GENES, ANTICARINOGENS AND COLON NEOPLASMS

描述（由申请人提供）：长期目标是利用遗传学和 流行病学，以确定预防结肠癌的目标。的 前列腺素生物合成是一个有前途的目标，因为 阿司匹林可以预防某些结肠癌。假设是基因 前列腺素产生的变化可能与阿司匹林的作用相似， 关于预防机制。工作将集中在自然发生的突变， 人和小鼠核前列腺素途径中的靶向突变 定义为：胞质磷脂酶A前列腺素H合酶2（PTGS 2/考克斯-2）， 造血前列腺素D合酶（H-PGDS）和过氧化物酶体 增殖物激活受体γ该项目建立在10个发现之间 PTGS 2/考克斯-2突变（Val 5llAla）的非洲裔美国人的百分比接近 酶的活性部位。具体目标是：（1）进行病例对照 大肠腺瘤和癌症患病率与遗传因素的分析 PTGS 2/考克斯-2和H-PGDS中的变异;（2）评估人类个体间变异 PTGS 2/考克斯-2活性相对于Va 1511 Ala酶变体;（3） 开发H-PGDS中鉴定的新变体的体外表达测定;以及 (4)开发H-Pgds变异敲除小鼠模型以补充人类 流行病学研究。三项病例对照研究将用于评估 遗传变异对结肠肿瘤的影响：Kaiser乙状结肠镜检查研究 腺瘤（1,700例受试者）;北卡罗来纳州大学的一项结肠镜检查研究， 腺瘤（800例受试者）;非裔美国人癌症病例和对照 （大约400人）来自多种族队列研究。结果可能会导致更好的 了解阿司匹林和非甾体类药物的保护机制 消炎药

DESCRIPTION (provided by applicant): The long-term goal is to use genetics and epidemiology to identify targets for prevention of colon cancer. The application is on prostaglandin biosynthesis as a promising target, because aspirin prevents some cases of colon cancer. The hypothesis is that genetic variation in prostaglandin production may mimic aspirin effects and shed light on preventive mechanisms. Work will focus on naturally-occurring mutations in people and targeted mutations in mice in a nuclear prostaglandin pathway defined by: cytosolic phospholipase A prostaglandin H synthase 2 (PTGS2/Cox-2), hematopoietic prostaglandin D synthase (H-PGDS), and peroxisome proliferator-activated receptor gamma. The project builds on discovery among 10 percent of African Americans of a PTGS2/Cox-2 mutation (Val5llAla) near the active site of the enzyme. Specific aims are to: (1) conduct case-control analyses on prevalence of colorectal adenomas and cancer in relation to genetic variants in PTGS2/Cox-2 and H-PGDS; (2) assess human interindividual variation in PTGS2/Cox-2 activity in relation to the Va151 1 Ala enzyme variant; (3) develop in vitro expression assays for novel variants identified in H-PGDS; and (4) develop a knockout mouse model of variation in H-Pgds to complement human epidemiologic studies. Three case-control studies will be used to assess effects of genetic variation on colon neoplasms: a Kaiser sigmoidoscopy study of adenomas (1,700 subjects); a Univ. of North Carolina colonoscopy study of adenomas (800 subjects); and African American cancer cases and controls (roughly 400) from the Multiethnic Cohort Study. Results may lead to better understanding of protective mechanisms involving aspirin and nonsteroidal anti-inflammatory drugs.