GENETIC VARIABILITY AS PROGNOSTIC OR PREDICTIVE FACTORS IN COLORECTAL INTRAEPITHE

该项目的翻译目标是确定可用于 个性化定制结肠癌预防治疗，以减少临床显著的发展 结直肠上皮内瘤变（IEN）在人类结肠癌的风险增加。 本提案中要检验的假设是，个体对某些结肠癌的反应 预防剂，包括特异性非甾体抗炎药（NSAIDS）和靶向 多胺代谢的特征受宿主因素的影响，包括遗传背景和饮食。 提出了三个具体目标来检验这一假设。首先，我们将确定是否遗传变异， 编码鸟氨酸脱羧酶（ODC）的宿主基因可以解释结直肠癌的个体差异， 粘膜多胺含量。我们还将确定ODC和/或黄素 单加氧酶3（FM 03）基因调节化学预防剂的作用和/或生物利用度 联合使用舒林酸和二氟甲基鸟氨酸（DFMO）减少结肠息肉 复发其次，我们将确定ODC G316 A启动子变异等位基因之间的关联是否 阿司匹林使用者的腺瘤复发与其他影响多胺代谢的基因有关。这一目标 将集中在亚精胺/精胺N1-乙酰转移酶（SSAT），并确定是否乙酰化多胺， 其是多胺输出的底物，可能是NSAID作用的有用生物标志物。第三，我们将评估 阿司匹林的使用，多胺的饮食来源和基因修饰剂的独立和联合作用， 多胺合成（ODC）对结直肠腺瘤复发风险的影响。我们将汇总三个腺瘤的数据， 复发研究，包括息肉预防试验（PPT），麦麸纤维（WBF）和 熊去氧胆酸（UDCA）预防结肠息肉试验，以评估这些对总体腺瘤的影响 复发和晚期病变的复发。 该项目的长期目标是确定宿主和腺瘤因素的影响，作为肿瘤发生的预测因子。 用于结肠直肠腺瘤，特别是晚期的、临床上显著的病变， 并利用这些信息来降低结肠直肠癌高危人群的发病率， 发展这种疾病。

The translational goal of this project is to identify host characteristics that can be used to individually tailor colon cancer prevention therapy in order to reduce the development of clinically significant colorectal intraepithelial neoplasia (IEN) in humans with elevated risk for colon cancer. The hypothesis to be tested in this proposal is that individual responses to certain colon cancer preventive agents, including specific non-steroidal anti-inflammatory drugs (NSAIDS) and agents that target features of polyamine metabolism, are influenced by host factors, including genetic background, and diet. Three specific aims are proposed to test this hypothesis. First, we will determine if genetic variability in the host gene encoding ornithine decarboxylase (ODC) can explain individual variability in colorectal mucosal polyamine contents. We will also determine if variability in the ODC and/or the flavin monooxygenase 3 (FM03) genes modulate the action and/or bioavailability of the chemopreventive agents sulindac and difluoromethylornithine (DFMO) when given in combination for the reduction of colon polyp recurrence. Second, we will determine if the association between the ODC G316A promoter variant alleles and adenoma recurrence in aspirin users involves other genes, which affect polyamine metabolism. This aim will focus on the spermidine/spermine N1-acetyltransferase (SSAT), and determine if acetylated polyamines, which are substrates for polyamine export, may be a useful biomarker of NSAID action. Third, we will assess the independent and joint effects of aspirin use,dietary sources of polyamines, and gene modifiers of polyamine synthesis (ODC) on risk of colorectal adenoma recurrence. We will pool data from three adenoma recurrence studies, including the Polyp Prevention Trial (PPT), Wheat Bran Fiber (WBF) and Ursodeoxycholic Acid (UDCA) colon polyp prevention trials to assess these effects on overall adenoma recurrence and recurrence of advanced lesions. The long-term goal of this project is to determine the influence of host and adenoma factors as predictors of efficacy for the chemoprevention of colorectal adenomas, particularly advanced, clinically significant lesions, and to use this information to reduce the incidence of colorectal cancer in individuals with high risk of developing this disease.