Apoptosis in Colon Cancer Chemoprevention

申请人的描述 结肠癌仍然是美国癌症死亡的第二大原因。 美国各州，对男性和女性都有影响。这次会议的主要主题是 该计划是关于细胞凋亡在结肠癌发生和结肠癌中的研究 化学预防。对实验啮齿动物模型和人类的研究表明 遗传和肠腔危险因素降低细胞周转率，在 部分是通过减少正常和肿瘤结肠组织中的细胞凋亡。 肠腔的危险因素包括次级胆汁酸，它们是 受遗传和饮食因素的影响。我们的计划解决了这两个问题 遗传和肠腔危险因素，正如我们假设的那样 这两个因子下游的信号和代谢通路介导细胞 结肠组织的周转和随后的结肠癌风险。一个推论 这一假设是这些下游通路是合理的目标 人类结肠癌的化学预防策略。为了检验这一假设， 我们设计了具有互动性和互补性的项目和核心。 一个项目研究包括Ki-ras在内的基因的生化效应。 癌基因和APC和P53抑癌基因，这两个基因经常 在人类结肠癌中发生突变。第二个项目侧重于硝酸盐的作用 胆汁酸中的氧化物诱导细胞凋亡。第三个项目侧重于研究 参与信号转导的AP-1转录因子 由APC和胆汁酸共同介导。这些项目的具体目标是 确定遗传和肠腔危险因素在细胞中的作用 结肠组织的周转，以描述其背后的机制 过程，并调查特定药理的后果 和/或饮食干预对细胞周转和结肠癌发生的影响。这个 项目将使用转基因细胞培养和 结肠癌的啮齿动物模型，以及各种生化、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 转基因结肠啮齿动物模型的病理学、选育和维持 致癌、生物测定、管理和评估。长期目标 细胞凋亡在结肠癌化学预防项目中的拨款是为了 了解人类结肠癌的发生机制，然后利用这个 为结肠癌制定合理的治疗策略提供信息 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.