Molecular Mechanisms of Reactive Epithelial Changes in Pediatric Eosinophilic Esophagitis

小儿嗜酸性食管炎反应性上皮变化的分子机制

• 批准号: 10191109
• 负责人: Dominique Bailey
• 金额: $ 16.54万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10191109
• 关键词: 3-Dimensional; Advisory Committees; Albumins; Basal Cell; Basal Cell Hyperplasia; Binding Sites; Biological Assay; Biology; Biopsy; Cell Nucleus; Cellular biology; Child; Childhood; Chronic; Data; Development; Developmental Biology; Disease; Environment; Eosinophilic Esophagitis; Epithelial; Epithelial Cells; Esophageal Diseases; Esophageal Tissue; Esophagus; Flow Cytometry; Foundations; Functional disorder; Future; Gastroenterologist; Genetic Models; Genetic Transcription; Goals; Healthcare; Histologic; Human; Hyperplasia; Immune; Immunology; Incidence; Inflammation; Inflammatory; Interleukin-13; Interleukin-13 Overexpression; K-Series Research Career Programs; Luciferases; Mediating; Mediator of activation protein; Mentors; Mentorship; Modeling; Molecular; Morbidity - disease rate; Mus; Nuclear; Organoids; Pathogenesis; Pathologic; Pathway interactions; Patients; Physicians; Proteins; Research; Research Design; Research Proposals; Research Training; Role; STAT6 gene; Scientist; Signal Pathway; Signal Transduction; System; Testing; Training; Transcription Initiation Site; Translating; Universities; Verteporfin; Weaning; Work; base; career; career development; chromatin immunoprecipitation; cytokine; disease mechanisms study; early onset; epithelial stem cell; experience; experimental study; gain of function; in silico; in vitro Assay; in vivo; inhibitor/antagonist; innovation; insight; knock-down; mouse model; multidisciplinary; new therapeutic target; novel; novel therapeutic intervention; overexpression; potential biomarker; pre-clinical; programs; research and development; skills; small hairpin RNA; stem cell biology; therapeutic target; young adult

PROJECT SUMMARY Eosinophilic esophagitis (EoE) is a newly described immune-mediated disease and a leading cause of esophageal morbidity in children and young adults. Histologically, pediatric EoE is characterized by esophageal basal cell hyperplasia (BCH) and extensive Th2-associated inflammation. Despite many advances in our understanding of the pathophysiology of EoE, the molecular mechanisms leading to the development of BCH in pediatric EoE remain to be elucidated. The proposed training in this mentored career development award outlines a five-year integrated program of mentored research and career development activities to support Dr. Dominique Bailey's development into an independent physician-scientist. This comprehensive program will build on Dr. Bailey's experience as pediatric gastroenterologist and her background in developmental biology by enabling her to develop new skills and advanced expertise in 3D organoid culture systems, flow cytometry, epithelial stem cell biology, and immunology through formal coursework and implementation of a thoughtfully designed research plan. Specifically, her research proposal aims to utilize innovative approaches to explore the molecular mechanisms underlying BCH in pediatric EoE. Using a novel conditional IL-13 overexpression mouse model of early onset EoE, we have been able to study Th2-driven BCH. Our preliminary data demonstrate increased levels of yes-associated protein 1 (YAP) in the nuclei of hyperplasic esophageal basal cells in these mice and pediatric EoE patient biopsies. However, the role of YAP in EoE pathogenesis has not been clearly investigated. Based on these findings, the overall hypothesis is that YAP mediates IL-13-induced BCH during the pathogenesis of EoE. In Aim 1, we will use YAP loss- and gain-of function mouse models to test the hypothesis that YAP activation promotes BCH. In Aim 2, using in vivo and in vitro assays, we will elucidate the signaling pathway through which IL-13 directly modulates the transcription of YAP, thereby resulting in BCH. In Aim 3, we will begin to translate findings to pediatric EoE patients to directly assess the YAP expression in pediatric EoE biopsies and test whether YAP inhibition blocks BCH in organoids. Overall, findings from the proposed studies will significantly advance our understanding of the pathophysiology of pediatric EoE and provide new insights into potential biomarkers and novel therapeutic targets for pediatric EoE. Dr. Bailey's mentors and Advisory Committee, comprised of a multidisciplinary team of experts in field of GI epithelial biology, immunology and eosinophilic diseases, will guide her through the research and training goals outlined in her proposal and establish the foundation for a future R01 application. Collectively, Dr. Bailey's program proposal, mentorship and Advisory Team and Columbia University's supportive research environment will help to achieve her long-term goal of developing an independent academic research career focused on the role of epithelial barrier dysfunction during the EoE pathogenesis.

项目摘要 嗜酸性粒细胞性食管炎（EoE）是一种新近发现的免疫介导的疾病， 儿童和青年食管发病率。在组织学上，小儿EoE的特征是食管 基底细胞增生（BCH）和广泛的Th 2相关炎症。尽管我们在这方面取得了许多进展， 了解EoE的病理生理学，导致BCH发展的分子机制， 小儿EoE仍有待阐明。在这个指导职业发展奖的拟议培训 概述了一个为期五年的指导研究和职业发展活动的综合计划，以支持博士。 多米尼克贝利的发展成为一个独立的物理学家，科学家。这一综合方案将建立 关于贝利博士作为儿科胃肠病学家的经验和她在发育生物学方面的背景， 使她能够在3D类器官培养系统，流式细胞术， 上皮干细胞生物学和免疫学通过正式的课程和周到的实施 设计研究计划。具体而言，她的研究建议旨在利用创新方法探索 儿童EoE中BCH潜在的分子机制。 使用一种新的条件性IL-13过表达的早发性EoE小鼠模型，我们已经能够研究 Th 2驱动的BCH。我们的初步数据表明，在高血压患者中，是相关蛋白1（雅普）的水平增加。 这些小鼠和儿童EoE患者活检组织中增生的食管基底细胞核。然而，作用 雅普在EoE发病机制中的作用尚未明确研究。根据这些发现，总体假设 雅普在EoE发病过程中介导IL-13诱导的BCH。在目标1中，我们将使用雅普损失， 功能获得性小鼠模型以检验雅普激活促进BCH的假设。在目标2中，使用体内 在体外试验中，我们将阐明IL-13直接调节 转录雅普，从而导致BCH。在目标3中，我们将开始将发现转化为儿科EoE 患者直接评估儿科EoE活检中的雅普表达，并测试雅普抑制是否阻断 类器官中的BCH。总的来说，拟议研究的结果将大大促进我们对 儿童EoE的病理生理学，并为潜在的生物标志物和新的治疗方法提供新的见解 儿童EoE的目标。贝利博士的导师和咨询委员会，由一个多学科的团队， 胃肠上皮生物学、免疫学和嗜酸性粒细胞疾病领域的专家将指导她完成这项研究 和她的提案中概述的培训目标，并为未来的R 01应用奠定基础。总的来说， 博士Bailey的项目提案、指导和咨询团队以及哥伦比亚大学的支持性研究 环境将有助于实现她发展独立学术研究事业的长期目标 集中于上皮屏障功能障碍在EoE发病过程中的作用。