Apoptosis in Colon Cancer Chemoprevention

申请人描述 结肠癌仍然是美国癌症死亡的第二大原因。 影响到男性和女性。这本书的主题是 该项目是研究结肠癌发生和结肠癌中的细胞凋亡 化学预防对实验啮齿动物模型和人类的研究表明， 遗传和肠腔风险因素降低细胞更新， 部分通过减少正常和肿瘤结肠组织中的细胞凋亡。 肠腔风险因素包括次级胆汁酸， 受到遗传和饮食因素的影响。我们的计划同时解决了 遗传和肠腔风险因素，因为我们假设， 这两种因子下游的信号传导和代谢途径介导细胞凋亡， 结肠组织中的周转，以及随后的结肠癌风险。一个推论 这一假设的一个重要原因是，这些下游途径是 结肠癌的化学预防策略。为了验证这个假设， 我们设计了互动和互补的项目和核心。 其中一个项目研究基因的生化效应子，包括Ki-ras 癌基因和APC和p53肿瘤抑制基因，这是经常 在人类结肠癌中发生了突变第二个项目的重点是氮的作用 胆汁酸氧化物诱导细胞凋亡。第三个项目强调研究 AP-1转录因子，参与信号通路 由APC和胆汁酸介导。这些项目的具体目标是 确定遗传和肠腔风险因素在细胞中的作用， 结肠组织中的周转，以描述这些机制的基础 过程，并研究特定药理学的后果 和/或饮食干预对细胞更新和结肠癌发生的影响。的 这些项目将利用基因改变的细胞培养来实现这些目标， 结肠癌的啮齿动物模型，以及各种生物化学、分子和 细胞生物学技术四个核心在细胞和组织中提供支持 结肠的病理学、繁殖和维持遗传改变的啮齿动物模型 致癌作用、生物统计学、给药和评估。远景目标 结肠癌化学预防计划项目拨款的凋亡是为了 了解人类结肠癌发生的机制，然后使用这个 结肠癌的治疗方法有哪些 预防和/或治疗。

APPLICANT'S DESCRIPTION Colon cancer remains the second leading cause of cancer death in the United States of America, affecting both males and females. The major theme of this program is the study of apoptosis in colon carcinogenesis and colon cancer chemoprevention. Studies in experimental rodent models and humans indicate that genetic and intestinal luminal risk factors decrease cell turnover, in part by decreasing apoptosis, in normal and neoplastic colonic tissues. Intestinal luminal risk factors include the secondary bile acids, which are affected by both genetic and dietary factors. Our program addresses both genetic and intestinal luminal risk factors, as we hypothesize that common signaling and metabolic pathways downstream of both these factors mediate cell turnover in colonic tissues and, subsequently, colon cancer risk. A corollary of this hypothesis is that these downstream pathways are rational targets for colon cancer chemoprevention strategies in humans. To test this hypothesis, we have designed projects and cores that are interactive and complementary. One project studies biochemical effectors of genes, including the Ki-ras oncogene and the APC and p53 tumor suppressor genes, which are frequently mutated in human colon cancers. A second project focuses on the role of nitric oxide in bile acid induced apoptosis. The third project emphasizes studies of the AP-1 transcription factor, which is involved in signaling pathways mediated by both APC and bile acids. The specific aims of the projects are to determine the roles of genetic and intestinal luminal risk factors in cell turnover in colonic tissues, to describe mechanisms underlying these processes, and to investigate the consequences of specific pharmacological and/or dietary interventions on cell turnover and colon carcinogenesis. The projects will address these aims using genetically altered cell culture and rodent models of colon cancer, and a variety of biochemical, molecular and cellular biology technologies. Four cores provide support in cell and tissue pathology, breeding and maintaining genetically altered rodent models of colon carcinogenesis, biometry and administration and evaluation. The long-term goal of the Apoptosis in Colon Cancer Chemoprevention Program Project Grant is to understand mechanisms of colon carcinogenesis in humans and then to use this information to establish the rational for strategies of colon cancer prevention and/or treatment.