The Role of Periostin and Th2 Cytokines in Eosinophilic Esophagitis Fibrogenesis

描述(由申请者提供)：这份NIH导师职业发展奖提案描述了一项为期4年的培训计划，候选人是一名儿科胃肠病专家，长期目标是成为一名独立的、有资金支持的内科科学家，专注于嗜酸性食管炎(EoE)的纤维形成和组织重塑研究。为了实现这些目标，候选人和她的导师制定了一项综合计划，包括创新的科学思想、基础科学和翻译研究领域的高级培训，以及详细的职业发展计划。这项建议建立在候选人在奖学金和K12培训期间发展的基础研究基础上，特别是她对食道成纤维细胞和食道上皮细胞表达Periostin的初步发现，Periostin是一种在EoE食道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症与组织重塑有关，其特征是一种独特的上皮下纤维化模式，导致疼痛的粘膜撕裂、吞咽疼痛、吞咽困难和狭窄。EoE纤维化的发病机制尚不清楚，目前尚无预防组织重塑的治疗方法。此前，候选人已经展示了Th2细胞因子IL-13和IL-4在EoE中的突出作用。她假设，在EoE患者的食道中，IL-13和/或IL-4通过增加食道粘膜中Periostin的表达来推动纤维化形成。为了验证这一假设，她将使用新型的、端粒酶永生化的食道成纤维细胞和上皮细胞系。她还将创建器官型3D细胞培养，以研究两个粘膜间隔(上皮和间充质)之间的信号传递。她提出了三个具体目标：(1)阐明IL-13和IL-4调节食道成纤维细胞和鳞状上皮细胞Periostin表达的机制；(2)表征IL-13、IL-4和Periostin对食道成纤维细胞的“直接”和“间接”促纤维化作用；(3)在器官模型中证实IL-13和/或IL-4可以导致STAT3介导的Periostin表达和纤维化效应，并探讨STAT3通路激活、Periostin表达和EOE患者食道活检标本中纤维化的关系。这项建议旨在确定潜在的分子靶点，以防止EoE的组织重塑。候选人将在朗达·苏扎博士和斯图尔特·斯佩克勒博士的指导下进行这些研究，他们是在食道疾病分子研究方面拥有卓越研究记录的高级翻译调查人员。此外，咨询委员会还包括EoE方面的国际权威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，她概述了在纤维化、赠款撰写、生物统计学、生物伦理学和疾病动物模型方面的特定方法和正式的校内外课程的高级培训。德克萨斯大学西南医学中心、达拉斯退伍军人医学中心和儿童医学中心将提供必要的资源和智力环境，促进这名候选人向独立调查人员的转变。

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.