H. PYLORI AND IL-1Beta IN ESOPHAGEAL ONCOGENESIS

描述(申请人提供)：食管腺癌在过去40年中上升的原因尚未确定。幽门螺杆菌是消化性溃疡和胃癌的主要危险因素，CagA+菌株的风险更高。幽门螺杆菌引起的胃炎性反应可能会减少食道的产酸和反流。幽门螺杆菌对宿主黏膜炎症反应的不同可归因于IL-1β基因的多态性。这项研究计划将调查IL-1β基因的多态如何影响食道癌的风险。假设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-1beta-31*T等位基因和功能相关的IL-1RN等位基因降低了食管炎、化生和腺癌的风险。为了验证这一假设，将进行一项针对成年患者的前瞻性横断面研究，这些患者接受门诊内窥镜检查。人口学和临床资料将通过问卷调查获得。将从患者身上采集血液，以检测全细胞幽门螺杆菌抗原和CagA的免疫球蛋白，并从分离的白细胞中提取DNA用于IL-1基因分型。将从胃和远端食道进行活检，患者将在内窥镜评估后接受24小时的pH监测，以评估食管酸暴露。活检将用于直接从胃培养幽门螺杆菌，通过组织学鉴定微生物，评估组织的组织状态，测量胃和食道中的IL-1，并测量食道中Ki-67和COX-2的表达。 具体目的1是确定H.py/Ori菌株的特性对胃和食道粘膜IL-1β蛋白表达的影响，以及对食管腺癌的前驱病变(炎症、化生和异型增生)发展的影响。 具体目的#2是确定IL-1β-31和IL-1RN等位基因与食管酸暴露以及幽门螺杆菌定植有关的流行情况。特别是，将评估IL-1β-31和IL-1RN等位基因对幽门螺杆菌定植或不定植患者胃食道连接部(GEJ)细胞增殖和环氧合酶-2(COX-2)表达的影响。具体目的#3是评估根除幽门螺杆菌对GEJ细胞增殖的影响，以及与IL-1β-31等位基因相关的IL-1β和COX-2的表达。通过这些研究，应该能够评估微生物对腺癌风险的贡献以及宿主基因对腺癌风险的贡献，并开始确定相关的细胞通路。

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.