Long-Chain Fatty Acids, Oxidative Stress and Colorectal Neoplasm Risk

长链脂肪酸、氧化应激和结直肠肿瘤风险

基本信息

批准号：
8549124
负责人：
Harvey J. Murff
金额：
$ 10.11万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8549124
关键词：
Abbreviations Animal Model Anti-Inflammatory Agents Anti-inflammatory Antioxidants Arachidonic Acids Biological Biological Markers Cancer Etiology Case-Control Studies Cell Cycle Checkpoint Cell Proliferation Chronic Clinical Clinical Data Colonoscopy Colorectal Colorectal Adenoma Colorectal Cancer Colorectal Neoplasms Colorectal Polyp Consumption DNA Damage DNA Repair Data Diet Dietary Factors Dinoprostone Docosahexaenoic Acids Dysplasia Eicosanoids Erythrocytes Exhibits Experimental Models F2-Isoprostanes Fatty Acids Fish Oils Fishes Free Radicals Funding Gene Mutation Goals Homeostasis Human Individual Inflammation Inflammatory Isoprostanes Lesion Ligands Linoleic Acids Lipid Peroxidation Malignant Neoplasms Marines Mediating Membrane Omega-3 Fatty Acids Oxidative Stress PTGS2 gene Pathway interactions Phospholipids Polyps Polyunsaturated Fatty Acids Post-Translational Protein Processing Premalignant Production Property Prostaglandin Receptor Prostaglandin-Endoperoxide Synthase Prostaglandins Proteins Qualifying Reporting Research Research Proposals Risk Rodent Model Sampling Second Primary Cancers Supplementation Tennessee Testing Tissues United States Universities Villous Work adenoma alpha-Linolenic Acid base carcinogenesis eicosapentanoic acid lifestyle factors long chain fatty acid monocyte mortality public health relevance research study urinary

项目摘要

DESCRIPTION (provided by applicant):Colorectal cancer is the third most common cancer and the second leading cause of cancer related mortality in the United States. Chronic inflammation and genotoxic free radicals are contributors to colorectal carcinogenesis. As such, our long-term goals are to identify and evaluate lifestyle and dietary factors that can reduce the risk of colorectal cancer through direct modulation of oxidative stress and chronic inflammation. Eicosapentanoic acid is an omega-3 polyunsaturated fatty acid found predominately in marine fish and has consistently demonstrated cancer inhibitory activity in animal models. Eicosapentanoic acid exhibits anti- inflammatory actions while arachidonic acid, an omega-6 polyunsaturated fatty acid, appears pro- inflammatory. Our overarching hypothesis is that individuals with increased dietary ratios of arachidonic acid to eicosapentanoic acid will have an increased risk of colorectal adenoma and that this increased risk is mediated through pro-inflammatory eicosanoids and increased oxidative stress. The specific aims of this research proposal are: 1) To test the hypothesis that a greater erythrocyte phospholipid membrane arachidonic acid to eicosapentanoic acid ratio is associated with an increased risk of colorectal adenomas; 2) To test the hypothesis that an increase in urinary levels of F2-isoprostanes is associated with an increase risk of colorectal adenomas while an increase in urinary levels of F3-isoprostanes is associated with a decreased risk of colorectal adenomas and; 3) To test the hypothesis that a greater arachidonic acid to eicosapentanoic acid ratio is associated with increased levels of prostaglandin E2 and urinary F2-isoprostanes and decreased levels of urinary F3-isoprostanes. To complete these aims we will perform a case-control study of 700, non-advanced colorectal adenomas, 350 advanced colorectal adenoma cases and 1050 polyp-free controls using data collected as part of the Tennessee Colorectal Polyp Study. Our research team is uniquely qualified to complete these aims as all samples and clinical data needed for the study have been collected as part of the on-going Tennessee Colorectal Polyp Study, the largest colonoscopy-based adenoma case-control study in the United States. In addition, our colleagues at Vanderbilt University are global leaders in eicosanoid research. The results from these experiments will contribute to our understanding of the colorectal cancer protective ability of eicosapentanoic acid in humans as well as potential mechanisms underlying this effect. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer related mortality in the United States. Omega-3 fatty acids, as found in fish and fish oil supplements, are being increasingly consumed because of their reported anti-inflammatory properties. The purpose of this study is to determine if omega-3 fatty acids reduce the risk of colorectal adenomas and diminishes the production of inflammatory and oxidative stress biomarkers.

描述（由申请人提供）：大肠癌是美国第三大常见的癌症，也是与癌症相关死亡率的第二大主要原因。慢性炎症和遗传毒性自由基是结直肠癌发生的因素。因此，我们的长期目标是识别和评估生活方式和饮食因素，可以通过直接调节氧化应激和慢性炎症来降低结直肠癌的风险。 eicosapentanoic酸是一种主要在海洋鱼类中发现的omega-3多不饱和脂肪酸，并且在动物模型中一直表现出癌症抑制活性。 eicosapentanoic酸表现出抗炎性作用，而金黄酮（Omega-6多不饱和脂肪酸）似乎是炎症性的。我们的总体假设是，蛛网膜酸饮食比增加的个体将增加结直肠腺瘤的风险，并且这种增加的风险是通过促炎的类花生酸酯和增加的氧化应激来介导的。该研究提案的具体目的是：1）检验以下假设：较大的红细胞磷脂膜花生四烯酸与eicosapentanoic酸比率与大肠腺瘤的风险增加有关； 2）检验以下假设：F2-异前列腺尿液水平的升高与大肠腺瘤的风险增加有关，而F3-异丙型尿液水平的增加与结直肠腺瘤的风险降低有关。 3）为了检验较大的花生四烯酸与Eicosapentanoic酸比的假设与前列腺素E2和尿液F2-异前体的水平升高以及尿液F3-异丙烷基水平降低有关。为了完成这些目的，我们将使用作为田纳西州大肠息肉研究的一部分收集的数据，对700个，非先进的结直肠腺瘤，350个晚期大肠腺瘤病例和1050次无息肉对照进行的病例对照研究。我们的研究团队具有独特的资格来完成这些目标，因为该研究所需的所有样本和临床数据是作为正在进行的田纳西州近直肠息肉研究的一部分，这是美国最大的基于结肠镜检查的最大腺瘤病例对照研究。此外，我们在范德比尔特大学的同事是eicosanoid Research的全球领导者。这些实验的结果将有助于我们理解人类中eicosapentanoic酸的结直肠癌保护能力以及这种作用的潜在机制。公共卫生相关性：大肠癌是美国与癌症相关死亡率的第二大主要原因。在鱼油补充剂中发现的omega-3脂肪酸由于报道的抗炎特性而被日益消耗。这项研究的目的是确定omega-3脂肪酸是否降低了结直肠腺瘤的风险，并减少了炎症和氧化应激生物标志物的产生。