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: 7893330
• 负责人: Dean E. Brenner
• 金额: $ 88.74万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893330
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Arachidonic Acids; Biological Assay; Biological Markers; Cardiovascular system; Colon; Colorectal; Colorectal Adenocarcinoma; 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; Preventive Intervention; 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; Urine; Wild Type Mouse; base; cancer prevention; carcinogenesis; colorectal cancer prevention; cyclooxygenase 1; cyclooxygenase 2; design; feeding; in vivo; inhibitor/antagonist; mouse model; neoplastic; 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 需要确定和开发更有利的基于治疗指数的癌症预防药物。 干预措施。本项目的总体目标是检验用iu 3脂肪酸替代106脂肪酸的假设。 结肠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）可用于胰高血糖素-H脱氢酶（PGHS）-1和2，以减少局部 前列腺素（PG）E2浓度。结肠粘膜PGE_2减少可减少癌变 应激并最终减少结肠上皮中瘤形成的发展。我们还假设 足以减少局部PGE 2的鱼油剂量可以通过血浆EPA 1AA比率来预测， 个性化。PGE 2浓度的降低足以减少增殖并增强增殖。 可以研究结肠直肠粘膜隐窝的细胞凋亡。目标#1将定义对饮食的剂量反应 鱼油在小鼠中的作用以及血浆和结肠粘膜EPA：AA比率在减少后的关系 PGHS-1和PGHS-2野生型小鼠的结肠粘膜中的PGE 2的量将被喂食配制成匹配多个 人体脂肪酸摄入量。血浆和结肠粘膜EPA：AA比值和PGE_2浓度 将分析结肠粘膜和尿液。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。临床试验将确定是否鱼油补充剂在人类的一个 正常饮食可以产生在小鼠模型中定义的结肠直肠粘膜和血浆EPA 1AA比率， 降低大肠黏膜PGE 2，降低大肠隐窝增殖指数，增强细胞凋亡 独立贝叶斯驱动的生物标志物适应性I期设计基于个体差异个体化剂量 生物标志物响应。在该项目中获得的数据将确定可行性，未来的设计和 β 3脂肪酸作为结直肠癌潜在预防剂的II期临床试验的生物标志物终点 腺癌