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.
Eosinophilic esophagitis (EoE) is a recently recognized esophageal disorder associated with eosinophil- predominant inflammation and significant tissue remodeling characterized by prominent subepithelial fibrosis leading to painful mucosal tears, odynophagia, dysphagia, and ultimately esophageal strictures in children and adults. The pathogenesis of fibrosis in EoE is not understood and no treatment has been shown to prevent tissue remodeling in EoE. This proposal seeks to understand the pathophysiological roles of IL-13, IL-4, periostin, epithelial cells, and fibroblasts in the subepithelial fibrosis that complicats EoE, and to identify potential molecular targets to prevent tissue remodeling in EoE.
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