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: 6915706
• 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/6915706
• 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）：在过去四十年中食管腺癌增加的原因尚未确定。 H.幽门螺杆菌是发展消化性溃疡疾病和胃癌的主要危险因素，CagA +菌株的危险性更高。 H.幽门可以减少食管中的酸产生和反流。 宿主对H. pylori感染与IL-1 β多态性有关。 该研究计划将调查IL-1 β基因座的多态性如何影响食管癌发生的风险。 假设通过调节宿主对H.幽门螺杆菌和随后的酸产生，IL-1 β-31 *T等位基因和功能相关的IL-1 RN等位基因降低食管炎症、化生和腺癌的风险。 为了检验这一假设，将对转诊接受门诊内镜检查的成人患者进行前瞻性横断面研究。 将通过问卷调查获得人口统计学和临床数据。 将从患者中采集血液，以测量IgG至全细胞H。pylori抗原以及CagA，并从分离的白细胞中提取DNA用于IL-1基因分型。 将从胃和远端食管进行活检，患者将在内镜评价后接受24小时pH监测，以评价食管酸暴露。 活组织切片将用于培养H。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，以及测量食管中的Ki-67和考克斯-2表达。 具体目标#1是确定H的影响。py/ori菌株特征对胃和食管粘膜IL-1 β蛋白表达的影响，以及对食管腺癌前体病变（炎症、化生和异型增生）发展的影响。 具体目标#2是确定IL-1 β-31和IL-1 RN等位基因与食管酸暴露以及与H.幽门定植。 特别是，在有或无H.将评价幽门定殖。 具体目标#3是评估H的效果。幽门螺杆菌根除对GEJ细胞增殖以及与IL-1 β-31等位基因相关的IL-1 β和考克斯-2表达的影响。 通过这些研究，应该能够评估微生物和宿主基因型对腺癌风险的贡献，以及开始定义相关的细胞途径。