The role of gastrin in esophageal submucosal gland acinar ductal metaplasia

胃泌素在食管粘膜下腺腺泡导管化生中的作用

• 批准号: 9767122
• 负责人: Katherine Garman
• 金额: $ 42.35万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767122
• 关键词: Acids; Address; Barrett Esophagus; CCKBR gene; Cells; Cholecystokinin B Receptor; Clinical; Colon; Data; Development; Disease; Dose; Duct (organ) structure; Ductal; Dysplasia; Esophageal; Esophageal Adenocarcinoma; Esophageal injury; Esophagectomy; Esophagus; Family suidae; Gastrins; Gastroesophageal reflux disease; Gene Expression; Genetic; Gland; Human; In Vitro; Incidence; Injury; Lead; Malignant Neoplasms; Measures; Metaplasia; Modeling; Pancreas; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Pre-Clinical Model; Prevention; Proton Pump Inhibitors; Radiofrequency Interstitial Ablation; Receptor Signaling; Reporting; Research; Risk; Rodent; Role; Safety; Sampling; Serum; Signal Transduction; Source; Stomach; Structure; Testing; Translations; Work; clinically relevant; cohort; experimental study; human data; in vivo; in vivo Model; novel; preclinical study; prevent; progenitor; prospective; receptor expression; repaired; response; single-cell RNA sequencing; therapeutic evaluation; three dimensional cell culture

Project Summary / Abstract: Barrett’s esophagus (BE) is a precursor to esophageal adenocarcinoma, a cancer with increasing incidence and a five-year survival less than 17%. BE and esophageal adenocarcinoma arise in the setting of abnormal esophageal repair. Our prior work has shown that patients with esophageal injury or BE display acinar ductal metaplasia within esophageal submucosal glands (ESMGs). Furthermore, using a pig model, we have found that ESMGs respond to injury with proliferation and a shift to a ductal phenotype with expression of BE markers. However, the factors that contribute to development of this metaplasia are unknown. Our preliminary data suggest that metaplasia in ESMGs may be elicited by elevated gastrin exposure as we have identified: 1) increased expression of the gastrin receptor in the ESMGs and 2) ESMG proliferation in response to gastrin in vitro. These findings are clinically relevant since proton pump inhibitors (PPIs), which are commonly used for acid suppression and currently recommended for BE, raise serum gastrin levels. Elevated gastrin levels are associated with increased risk of metaplasia, dysplasia and cancer in the stomach, colon and pancreas. The objective of this proposal is to determine the effects of PPIs and elevated gastrin on esophageal proliferation and metaplasia in ESMGs, the highly specialized submucosal structures that contain esophageal progenitors and respond to esophageal injury. To accomplish this objective, we will use our novel in vitro and in vivo porcine models of ESMGs and esophageal repair, and our large cohort of human esophagectomy samples. Our central hypothesis is that gastrin promotes proliferation, and metaplasia within ESMGS via the gastrin receptor (CCKBR). We will test the hypothesis that gastrin signaling drives esophageal proliferation and acinar ductal metaplasia through the gastrin receptor by pursuing three specific aims: 1) Quantify effects of the gastrin receptor (CCKBR) activation and inhibition on ESMG proliferation and differentiation using in vitro and in vivo porcine models. 2) Determine the downstream mechanisms between gastrin exposure and acinar ductal metaplasia. 3) Validate gastrin receptor and signaling targets in human ESMGs and develop ex vivo platforms to test therapies for acinar ductal metaplasia and BE prevention. Through the proposed aims, we will establish pre-clinical models to determine the pathological effects of gastrin on ESMG proliferation and induction of acinar ductal metaplasia. This will be accomplished by characterizing injury-induced changes in gastrin receptor expression and down-stream signaling effects of gastrin levels found with PPI use. The proposed aims will address the current debate regarding safety of PPIs and elevated gastrin levels in esophageal metaplasia and dysplasia and these studies could lead to rapid translation of our findings.

项目摘要/摘要： 巴雷特食道(BE)是食管腺癌的先兆，食管腺癌是一种发病率越来越高的癌症 五年存活率不到17%。BE和食管腺癌发生在异常的环境中 食道修复。我们先前的工作表明，食道损伤或BE患者表现为腺泡导管 食道粘膜下腺(ESMGs)内的化生。此外，使用猪模型，我们发现 ESMGs对损伤的反应是增殖，并转变为表达BE的导管表型 记号笔。然而，促进这种化生发展的因素尚不清楚。我们的预赛 数据表明，ESMGs中的化生可能是由于胃泌素暴露增加而引起的，正如我们已经确认的：1) 胃泌素受体在ESMG中的表达增加及2)胃泌素对ESMG增殖的影响 体外培养。这些发现具有临床意义，因为质子泵抑制剂(PPI)通常用于 抑酸，目前推荐用于BE，可提高血清胃泌素水平。胃泌素水平升高 与胃、结肠和胰腺的化生、不典型增生和癌症的风险增加有关。这个 这项建议的目的是确定PPI和升高的胃泌素对食道增殖的影响 和ESMGs中的化生，ESMGs是含有食管祖细胞的高度专业化的粘膜下结构 并对食道损伤做出反应。为了实现这一目标，我们将在体外和体内使用我们的新技术 ESMGs和食道修复的猪模型，以及我们的大量人类食道切除样本。 我们的中心假设是胃泌素通过胃泌素促进ESMGS内的增殖和化生。 受体(CCKBR)。我们将检验胃泌素信号驱动食道增殖和腺泡形成的假设。 通过胃泌素受体实现三个特定目标的导管化生：1)量化胃泌素的作用 受体(CCKBR)在体内外对ESMG增殖和分化的激活和抑制作用 猪模特。2)确定胃泌素暴露和腺泡导管之间的下游机制 化生。3)验证人ESMGs的胃泌素受体和信号靶点，建立体外实验平台 目的：测试腺泡导管化生的治疗方法并加以预防。通过提出的目标，我们将建立 确定胃泌素对ESMG增殖和诱导ESMG的病理作用的临床前模型 腺泡导管化生。这将通过表征损伤诱导的胃泌素变化来实现 使用PPI时，胃泌素水平的受体表达和下行信号效应。建议数 AIMS将解决目前关于PPI的安全性和食道中胃泌素水平升高的争论 化生和异型增生以及这些研究可能会导致我们的发现迅速得到翻译。