Inflammation And Submucosal Glands During Esophageal Injury And Repair

食管损伤和修复过程中的炎症和粘膜下腺

• 批准号: 10713940
• 负责人: Katherine Garman
• 金额: $ 66.4万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713940
• 关键词: Acids; Acinus organ component; Acute; Address; Adenocarcinoma Cell; Aftercare; Area; Barrett Esophagus; Barrett' s carcinogenesis; Biological Markers; Cells; Chemoprevention; Chemopreventive Agent; Chronic; Clinical; Coculture Techniques; Complex; Databases; Development; Disease; Distal; Duct (organ) structure; Dysplasia; Epithelium; Esophageal Adenocarcinoma; Esophageal injury; Esophagectomy; Esophagogastric Junction; Esophagus; Etiology; Excision; Family suidae; Gastroesophageal reflux disease; Gene Expression; Genes; Gland; Goals; High grade dysplasia; Histologic; Human; IL8 gene; Immune; Individual; Inflammation; Inflammatory; Inherited; Injury; Intervention; Knowledge; Lesion; Ligands; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediating; Metaplasia; Modeling; Molecular; Molecular Profiling; Mucinous; Mucous Membrane; Names; Non-Steroidal Anti-Inflammatory Agents; Organ; Organoids; Outcome; Pancreas; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Population; Predisposition; Prevention; Prevention strategy; Preventive; Process; Program Research Project Grants; Proliferating; Radiofrequency Interstitial Ablation; Recurrence; Reflux; Refractory; Reporting; Research; Residual state; Risk; Role; Sampling; Signal Pathway; Signal Transduction; Source; Specimen; Squamous Cell; Submucosa; Testing; Therapeutic; Transitional Cell; Treatment Failure; biomarker identification; cancer prevention; cancer risk; carcinogenesis; chemokine; cohort; cytokine; evidence base; experimental study; gastroesophageal junction adenocarcinoma; healing; immune cell infiltrate; immunoregulation; improved; improved outcome; in vivo; injury and repair; insight; mortality; pre-clinical; prevent; progenitor; programs; recruit; repaired; response to injury; screening; spatiotemporal; stem cells; stomach cardia; synergism; tumor; tumor-immune system interactions; wound healing

PROJECT SUMMARY The etiology of Barrett's esophagus (BE), a complex metaplastic disorder of the distal esophagus, remains elusive. Patients with BE are at an increased risk of developing esophageal adenocarcinoma (EAC), a lethal, and increasingly prevalent disease, and the most common esophageal malignancy in the U.S. Our long-term objective is to identify the causative mechanisms underlying the onset and malignant progression of BE, and to develop evidence-based biomarkers and chemopreventive/therapeutic strategies for subsequent clinical intervention. Project 2 of this program addresses a controversial area in the field that has been understudied. Esophageal submucosal glands (ESMGs) represent a progenitor cell source in the esophagus and our group has previously demonstrated increased proliferation and acinar ductal metaplasia (ADM) in ESMGs in the context of injury and EAC. We have observed immune cell infiltrates in ESMGs associated with ADM, but important knowledge gaps persist about the types of immune cells found in areas of ADM and the effect of this microenvironment on ADM, wound healing, and the molecular programs associated with BE/EAC. Project 2 will thus investigate the relationship between injury-induced cytokines such as C-X-C motif chemokine ligand 8 (CXCL8 or IL8)), esophageal wound healing, and ADM. Ongoing inflammation and abnormal signaling in ESMGs and at the GEJ may provide a persistent source of abnormal progenitor cells after radiofrequency ablation, contributing to treatment failures including refractory and recurrent dysplasia and progression to EAC. The proposed project will address preclinical questions about how to improve outcomes after radiofrequency ablation or endoscopic resection of early lesions, including high grade dysplasia and very early cancers. To address these research questions, we will use our 1) large human esophagectomy database that includes failed- radiofrequency ablation cases that resulted in esophagectomy, and 2) our porcine radiofrequency ablation model and porcine and patient-derived organoids. Our project has strong synergy with both projects 1 and 3, expanding the scope our program project grant to include models with ESMGs and allowing comparison to wound healing at the gastroesophageal junction. We will investigate how targeting the inflammation in ESMGs and at the gastroesophageal junction may provide a potential cancer interception and preventive strategies. .

项目概要 巴雷特食管 (BE) 是一种复杂的远端食管化生性疾病，其病因仍不清楚 难以捉摸。 BE 患者患食管腺癌 (EAC) 的风险增加，这是一种致命的、 和日益流行的疾病，以及美国最常见的食管恶性肿瘤。我们的长期 目的是确定 BE 发病和恶性进展的致病机制，并 为后续临床开发循证生物标志物和化学预防/治疗策略 干涉。该计划的项目 2 解决了该领域中一个尚未得到充分研究的有争议的领域。 食管粘膜下腺（ESMG）代表食管和我们小组的祖细胞来源 先前已证明 ESMG 中的增殖和腺泡导管化生 (ADM) 增加 伤害和 EAC 的背景。我们观察到免疫细胞浸润与 ADM 相关的 ESMG，但是 关于 ADM 区域中发现的免疫细胞类型及其影响，仍然存在重要的知识差距 微环境对 ADM、伤口愈合以及与 BE/EAC 相关的分子程序的影响。项目2将 因此研究损伤诱导的细胞因子（例如 C-X-C 基序趋化因子配体 8）之间的关系 （CXCL8 或 IL8））、食管伤口愈合和 ADM。 ESMG 中持续的炎症和异常信号传导 并且在 GEJ 处可能会在射频消融后提供异常祖细胞的持续来源， 导致治疗失败，包括难治性和复发性不典型增生以及进展为 EAC。这 拟议的项目将解决有关如何改善射频消融后结果的临床前问题 或内窥镜切除早期病变，包括高度不典型增生和非常早期的癌症。致地址 这些研究问题，我们将使用我们的 1) 大型人类食管切除术数据库，其中包括失败的- 导致食管切除术的射频消融病例，以及 2) 我们的猪射频消融模型 以及猪和患者来源的类器官。我们的项目与项目1和项目3具有很强的协同效应，扩大了 我们的计划项目授予的范围包括具有 ESMG 的模型并允许与伤口愈合进行比较 在胃食管连接处。我们将研究如何针对 ESMG 中的炎症以及 胃食管连接处可能提供一种潜在的癌症拦截和预防策略。 。