P1 - Omega-3 fatty acids and Colorectal Cancer Prevention

P1 - Omega-3 脂肪酸和结直肠癌预防

• 批准号: 8729837
• 负责人: Dean E. Brenner
• 金额: $ 16.31万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8729837
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Arachidonic Acids; Biological Assay; Biological Markers; Cardiovascular system; Colon; Colorectal; Colorectal Adenocarcinoma; Cyclooxygenase Inhibitors; Data; Development; Diet; Diet Modification; Dinoprostone; Dose; Drug Formulations; Eicosapentaenoic Acid; Epidemiology; Epithelial; Epithelium; Event; Fatty Acids; Fatty acid glycerol esters; Fish Oils; Future; Genetic Polymorphism; Goals; Homeostasis; Human; Individual; Inflammatory; Intake; Intervention; Malignant Neoplasms; Mediating; Membrane; Mucous Membrane; Mus; Neoplasms; Nutritional; Omega-3 Fatty Acids; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Physiological; Plasma; Population; Predisposition; Preventive; Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Receptor Activation; Risk; Rodent; Rodent Model; S-Phase Fraction; Serum; Simulate; Source; Stress; Supplementation; Testing; Therapeutic Index; Toxic effect; Translating; Translational Research; Urine; Wild Type Mouse; base; cancer prevention; carcinogenesis; colorectal cancer prevention; cyclooxygenase 1; cyclooxygenase 2; design; feeding; in vivo; mouse model; neoplastic; preventive intervention; receptor; response

Project 1 There is a need to identify and develop more favorable therapeutic index-based cancer preventive interventions. The overall goal of this project is to test the hypothesis that substituting iu3 fatty acids for 106 fatty acids in colorectal mucosal membranes will sufficiently modify the ratio of eicosapentaenoic acid (EPA) to arachidonic acid (AA) available to prostaglandin-H synthases (PGHS)-1 and 2 to reduce local prostaglandin (PG)E2 concentrations. Reduction of colonic mucosal PGE2 will reduce the carcinogenesis stress and ultimately reduce the development of neoplasia in the colonic epithelium. We also hypothesize that the dose of fish oil sufficient to reduce local PGE2 can be predicted by plasma EPAiAA ratio and thus be individualized. The reduction of PGE2 concentrations sufficient to reduce proliferation and enhance apoptosis of the colorectal mucosal crypt may be searched. Aim #1 will define tlie dose response to dietary fish oil in mice and the relationshipo between the plasma and colonic mucosal EPA:AA ratio upon reduction of PGE2 in colonic mucosa of PGHS-1 and -2 wild type mice will be fed diets formulated to match multiple human fatty acid intakes. The plasma and colonic mucosal EPA:AA ratios and PGE2 concentrations in colonic mucosa and urine will be assayed. Data in Aim 1 are necessary to define the design of a Phase I clinical trial proposed in Aim 2. The clincal trial will determine if fish oil supplementation in humans on a normal diet can produce a colorectal mucosal and plasma EPAiAA ratio defined in the mouse models that will reduce colorectal mucosal PGE2, reduce colorectal crypt proliferation index and enhance apoptosis indicies. A Bayesian driven biomarker adaptive phase I design individualizes dose on the basis of individual biomarker response. The data obtained in this project will determine the feasibility, future design and biomarker endpoints of Phase II clinical trials of u)3 fatty acids as potential preventives of colorectal adenocarcinoma.

项目1 需要识别和开发更有利的基于治疗指数的癌症预防 干预措施。该项目的总体目标是检验用 iu3 脂肪酸替代 106 结直肠粘膜中的脂肪酸将充分改变二十碳五烯酸（EPA）的比例 花生四烯酸 (AA) 可用于前列腺素 H 合酶 (PGHS)-1 和 2，以减少局部 前列腺素 (PG)E2 浓度。减少结肠粘膜PGE2将减少癌变 压力并最终减少结肠上皮肿瘤的发展。我们还假设 足以降低局部 PGE2 的鱼油剂量可以通过血浆 EPAiAA 比率来预测，从而可以 个性化。 PGE2浓度的降低足以减少增殖并增强 可以检查结直肠粘膜隐窝的细胞凋亡。目标#1将定义饮食的剂量反应 小鼠鱼油与血浆和结肠粘膜 EPA:AA 比例降低后的关系 PGHS-1和-2野生型小鼠结肠粘膜中PGE2的含量将被喂食配制为匹配多种的饮食 人体脂肪酸的摄入量。血浆和结肠粘膜 EPA:AA 比率和 PGE2 浓度 将检测结肠粘膜和尿液。目标 1 中的数据对于定义第一阶段的设计是必要的 目标 2 中提出的临床试验。该临床试验将确定人体补充鱼油是否对 正常饮食可以产生小鼠模型中定义的结直肠粘膜和血浆 EPAiAA 比率， 会降低结直肠粘膜PGE2，降低结直肠隐窝增殖指数，增强细胞凋亡 指标。贝叶斯驱动的生物标志物适应性 I 期设计根据个体情况个性化剂量 生物标志物反应。本项目获得的数据将决定可行性、未来的设计和 u)3 脂肪酸作为结直肠潜在预防剂的 II 期临床试验的生物标志物终点 腺癌。