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: 10435522
• 负责人: Katherine Garman
• 金额: $ 49.47万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435522
• 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.

项目概要/摘要： Barrett食管（BE）是食管腺癌的前兆，食管腺癌是一种发病率不断增加的癌症 五年存活率低于17% BE和食管腺癌发生在异常的 食管修复我们先前的工作表明，食管损伤或BE患者的腺泡导管 食管粘膜下腺体（ESMGs）内的化生。此外，使用猪模型，我们发现 ESMG对损伤的反应是增殖和向表达BE的导管表型的转变 标记。然而，导致这种化生发展的因素尚不清楚。我们的初步 数据表明，ESMG中的化生可能是由升高的胃泌素暴露引起的，正如我们所确定的：1） ESMG中胃泌素受体表达增加和2）ESMG对胃泌素受体的反应性增殖 体外这些发现具有临床相关性，因为质子泵抑制剂（PPI）通常用于 酸抑制和目前推荐用于BE，提高血清胃泌素水平。胃泌素水平升高 与胃、结肠和胰腺化生、发育不良和癌症的风险增加有关。的 本提案的目的是确定PPI和升高的胃泌素对食管增殖的影响 ESMG是一种高度特化的粘膜下结构，含有食管祖细胞 并对食管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 ESMG和食管修复的猪模型，以及我们的大型人类食管切除术样本队列。 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管增殖和腺泡增殖的假设。 通过追求三个具体目标，通过胃泌素受体研究导管化生：1）量化胃泌素的作用， 受体（CCKBR）激活和抑制ESMG增殖和分化的体外和体内研究 猪模型2)确定胃泌素暴露和腺泡导管之间的下游机制 化生3)人ESMG中的胃泌素受体和信号传导靶点并开发离体平台 以测试腺泡导管化生和BE预防的疗法。通过提出的目标，我们将建立 临床前模型，以确定胃泌素对ESMG增殖和诱导ESMG增殖的病理作用。 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 受体表达和下游信号作用的胃泌素水平发现与PPI的使用。拟议 目的是解决目前关于PPI安全性和食管癌患者胃泌素水平升高的争论， 化生和异型增生，这些研究可能会导致我们的研究结果的快速翻译。