H. PYLORI AND IL-1Beta IN ESOPHAGEAL ONCOGENESIS

食管癌发生中的幽门螺杆菌和 IL-1Beta

• 批准号: 6767037
• 负责人: FRITZ FRANCOIS
• 金额: $ 13.81万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6767037
• 关键词: Helicobacter; adenocarcinoma; biopsy; blood chemistry; cancer risk; clinical research; endoscopy; enzyme linked immunosorbent assay; esophagogastric junction; esophagus neoplasm; gastric acid; genetic polymorphism; genotype; host organism interaction; human subject; immunocytochemistry; infection related neoplasm /cancer; interleukin 1; parasite /microorganism carcinogen; polymerase chain reaction; posttranslational modifications; prostaglandin endoperoxide synthase; questionnaires; reflux esophagitis; statistics /biometry; tissue /cell culture

DESCRIPTION (provided by applicant): The reasons for the rise in esophageal adenocarcinoma in the last four decades are yet to be determined. H. pylori is the major risk factor for the development of peptic ulcer disease and gastric cancer, with the risk being higher with CagA + strains. The gastric inflammatory response to H. pylori may decrease acid production and reflux in the esophagus. Differences in the host mucosal inflammatory response to H. pylori have been attributed to IL-1beta polymorphisms. The study plan will investigate how polymorphisms in the IL-1beta locus might affect the risk for esophageal cancer development. The hypothesis is that by modulating the host inflammatory response to H. pylori and subsequent acid production, the IL-1beta-31*T allele and the functionally related IL-1RN allele decrease the risk of esophageal inflammation, metaplasia, and adenocarcinoma. To test this hypothesis, a prospective cross-sectional study of adult patients referred for ambulatory endoscopy will be performed. Demographic and clinical data will be obtained via questionnaire. Blood will be obtained from patients to measure lgG to whole cell H. pylori antigens as well as to CagA, and DNA will be extracted from isolated leukocytes for IL-1 genotyping. Biopsies will be taken from the stomach and distal esophagus, and patients will undergo 24-h pH monitoring after endoscopic evaluation to evaluate esophageal acid exposure. Biopsies will be used to culture H. pylori directly from the stomach, to identify the organism by histology, to assess the histologic status of the tissues, to measure IL-1 in the stomach and esophagus, and to measure Ki-67 and COX-2 expression in the esophagus. Specific aim #1 is to determine the effect of H. py/ori strain characteristics on gastric and esophageal mucosal IL-1beta protein expression, and on the development of the precursor lesions (inflammation, metaplasia, and dysplasia) to esophageal adenocarcinoma. Specific aim #2 is to determine the prevalence of the IL-1beta-31and IL-1RN alleles in relation to esophageal acid exposure, also in relation to H. pylori colonization. In particular, the effect of the IL-1beta-31and IL-1RN alleles on gastroesophageal junction (GEJ) cellular proliferation and cyclooxygenase-2 (COX-2) expression in patients with or without H. pylori colonization will be evaluated. Specific aim #3 is to evaluate the effect of H. pylori eradication on GEJ cellular proliferation, and on IL-1beta and COX-2 expression in relation to the IL-1beta-31 allele. From these studies, both the microbial contribution and the host genotype contribution to adenocarcinoma risk should be able to be assessed, as well as to begin to define relevant cellular pathways.

描述（由申请人提供）：在过去的四十年中，食管腺癌发病率上升的原因尚未确定。幽门螺杆菌是消化性溃疡疾病和胃癌发生的主要危险因素，且CagA +菌株的风险更高。胃对幽门螺杆菌的炎症反应可减少食道的胃酸产生和反流。宿主粘膜对幽门螺杆菌炎症反应的差异归因于il -1 β多态性。该研究计划将调查il -1 β位点的多态性如何影响食管癌发展的风险。假设是通过调节宿主对幽门螺杆菌的炎症反应和随后的酸产生，il -1 β -31*T等位基因和功能相关的IL-1RN等位基因降低了食管炎症、化生和腺癌的风险。为了验证这一假设，一项前瞻性横断面研究的成人患者转诊门诊内窥镜将进行。人口统计和临床数据将通过问卷调查获得。将从患者身上采集血液，测量lgG对全细胞幽门螺杆菌抗原和CagA的含量，并从分离的白细胞中提取DNA，进行IL-1基因分型。将从胃和食管远端进行活检，患者将在内镜评估后进行24小时pH监测以评估食管酸暴露。活组织检查将用于直接从胃中培养幽门螺杆菌，通过组织学鉴定生物体，评估组织的组织学状态，测量胃和食管中的IL-1，以及测量食管中Ki-67和COX-2的表达。