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. .

项目摘要 Barrett食管（BE）是一种复杂的食管远端化生性疾病，其病因仍不清楚， 难以捉摸。BE患者发生食管腺癌（EAC）的风险增加， 和日益普遍的疾病，和最常见的食管恶性肿瘤在美国。 目的是确定BE发病和恶性进展的致病机制， 开发循证生物标志物和化学预防/治疗策略，用于后续临床 干预该计划的项目2解决了一个有争议的领域，一直研究不足。 食管粘膜下腺（ESMGs）代表了食管中的祖细胞来源， 先前已经证明，在ESMG中， 伤害和EAC的背景。我们已经观察到与ADM相关的ESMG中的免疫细胞浸润，但 重要的知识差距持续存在的免疫细胞的类型中发现的ADM和这种影响， 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 从而研究损伤诱导的细胞因子如C-X-C基序趋化因子配体8与细胞凋亡的关系， （CXCL 8或IL 8））、食管伤口愈合和ADM。 并且在GEJ处可能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异型增生以及进展为EAC。的 拟议的项目将解决如何改善射频消融术后结果的临床前问题 或内窥镜切除早期病变，包括高度异型增生和极早期癌症。解决 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都有很强的协同作用， 我们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 在胃食管交界处我们将研究如何在ESMG中靶向炎症， 胃食管交界处可能提供潜在的癌症拦截和预防策略。 .