The Role of Periostin and Th2 Cytokines in Eosinophilic Esophagitis Fibrogenesis

骨膜素和 Th2 细胞因子在嗜酸性食管炎纤维形成中的作用

• 批准号: 8724491
• 负责人: Edaire Cheng
• 金额: $ 14.87万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8724491
• 关键词: Adult; Advisory Committees; Animal Disease Models; Basic Science; Bioethics; Biometry; Biopsy Specimen; Cell Culture Techniques; Cell Line; Cell membrane; Cells; Child; Childhood; Chronic; Complex; Conditioned Culture Media; Data; Deglutition Disorders; Development Plans; Disease; Environment; Eosinophilia; Eosinophilic Esophagitis; Epithelial; Epithelial Cells; Epithelium; Esophageal; Esophageal Diseases; Esophageal Squamous Cell; Esophageal Stenosis; Esophageal mucous membrane; Esophagus; Evaluation; Extracellular Matrix Proteins; Extramural Activities; Fellowship; Fibroblasts; Fibrosis; Fostering; Functional disorder; Funding; Gastroenterologist; Genes; Goals; Grant; Histologic; Immune; Inflammation; Inflammatory; Integrins; Interleukin-13; Interleukin-4; International; Intervention; K-Series Research Career Programs; Laboratories; Lamina Propria; Measures; Mediating; Medical center; Mentors; Mesenchymal; Mesenchyme; Methodology; Modeling; Molecular; Molecular Target; Myofibroblast; Organ; Pain; Pathogenesis; Pathway interactions; Patients; Pattern; Physicians; Post-Transcriptional Regulation; Process; Production; Research; Research Personnel; Resources; Role; SECTM1 gene; STAT3 gene; Scientist; Signal Transduction; Specimen; Symptoms; System; Telomerase; Testing; Texas; Tissues; Training; Training Programs; Transcriptional Activation; Transcriptional Regulation; Translational Research; United States National Institutes of Health; Universities; Writing; authority; base; career development; cell type; crosslink; cytokine; eosinophil; fibrogenesis; inhibitor/antagonist; innovation; mast cell; novel; painful swallowing; periostin; prevent; programs; public health relevance; research and development; research study; therapeutic target; transdifferentiation

DESCRIPTION (provided by applicant): This NIH Mentored Career Development Award proposal describes a 4 year training program for the candidate, a pediatric gastroenterologist with the long-term goal of becoming an independent and funded physician-scientist with a research focus on fibrogenesis and tissue remodeling in eosinophilic esophagitis (EoE). To accomplish these goals, the candidate and her mentors have developed an integrated plan including innovative scientific ideas, advanced training in the field of basic science and translational research, and a detailed career development plan. This proposal builds on the basic research developed during the candidate's fellowship and K12 training, specifically on her preliminary findings of esophageal fibroblasts and esophageal epithelial cells expressing periostin, an extracellular matrix protein highly upregulated in the EoE esophagus. The chronic esophageal eosinophilia of EoE is associated with tissue remodeling characterized by a unique pattern of subepithelial fibrosis leading to painful mucosal tears, odynophagia, dysphagia, and strictures. The pathogenesis of fibrosis in EoE is not understood, and no treatment has been shown to prevent tissue remodeling. Previously, the candidate has demonstrated a prominent role for Th2 cytokines, IL-13 and IL-4, in EoE. She hypothesizes that, in the esophagus of EoE patients, IL-13 and/or IL-4 drive fibrogenesis by increasing esophageal mucosal expression of periostin. To test this hypothesis, she will use novel, telomerase- immortalized esophageal fibroblast and epithelial cell lines. She will also create organotypic 3D cell cultures to study signaling between the two mucosal compartments (epithelium and mesenchyme). She proposes three specific aims: (1) To delineate the mechanism whereby IL-13 and IL-4 regulate periostin expression by esophageal fibroblasts and squamous epithelial cells; (2) To characterize the "direct" and "indirect" pro-fibrotic effects of IL-13, IL-4, and periostin on esophageal fibroblast; (3) To confirm that IL-13 and/or IL-4 can cause STAT3-mediated periostin expression and fibrotic effects in organotypic models, and to correlate STAT3 pathway activation, periostin expression, and fibrosis in esophageal biopsy specimens from EoE patients. This proposal seeks to identify potential molecular targets to prevent tissue remodeling in EoE. The candidate will perform these studies under the guidance of Drs. Rhonda Souza and Stuart Spechler, senior translational investigators with a record of research excellence in the molecular study of esophageal diseases. In addition, the advisory committee includes Dr. Glenn Furuta, an international authority on EoE, and Dr. Frederick Grinnell, a fibrosis expert. To augment her research and career development program, she has outlined advance training in specific methodologies and formal intramural and extramural coursework in fibrosis, grant writing, biostatistics, bioethics, and animal models of disease. The University of Texas Southwestern Medical Center, Dallas VA Medical Center, and Children's Medical Center will provide the necessary resources and intellectual environment to foster this candidate's transition to an independent investigator.

