EPITHELIAL HOMEOSTASIS IN APC GENE MUTATION

APC基因突变被广泛认为是重要的早期突变 结直肠癌发生中的事件。 人类的可用性和 携带 APC 种系突变的小鼠提供了独特的 研究结直肠癌发病机制和肿瘤的机会 预防。 非甾体类抗炎药 (NSAID) 可以 预防和逆转受影响肠粘膜的肿瘤变化 APC基因突变所致。 其中一些肿瘤性变化，例如 肠上皮细胞增殖和凋亡水平发生改变 即使是 APC 患者组织学正常的粘膜 突变。 通过研究 APC 突变个体的粘膜 在服用 NSAID 之前和期间，我们可以获得 有关结直肠癌发病机制的信息，以及 开发有用的预测生物标志物来评估癌症 化学预防策略。 在本提案中，我们描述了一项研究 APC基因突变对肠上皮细胞的影响 Apc 小鼠的周转时间和花生四烯酸代谢 突变。 利用这些上皮稳态的测量结果，我们 将研究几种非甾体抗炎药和其他相关药物对 肠道癌的发生与Apc突变有关。 最后，我们将 将此信息应用于 NSAID 诱导的肿瘤消退的研究 患有家族性腺瘤性息肉病的人类 其特征是 APC 基因种系突变。

Mutation of the APC gene is widely recognized as an important early event in colorectal carinogenesis. The availability of humans and mice carrying germline mutations in APC provides a unique opportunity to study both colorectal cancer pathogenesis and tumor prevention. Nonsteroidal antiinflammatory drugs (NSAIDs) can prevent and reverse neoplastic changes in intestinal mucosa affected by APC gene mutation. Some of these neoplastic changes, such as altered levels of enterocyte proliferation and apoptosis, are present even in histologically-normal mucosa from individuals with APC mutation. By studying the mucosa of individuals with APC mutation before and during administration of NSAIDs, we can obtain information concerning the pathogenesis of colorectal cancer, as well as develop useful predictive biomarkers to evaluate cancer chemoprevention strategies. In this proposal, we describe a study of the effect of APC gene mutation upon intestinal epithelial cell turnover time and arachidonic acid metabolism in mice with Apc mutation. Using these measurements of epithelial homeostasis, we will study the effect of several NSAIDs and other related agents upon intestinal carcinogenesis related to Apc mutation. Finally, we will apply this information to a study of NSAID-induced tumor regression in humans with Familial Adenomatous Polyposis, a condition characterized by germline mutation of the APC gene.