Prostaglandin Synthesis, Genetics and Colorectal Cancer

前列腺素合成、遗传学和结直肠癌

基本信息

批准号：
7367004
负责人：
CORNELIA M ULRICH
金额：
$ 55.59万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7367004
关键词：
ALOX15 gene Acids Adenomatous Polyposis Coli Affect Amino Acids Anti-Inflammatory Agents Anti-inflammatory Arachidonate 15-Lipoxygenase Arachidonic Acids Aspirin Biochemical Biological Assay Biological Markers C-reactive protein Candidate Disease Gene Case-Control Studies Characteristics Chemoprevention Chemopreventive Agent Colon Colon Carcinoma Colorectal Colorectal Adenoma Colorectal Cancer Colorectal Neoplasms Colorectal Polyp Consumption Data Dietary Factors Dietary Fatty Acid Dietary intake Dinoprostone Drug Delivery Systems Drug usage Eicosanoids Enzymes Epoprostenol Family history of Genes Genetic Genetic Polymorphism Genetic Transcription Genetic Variation Genotype Genus Cola Goals Grant Haplotypes Health Status Impact evaluation Inflammation Inflammatory Intake Interdisciplinary Study Investigation Isoenzymes Link Lipoxygenase 2 Metabolic Pathway Microsatellite Instability Mutation Omega-3 Fatty Acids PTGS1 gene PTGS2 gene Participant Pathway interactions Patients Peroxides Pharmaceutical Preparations Physical activity Polyps Population Process Production Prostacyclin synthase Prostaglandin D2 Prostaglandin E Receptor Prostaglandin H2 Prostaglandin-Endoperoxide Synthase Prostaglandins Prostaglandins I Proteins Randomized Controlled Trials Recruitment Activity Rectal Cancer Recurrence Research Research Design Research Personnel Risk Risk Reduction Role Signal Transduction Signaling Molecule Subgroup TP53 gene Testing Texas Thromboxanes Toxic effect Variant arachidonate base cancer genetics cancer risk carcinogenesis cost cyclooxygenase 1 cyclooxygenase 2 enzyme activity genetic variant glutathione peroxidase interdisciplinary collaboration interest programs receptor response tumor

项目摘要

Aspirin and other non-steroidal inflammatory drugs (NSAIDs) appear to be effective chemopreventive agents against colorectal carcinogenesis. The recognized NSAID targets are cyclooxygenase-1 and -2 (COX1 and 2, or PTGS1 and 2), key enzymes in conversion of arachidonate to prostaglandin (PG) signaling molecules. This interdisciplinary study will evaluate the association between colon and rectal cancer and genetic variability in enzymes and receptors linked to the synthesis of prostaglandins and related arachidonate metabolites. We have identified polymorphisms and haplotypes in key proteins in these pathways. Target proteins include PTGS1 and 2, the thromboxane, prostacyclin, PGD2 and PGE2 synthases, the 5, 12- and 15- lipoxygenases (ALOX5, ALOX12 and ALOX15), PGE2 receptors, and glutathione peroxidases. We will genotype two existing case-control study populations comprising 1676 colon cancer cases with 2004 controls and 827 rectal cancer cases with 1031 controls. Participants were recruited as part of two multi-center, population-based case-control studies in which information on health status, family history, dietary factors (including intakes of n-6 and n-3 fatty acids), physical activity, and NSAID use has been obtained. We propose to use a study design that maximizes available information regarding genetic variability in these key pathways by examining gene-wide haplotypes for sequenced genes (e.g., PTGS1, PTGS2, ALOX12, ALOX15, PGE2 synthase and PGE2 receptors), and a candidate-polymorphism approach for variants with supporting evidence for functional impact. Interactions with NSAID use and dietary fatty acid intakes will be investigated to determine responses of genetically defined subgroups. Using biochemical assays, we will also establish the enzymatic and pharmacological impact of polymorphisms in several key proteins. This biochemical information will be used to inform the genotyping results and the statistical analysis. Results from this collaborative study will provide a powerful test of the role of genetic variability in prostaglandin or eicosanoid synthesis in colorectal carcinogenesis and chemoprevention. They will also advance tailoring of chemoprevention in a way that maximizes benefit and minimizes toxicity.

阿司匹林和其他非甾体炎症药（NSAID）似乎是针对大肠癌发生的有效的化学预防剂。公认的NSAID靶标是环氧酶-1和-2（COX1和2，或PTGS1和2），关键酶转化为蛛网膜酸酯酯向前列腺素（PG）信号分子。这项跨学科研究将评估与前列腺素和相关蛛网酸代谢物合成的酶和受体中结肠和直肠癌之间的关联。我们已经确定了这些途径中关键蛋白中的多态性和单倍型。靶蛋白包括PTGS1和2，血栓烷，前列环蛋白，PGD2和PGE2合酶，5、12-和15-脂氧酶（Alox5，Alox12和Alox15），PGE2受体，以及谷胱甘肽过氧化物酶。我们将基因型两种现有的病例对照研究人群，其中包括1676例具有2004对照的结肠癌病例和827例直肠癌病例，有1031例对照。参与者被招募为两个基于人群的病例对照研究的一部分，其中已获得有关健康状况，家族史，饮食因素（包括N-6和N-3脂肪酸的摄入量），体育活动和NSAID使用的信息。我们建议使用一项研究设计，该设计通过检查序列基因的基因范围的单倍型（例如PTGS1，PTGS1，PTGS2，Alox12，Alox15，PGE2，PGE2合成酶和PGE2受体），以及对VARMOLPHIST的支持，可为差异构成支持的证据。将研究与NSAID使用和饮食脂肪酸摄入量的相互作用，以确定遗传定义的亚组的反应。使用生化测定，我们还将在几种关键蛋白质中建立多态性的酶促和药理学影响。该生化信息将用于告知基因分型结果和统计分析。这项协作研究的结果将对遗传变异性在前列腺素或类糖酸合成中的作用进行有力测试。他们还将以最大程度地提高毒性和最小化毒性的方式来推动化学预防量身定制。