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: 10599109
• 负责人: Dominique Bailey
• 金额: $ 16.55万
• 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/10599109
• 关键词: 3-Dimensional; Advisory Committees; Albumins; Basal Cell; Basal Cell Hyperplasia; Binding Sites; Biological Assay; Biology; Biopsy; Cell Nucleus; Cell Separation; Cellular biology; Child; Childhood; Chronic; Data; Development; Developmental Biology; Disease; Environment; Eosinophilic Esophagitis; Epithelial Cells; Epithelium; 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; Mentors; Mentorship; Modeling; Molecular; Morbidity - disease rate; Mus; Nuclear; Organoids; Pathogenesis; Pathologic; Pathway interactions; Patients; Physicians; Proliferating; Proteins; Research; Research Design; Research Proposals; Role; STAT6 gene; Scientist; Signal Pathway; Signal Transduction; System; Testing; Training; Transcription Initiation Site; Translating; Universities; Verteporfin; Weaning; Work; care burden; 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; innovation; insight; knock-down; loss of function; 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.

项目总结 嗜酸性食管炎(EoE)是一种新发现的免疫介导性疾病，是引起食管炎的主要原因之一。 儿童和青壮年食道发病率。组织学上，儿童EoE的特点是食道 基底细胞增生(BCH)和广泛的Th2相关性炎症。尽管我们在这方面取得了许多进步 了解EoE的病理生理、导致BCH发生的分子机制。 儿科EoE尚待阐明。本次辅导式职业发展奖建议的培训 概述了一项为期五年的指导研究和职业发展活动的综合计划，以支持Dr。 多米尼克·贝利成长为一名独立的内科科学家。这一全面的计划将建立 关于贝利医生作为儿科胃肠病专家的经验和她在发育生物学方面的背景 使她在3D有机物培养系统、流式细胞仪、 上皮干细胞生物学和免疫学通过正规课程的学习和深思熟虑的实施 设计了研究方案。具体地说，她的研究提案旨在利用创新的方法来探索 儿童EoE中BCH的分子机制。 使用一种新的早发性EoE条件性IL-13过表达小鼠模型，我们已经能够研究 Th2驱动的BCH。我们的初步数据显示，在老年人中，YAP的水平增加 这些小鼠的增生性食道基底细胞的核和儿童EoE患者的活检组织。然而，这个角色 YAP在EoE发病机制中的作用尚不清楚。基于这些发现，总体假设 在EoE的发病过程中，YAP介导了IL-13诱导的BCH。在目标1中，我们将使用YAP Lost-和 获得功能小鼠模型，以检验YAP激活促进BCH的假说。在目标2中，使用体内 在体外实验中，我们将阐明IL-13直接调节细胞周期的信号通路。 YAP的转录，从而导致BCH。在目标3中，我们将开始将研究结果转化为儿科EoE 患者直接评估儿童EoE活检组织中YAP的表达并检测YAP抑制是否被阻断 有机化合物中的BCH。总体而言，拟议研究的结果将极大地促进我们对 儿童EoE的病理生理机制，为潜在的生物标志物和新的治疗方法提供新的见解 儿科EoE的目标。贝利博士的导师和咨询委员会，由一个多学科团队组成 胃肠道上皮生物学、免疫学和嗜酸性粒细胞疾病领域的专家将指导她完成研究 以及她提案中概述的培训目标，并为未来的R01应用奠定基础。总而言之， 贝利博士的项目提案、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 重点阐述上皮屏障功能障碍在EoE发病机制中的作用。