GENES, ANTICARINOGENS AND COLON NEOPLASMS

描述(由申请者提供)：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。这个 前列腺素的生物合成是一个很有前途的目标，因为 阿司匹林可以预防某些结肠癌。假设是遗传的 前列腺素产量的变化可能模仿阿司匹林的作用并揭示 关于预防机制。工作将集中在自然发生的基因突变上 前列腺素核途径中的人和小鼠的靶向突变 定义：胞浆磷脂酶A前列腺素H合成酶2(Ptgs2/COX-2)， 造血前列腺素D合成酶与过氧化物酶体 增殖物激活受体伽马。该项目的基础是在10个国家中发现 Ptgs2/COX-2突变(Val5llAla)附近的非裔美国人的百分比 酶的活性部位。具体目标是：(1)开展病例控制 结直肠腺瘤和结直肠癌患病率与遗传因素的关系 Ptgs2/COX-2和H-PGDS的变异；(2)评估人类个体间的变异 Ptgs2/COX-2活性与Va151 1丙氨酸酶变异体的关系； 建立在H-PGDS中发现的新变异体的体外表达分析；以及 (4)建立H-PGDS基因敲除小鼠模型以补充人类 流行病学研究。将使用三项病例对照研究来评估 基因变异对结肠癌的影响：Kaiser乙状结肠镜检查研究 腺瘤(1700名受试者)；北卡罗来纳州的结肠镜检查研究 腺瘤(800名受试者)；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。结果可能会带来更好的结果 对阿司匹林和非类固醇保护机制的认识 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.