GENETIC VARIABILITY AS PROGNOSTIC OR PREDICTIVE FACTORS IN COLORECTAL INTRAEPITHE

遗传变异作为结直肠上皮内的预后或预测因素

• 批准号: 7383727
• 负责人: EUGENE W GERNER
• 金额: $ 34.03万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7383727
• 关键词: Affect; Age; Alleles; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Aspirin; Biological Availability; Biological Markers; Blood Cells; Cancer Etiology; Cessation of life; Characteristics; Chemoprevention; Chemopreventive Agent; Colon Carcinoma; Colonic Polyps; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Intraepithelial Neoplasia; Cultured Cells; DL-alpha-Difluoromethylornithine; Detection; Development; Diagnosis; Diet; Disease; Drug Exposure; Drug Interactions; Ethnic Origin; Fiber; Flavins; Gender; Genes; Genetic; Genetic Determinism; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Human; Human Volunteers; Incidence; Individual; Integration Host Factors; Intraepithelial Neoplasia; Joints; Lesion; Malignant Neoplasms; Measures; Meta-Analysis; Metabolism; Methods; Mixed Function Oxygenases; Non-Steroidal Anti-Inflammatory Agents; Odds Ratio; Ornithine Decarboxylase; Participant; Pharmaceutical Preparations; Polyamines; Polyp Prevention Trial; Predictive Factor; Prevention; Prevention therapy; Preventive; Progress Reports; Prostaglandins; Recurrence; Risk; Single Nucleotide Polymorphism; Source; Spermidine; Spermidine/Spermine N1-Acetyltransferase; Spermine; Staging; Sulindac; Testing; Tissues; Ursodeoxycholic Acid; Variant; Wheat Bran; Woman; adenoma; base; cancer prevention; clinically significant; cyclooxygenase 1; improved; men; prognostic; promoter; prospective; response; trait; urinary

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.

该项目的翻译目标是确定可用于 单独定制结肠癌预防治疗，以减少临床显着的发展 人类患结肠癌的风险较高的结直肠上皮内瘤变（IEN）。 该提案要测试的假设是个体对某些结肠癌的反应 预防药物，包括特定的非甾体抗炎药 (NSAIDS) 和靶向药物 多胺代谢的特征受到宿主因素的影响，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，我们要确定遗传变异是否存在 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/或黄素是否存在变异 单加氧酶 3 (FM03) 基因调节化学预防剂的作用和/或生物利用度 舒林酸和二氟甲基鸟氨酸 (DFMO) 联合用药可减少结肠息肉 复发。其次，我们将确定 ODC G316A 启动子变体等位基因之间是否存在关联 阿司匹林使用者的腺瘤复发涉及其他影响多胺代谢的基因。这个目标 将重点关注亚精胺/精胺 N1-乙酰转移酶 (SSAT)，并确定是否乙酰化多胺， 它们是多胺输出的底物，可能是 NSAID 作用的有用生物标志物。第三，我们将评估 阿司匹林使用、多胺饮食来源和基因修饰剂的独立和联合影响 多胺合成（ODC）对结直肠腺瘤复发风险的影响。我们将汇集来自三个腺瘤的数据 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）结肠息肉预防试验评估这些对整体腺瘤的影响 复发和晚期病变复发。 该项目的长期目标是确定宿主和腺瘤因素的影响作为预测因子 对结直肠腺瘤，特别是晚期、有临床意义的病变进行化学预防的功效， 并利用这些信息来降低结直肠癌高风险个体的发病率 患上这种疾病。