描述（由申请人提供）：这份 NIH 指导职业发展奖提案描述了针对候选人的 4 年培训计划，该候选人是一名儿科胃肠病学家，其长期目标是成为一名独立且受资助的医师科学家，重点研究嗜酸性食管炎 (EoE) 的纤维生成和组织重塑。为了实现这些目标，候选人和她的导师制定了一个综合计划，包括创新的科学理念、基础科学和转化研究领域的高级培训以及详细的职业发展计划。该提案建立在候选人奖学金和 K12 培训期间开展的基础研究的基础上，特别是基于她对表达骨膜素的食管成纤维细胞和食管上皮细胞的初步发现，骨膜素是一种在 EoE 食管中高度上调的细胞外基质蛋白。 EoE 的慢性食管嗜酸性粒细胞增多与组织重塑有关，其特征是独特的上皮下纤维化模式，导致疼痛性粘膜撕裂、吞咽痛、吞咽困难和狭窄。 EoE 纤维化的发病机制尚不清楚，也没有治疗方法可以阻止组织重塑。此前，该候选药物已证明 Th2 细胞因子、IL-13 和 IL-4 在 EoE 中发挥着重要作用。她推测，在 EoE 患者的食管中，IL-13 和/或 IL-4 通过增加食管粘膜骨膜素的表达来驱动纤维形成。为了检验这一假设，她将使用新型端粒酶永生化食管成纤维细胞和上皮细胞系。她还将创建器官型 3D 细胞培养物，以研究两个粘膜区室（上皮和间质）之间的信号传导。她提出了三个具体目标：（1）阐明IL-13和IL-4调节食管成纤维细胞和鳞状上皮细胞骨膜素表达的机制； (2) 表征IL-13、IL-4和periostin对食管成纤维细胞的“直接”和“间接”促纤维化作用； (3) 证实IL-13和/或IL-4可在器官型模型中引起STAT3介导的骨膜素表达和纤维化效应，并将EoE患者食管活检标本中的STAT3通路激活、骨膜素表达和纤维化相关联。该提案旨在确定潜在的分子靶标，以防止 EoE 中的组织重塑。候选人将在博士的指导下进行这些研究。 Rhonda Souza 和 Stuart Spechler 是高级转化研究人员，在食管疾病的分子研究方面拥有卓越的研究记录。此外，顾问委员会还包括EoE国际权威Glenn Furuta博士和纤维化专家Frederick Grinnell博士。为了加强她的研究和职业发展计划，她概述了特定方法的高级培训以及纤维化、资助写作、生物统计学、生物伦理学和疾病动物模型方面的正式校内和校外课程。德克萨斯大学西南医学中心、达拉斯退伍军人医疗中心和儿童医学中心将提供必要的资源和智力环境，以促进该候选人向独立研究者的过渡。