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: 8519617
• 负责人: EUGENE W GERNER
• 金额: $ 8.85万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8519617
• 关键词: Affect; Age; Alleles; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Aspirin; Biological Availability; Biological Markers; Blood Cells; Cancer Etiology; Cell Culture Techniques; Cessation of life; Characteristics; Chemoprevention; Chemopreventive Agent; Colon Carcinoma; Colonic Polyps; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Intraepithelial Neoplasia; 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; Joints; Lesion; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Measures; Meta-Analysis; Metabolism; Methods; Mixed Function Oxygenases; Non-Steroidal Anti-Inflammatory Agents; Odds Ratio; Ornithine Decarboxylase; PTGS1 gene; PTGS2 gene; Participant; Pharmaceutical Preparations; Polyamines; Polyp Prevention Trial; Predictive Factor; Prevention; Prevention therapy; Preventive; Prognostic Factor; Progress Reports; Prostaglandins; Recurrence; Risk; Single Nucleotide Polymorphism; Source; Specialized Program of Research Excellence; Spermidine; Spermidine/Spermine N1-Acetyltransferase; Spermine; Staging; Sulindac; Testing; Tissues; Ursodeoxycholic Acid; Variant; Wheat Bran; Woman; adenoma; advanced disease; base; cancer prevention; clinically significant; cyclooxygenase 1; high risk; improved; men; promoter; prospective; response; trait; treatment response; 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以用来用于的主机特征 单独量身定制结肠癌预防疗法，以减少临床意义的发展 结肠癌风险升高的人类上皮内肿瘤（IEN）。 该提议中要检验的假设是对某些结肠癌的个人反应 预防剂，包括特定的非甾体类抗炎药（NSAIDS）和针对目标的药物 多胺代谢的特征受宿主因素的影响，包括遗传背景和饮食。 提出了三个特定目标来检验这一假设。首先，我们将确定遗传变异性是否存在 宿主基因编码鸟氨酸脱羧酶（ODC）可以解释结直肠的个体变异性 粘膜多胺含量。我们还将确定ODC和/或黄素中的变异性是否存在 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 合并结合结肠息肉时给予硫酸和二氟甲基氨基氨酸（DFMO） 复发。其次，我们将确定ODC G316A启动子变体等位基因之间的关联是否 阿司匹林使用者中的腺瘤复发涉及其他基因，这些基因影响多胺代谢。这个目标 将专注于精子/精子N1-乙酰转移酶（SSAT），并确定乙酰化的多胺是否是 是多胺出口的底物，可能是NSAID作用的有用的生物标志物。第三，我们将评估 阿司匹林使用的独立和关节作用，多胺的饮食来源和基因修饰符 多胺合成（ODC）关于结直肠腺瘤复发的风险。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），小麦麸皮（WBF）和 Ursexyoxycholic（UDCA）结肠息肉预防试验，以评估这些对整体腺瘤的影响 晚期病变的复发和复发。 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素 对结直肠腺瘤的化学预防的功效，特别是晚期，临床意义的病变， 并使用这些信息来减少高风险的大肠癌的发生率 发展这种疾病。