ROLE OF BACTERIAL COLONIZATION IN DEVELOPMENT OF UPPER GI PATHOLOGY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 研究人员假设：1)正常的细菌菌群存在于食道中，并在胃食道反流病(GERD)演变为Barrett‘s食道和食管腺癌的过程中发生变化。2)特定的宿主和细菌因素可能决定了食管病的发生发展。3)IL-1b-31*T等位基因和功能相关的IL-1RN*2等位基因通过调节宿主对幽门螺杆菌的炎症反应以及随后的产酸和细胞增殖，降低食管炎、化生和腺癌的风险。 具体目标如下： 1.在群体水平上确定GERD相关疾病如食管炎和Barrett‘s食管炎患者的正常食道和食道中的细菌菌群 2.在物种水平上确定GERD相关疾病患者和正常食道中的细菌菌群。 3.检测正常食道及GERD相关疾病患者对食道定植细菌的体液免疫反应。 4.评估有无反流病患者幽门螺杆菌的存在及其菌株特征 5.通过检测GERD患者或正常食道患者的血清胃蛋白酶原来评估萎缩性胃炎的进展。 6.探讨幽门螺杆菌菌株特性对胃和食道黏膜IL-1b蛋白表达的影响，以及对炎症、化生和异型增生发生的影响。 7.探讨IL-1b-31和IL-1RN等位基因与食管酸暴露及幽门螺杆菌定植的关系。特别是，我们还将评估IL-1b-31和IL-1RN等位基因对幽门螺杆菌定植或未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。 8.观察根除幽门螺杆菌对GEJ细胞增殖及IL-1b和COX-2表达的影响。 这项研究将在因临床原因而转诊为内窥镜检查的门诊患者中进行。将进行内窥镜评估以评估胃肠道病理、食道细菌定植和幽门螺杆菌定植。活检将接受组织学检查，并确定COX-2的表达作为细胞调节异常的标志，并将进行pH监测，以确定超过24小时的食管酸暴露。采集的血液将用于评估幽门螺杆菌定植的血清学证据，以及评估细胞因子IL-1b基因位点的多态。 共有300名年龄在18至75岁之间的男性和女性患者因临床原因在贝尔维尤医院和VANYHHS接受上消化道内窥镜检查，他们将参加这项研究。 这项研究是对一项正在进行的试图了解细菌定植对GEJ炎症可能性的作用的“附加”研究(SPID#1229)。它将使用与原始研究相同的活检标本，但也将讨论宿主遗传学在炎症风险方面的作用。这项研究将有助于阐明从返流到巴雷特病和癌症的进展。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The investigators hypothesize the following: 1) Normal bacterial flora exists in the esophagus and that they change during the evolution of gastroesophageal reflux disease (GERD) into Barrett's esophagus and esophageal adenocarcinoma. 2) Specific host and bacterial factors may determine the development of esophageal disease. 3) The IL-1b-31*T allele and the functionally related IL-1RN*2 allele decrease the risk of esophageal inflammation, metaplasia, and consequent development of adenocarcinoma by modulating the host inflammatory response to H. pylori and subsequent acid production and cellular proliferation. The specific aims are as follows: 1. To define the bacterial flora at a population level in the normal esophagus and the esophagus of patients with GERD-related diseases such as esophagitis and Barrett's esophagus 2. To define the bacterial flora at a species level in the normal esophagus and the esophagus of patients with GERD-related diseases. 3. To determine host humoral immune responses to the esophageal colonizing bacteria in patients with a normal esophagus or with GERD-related diseases. 4. To assess the presence of H. pylori and its strain characteristics in patients with and without reflux disease 5. To assess for the progression of atrophic gastritis by examination of serum pepsinogens in the patients with GERD or with normal esophagus 6. To determine the effect of Helicobacter pylori strain characteristics on gastric and esophageal mucosal IL-1b protein expression, and on the development of inflammation, metaplasia, and dysplasia. 7. To determine the prevalence of the IL-1b-31 and IL-1RN alleles in relation to esophageal acid exposure, also in relation to H. pylori colonization. In particular, we also will evaluate the effect of the IL-1b-31 and IL-1RN alleles on gastroesophageal junction (GEJ) cellular proliferation and cyclooxygenase-2 (COX-2) expression in patients with or without H. pylori colonization. 8. To evaluate the effect of H. pylori eradication on GEJ cellular proliferation, and on IL-1b and COX-2 expression in relation to the IL-1b-31 allele The study will be conducted in outpatients referred for endoscopic evaluation for clinically indicated reasons. Endoscopic evaluation will be performed to assess for gastrointestinal pathology, esophageal bacterial colonization, and H. pylori colonization. Biopsies will be subjected to histologic review as well as determination of COX-2 expression as a marker of abnormal cellular regulation, and pH monitoring will be performed to determine esophageal acid exposure over 24 hours. Blood collected will be used for evaluating for serologic evidence of H. pylori colonization as well as for evaluating polymorphisms in the cytokine IL-1b gene locus. A total of 300 male and female patients between 18 and 75 years of age undergoing upper gastrointestinal endoscopy at Bellevue hospital and at the VANYHHS for clinically indicated reasons will be enrolled in this study. This study is an "add-on" study to an ongoing attempt to look at the role of bacterial colonization on the likelihood of GEJ inflammation (SPID #1229). It will utilize the same biopsy specimens as the original study but will also address the role of host genetics on the risk for inflammation. This study will help clarify the progression from reflux to Barrett's disease and to carcinoma.