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: 10197913
• 负责人: Katherine Garman
• 金额: $ 49.39万
• 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/10197913
• 关键词: Acids; Address; Barrett Esophagus; CCKBR gene; Cells; Cholecystokinin B Receptor; Clinical; Colon; Data; Development; Disease; Dose; Duct (organ) structure; Dysplasia; 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; human model; in vivo; in vivo Model; novel; porcine model; 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： Barrett的食道（BE）是食管腺癌的前体，这是一种癌症的癌症 五年生存率不到17％。 BE和食管腺癌发生在异常情况下 食管修复。我们先前的工作表明，食管损伤的患者或表现为腺泡导管 食管粘膜粘膜（ESMGS）内的化生。此外，使用猪模型，我们发现了 ESMGs通过增殖对伤害做出反应，并转向导管表型，表达BE 标记。但是，有助于发展这种化生的因素尚不清楚。我们的初步 数据表明，ESMG中的化生可以通过我们确定的胃链蛋白暴露升高引起：1） 胃蛋白受体在ESMG中的表达增加，而2）ESMG响应于胃蛋白 体外。这些发现在临床上是相关的，因为质子泵抑制剂（PPI）通常用于 酸抑制，目前建议进行BE，提高血清胃蛋白水平。胃蛋白水平升高 与胃，结肠和胰腺中化生，发育不良和癌症的风险增加有关。 该建议的目的是确定PPI和胃蛋白升高对食管增殖的影响 ESMG中的Metaplasia，含有食管祖细胞的高度专业的粘膜粘膜结构 并应对食管损伤。为了实现这一目标，我们将在体外和体内使用我们的小说 ESMG和食管修复的猪模型，以及我们的大量人类食管切除术样品。 我们的中心假设是胃蛋白通过胃蛋白促进ESMG内的增生和化生 受体（CCKBR）。我们将检验以下假设，即胃蛋白信号驱动食管增殖和腺泡 通过追求三个特定目的，通过胃蛋白受体进行导管化生：1）量化胃蛋白的影响 受体（CCKBR）激活和对ESMG增殖和分化的抑制 猪模型。 2）确定胃蛋白暴露与腺泡导管之间的下游机制 Metaplasia。 3）在人ESMG中验证胃蛋白受体和信号靶标，并开发离体平台 测试腺泡导管化生的疗法并进行预防。通过拟议的目标，我们将建立 临床前模型，以确定胃蛋白对ESMG增殖的病理影响和诱导 腺泡导管化生。这将通过表征损伤引起的胃链变化来实现 PPI使用发现的胃蛋白水平的受体表达和下游信号传导效应。提议 目标将解决有关PPI和食管中胃蛋白水平升高的当前辩论 变质和发育不良以及这些研究可能会导致我们的发现的快速翻译。