EPITHELIAL HOMEOSTASIS IN APC GENE MUTATION

APC基因的突变被广泛认为是一种重要的早期 结直肠癌发生中的事件。人类的可获得性和 携带APC生殖系突变的小鼠提供了一种独特的 研究结直肠癌发病机制和肿瘤的机会 预防。非类固醇抗炎药(NSAIDs)可以 预防和逆转受影响的肠粘膜的肿瘤性变化 由APC基因突变引起。其中一些肿瘤性变化，如 肠上皮细胞增殖和凋亡水平的改变 即使在APC患者的组织学正常的粘膜中也是如此 突变。通过研究APC突变个体的粘膜 在服用非甾体抗炎药之前和期间，我们可以获得 关于结直肠癌发病机制的信息，以及 AS开发有用的预测生物标记物来评估癌症 化学预防策略。在这项提案中，我们描述了一项关于 APC基因突变对肠上皮细胞的影响 APC小鼠周转时间与花生四烯酸代谢的关系 突变。使用这些上皮细胞动态平衡的测量，我们 将研究几种非甾体抗炎药和其他相关药物对 APC基因突变与肠癌的发生有关。最后，我们会 将这些信息应用于非甾体抗炎药诱导的肿瘤消退研究 在患有家族性腺瘤性息肉病的人中，一种情况 以APC基因的胚系突变为特征的。

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.