞及其变化 在细胞和分子标记的表达上，将被研究 它们在这些扁平粘膜中启动肿瘤形成的作用 动物。 因此，我们将完成对模型的描述并定义细胞 以及肿瘤形成之前和伴随的分子事件 由特定的饮食和遗传因素相互作用引发的。这 模型，它模拟了营养和遗传因素，这些因素 人类结肠癌的病因学和避免使用化学物质 未知与人类疾病相关的致癌物，应该是 对未来的化学和营养学研究非常有价值 预防结肠癌。

This application is a collaboration among 3 groups to develop and capitalize upon a unique mouse model in which the interaction of genetics and diet in the genesis of colon cancer can be defined. One of us has constructed the Apc 1638 mouse by inserting a targeted mutation in the Apc gene. This generates a truncated apc protein analogous to a major mutation which causes human familial polyposis. These mice develop multiple intestinal tumors at an early age, but in comparison to the previously reported Min mouse, in which a different mutation was randomly generated in the Apc gene, the Apc 1638 mice produce fewer intestinal tumors and consequently have a longer lifespan, in this model, we have found a dramatic affect of diet on the incidence of colonic neoplasms. A nutritional stress diet induces a large increase in tumors at an early stage in these animals. The diet is formulated on the principle of nutrient density to mimic major nutritional risk factors in the human Western diet - elevated fat and phosphate, decreased calcium and vitamin D. The purpose of the proposed experiments is to exploit this unique system for studies of gastrointestinal cancer etiology, pathogenesis and prevention. First, the model will be better characterized in terms of the kinetics of tumor formation in relation to morphometric parameters and pathology. Second, mutations, deletions and amplifications at loci mechanistically linked to the development and progression of colon cancer - Apc, dcc, p53, Ki-ras, c-myc - will be characterized in the tumors which arise, and carefully related to the pathology and etiological factors (ie targeted Apc mutation, nutritional elements, or both). This has not yet been reported for the Min mouse or other rodent models. Third, alterations of normal cell differentiation in the colon, including number and position of proliferating cells, apoptotic cells, and changes in expression of cellular and molecular markers, will be investigated for their role in initiating tumor formation in the flat mucosa of these animals. Thus, we will complete a description of the model and define the cellular and molecular events which precede and accompany tumor formation initiated by interaction of specific dietary and genetic factors. This model, which mimics the nutritional and genetic factors that underly the etiology of human colon cancer and which avoids the use of chemical carcinogens of unknown relevance to the human disease, should be extremely valuable for future studies in chemo- and nutritional prevention of colon cancer.