PROSTAGLANDINS AND COLON ADENOMAS

描述(由申请人提供)： 前列腺素代谢与非类固醇抗炎药(NSAIDs) 为结肠癌的化学预防提供了一条很有前途的途径。非甾体抗炎药 抑制前列腺素H合成酶(PTGS)。因此，一个假设是 前列腺素途径中自然产生的遗传变异可能会模仿 非甾体抗炎药的作用和对生化机制的阐明。这条路 提出了一种由胞浆磷脂酶定义的核前列腺素途径。 A2(CPLA2)、前列腺素H合成酶2(Ptgs2或COX-2)、造血 前列腺素D合成酶与过氧化物酶体增殖物激活受体 Gamma(PPARG)。之前的工作主要集中在Ptgs2上，包括一个新的突变 和一项病例对照研究。拟议中的项目 通过分析PGDS进一步发展了这一假说，PGDS是一种关键酶，它具有 几乎没有受到关注。具体目标是：(1)发展高效 已鉴定的PGDS变异体的表达分析；(2) 建立一种基因敲除小鼠模型以定量测定结肠腺瘤与 以及(3)制定关于先心病患病率的试点病例对照数据。 结直肠腺瘤与PGDS变异的关系。方法：体外实验 翻译、细菌和/或杆状病毒检测将用于表达 PGDS的变异体。林修博士(大阪生物科学研究所)将 提供在建议工作中使用的PGDS基因敲除鼠标。一只老鼠 携带PGDS基因敲除的基因将与商业上可获得的 容易患息肉病的菌株，以及基因敲除对息肉细胞数量和大小的影响 腺瘤将被确定。试点病例对照分析的受试者 将来自两项现有研究：Kaiser乙状结肠镜检查研究(1700 受试者)和北卡罗来纳大学结肠镜检查研究(800名受试者)。 分子基因分型将被用来评估PGDS变异体在 与Ptgs2变体相结合。拟议的研究应有所改进 了解非类固醇抗炎药的预防机制，并可能导致新的 化学预防药物的靶标。

DESCRIPTION (provided by applicant): Prostaglandin metabolism and nonsteroidal anti-inflammatory drugs (NSAIDS) represent a promising pathway for chemoprevention of colon cancer. NSAIDs inhibit prostaglandin H synthase (PTGS) enzymes. Therefore, one hypothesis is that naturally occurring genetic variants in a prostaglandin pathway may mimic the effect of NSAIDs and shed light on biochemical mechanisms. The pathway proposed is a nuclear prostaglandin pathway defined by cytosolic phospholipase A2 (cPLA2), prostaglandin H synthase 2 (PTGS2, or COX-2), hematopoietic prostaglandin D synthase (PGDS),and peroxisome proliferator-activated receptor gamma (PPARG). Previous work has focused on PTGS2, including a novel mutation among African Americans and a case-control study. The proposed project develops the hypothesis further by analyzing PGDS, a key enzyme that has received little attention. Specific aims are to: (1) develop efficient expression assays for PGDS variants that have already been identified; (2) develop a knockout mouse model to quantitate colon adenomas in relation to variants in PGDS; and (3) develop pilot case-control data on prevalence of colorectal adenomas in relation to PGDS variants. Methods: In vitro translation, bacterial, and/or baculovirus assays will be used for expression of PGDS variants. Dr. Osamu Hayaishi (Osaka Bioscience Institute) will provide the Pgds knockout mouse for use in the proposed work. A mouse carrying the Pgds knockout will be bred with a commercially available polyposis-prone strain, and the effect of the knockout on number and size of adenomas will be determined. Subjects for the pilot case-control analysis will come from two existing studies: a Kaiser sigmoidoscopy study (1,700 subjects) and a University of North Carolina colonoscopy study (800 subjects). Molecular genotyping will be used to assess the effect of PGDS variants in combination with PTGS2 variants. The proposed study should improve understanding of the mechanism of prevention by NSAIDs and may lead to new targets for chemopreventive agents.