PROSTAGLANDINS AND COLON ADENOMAS

描述（由申请人提供）： 前列腺素代谢和非甾体抗炎药（NSAIDS） 代表了结肠癌化学预防的一种有前途的途径。 NSAIDs 抑制前列腺素H合酶（PTGS）酶。 因此，一个假设是， 前列腺素途径中天然存在的遗传变异可能会模仿 NSAIDs的作用，并阐明生化机制。 该途径 提出了一种由胞浆磷脂酶定义的核前列腺素途径 A2（cPLA 2）、前列腺素H合酶2（PTGS 2或考克斯-2）、造血 前列腺素D合酶（PGDS）和过氧化物酶体增殖物激活受体 γ（PPARG）。 以前的工作集中在PTGS 2，包括一种新的突变 和一项病例对照研究。 拟建项目 通过分析PGDS进一步发展了这一假设，PGDS是一种关键酶， 很少受到关注。 具体目标是：（1）发展高效 已经鉴定的PGDS变体的表达测定;（2） 开发基因敲除小鼠模型，以定量结肠腺瘤与 PGDS的变异;（3）开发关于PGDS患病率的试点病例对照数据， 结直肠腺瘤与PGDS变异体的关系。 方法：体外 翻译、细菌和/或杆状病毒测定将用于表达 PGDS变体。 Osamu Hayaishi博士（大坂生物科学研究所）将 提供Pgds敲除小鼠用于拟定工作。 鼠标 携带Pgds基因敲除的小鼠将与市售的 的数量和大小的影响，敲除 将确定腺瘤。 初步病例对照分析的受试者 将来自两个现有的研究：一个凯撒乙状结肠镜研究（1700 受试者）和北卡罗来纳州大学结肠镜检查研究（800名受试者）。 将使用分子基因分型来评估PGDS变体在 与PTGS 2变体组合。 拟议的研究应改进 了解NSAIDs的预防机制，并可能导致新的 化学预防剂的目标。

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.