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抗炎药（NSAID）似乎是对抗结直肠癌的有效化学预防剂。公认的 NSAID 靶点是环氧合酶-1 和 -2（COX1 和 2，或 PTGS1 和 2），它们是将花生四烯酸转化为前列腺素 (PG) 信号分子的关键酶。这项跨学科研究将评估结肠癌和直肠癌与前列腺素和相关花生四烯酸代谢物合成相关的酶和受体的遗传变异之间的关系。我们已经鉴定了这些途径中关键蛋白质的多态性和单倍型。靶蛋白包括 PTGS1 和 2、血栓素、前列环素、PGD2 和 PGE2 合酶、5、12-和 15-脂氧合酶（ALOX5、ALOX12 和 ALOX15）、PGE2 受体和谷胱甘肽过氧化物酶。我们将对两个现有的病例对照研究人群进行基因分型，其中包括 1676 例结肠癌病例（2004 例对照）和 827 例直肠癌病例（1031 例对照）。受试者被招募为两项多中心、基于人群的病例对照研究的一部分，其中的信息包括健康状况、家族史、饮食因素（包括 n-6 和 n-3 脂肪酸的摄入量）、体力活动和 NSAID已获得使用。我们建议使用一种研究设计，通过检查测序基因的全基因单倍型（例如 PTGS1、PTGS2、ALOX12、ALOX15、PGE2 合酶和 PGE2 受体）和候选多态性，最大化有关这些关键途径遗传变异性的可用信息。具有功能影响支持证据的变体方法。将研究非甾体抗炎药的使用和膳食脂肪酸摄入量之间的相互作用，以确定基因定义的亚组的反应。通过生化测定，我们还将确定几种关键蛋白质多态性的酶学和药理学影响。该生化信息将用于告知基因分型结果和统计分析。这项合作研究的结果将为前列腺素或类二十烷酸合成中遗传变异在结直肠癌发生和化学预防中的作用提供有力的测试。他们还将以最大化效益和最小化毒性的方式推进化学预防的定制。