This R03 project emerges directly from studies described in Dr. Menard-Katcher?s K23 award. The proposed aims define a new direction of investigation within the broader goals of Dr. Menard-Katcher?s career development that will provide essential data, critical skills and important collaborations. Together these will provide a platform for R01 applications and complete research independence. Eosinophilic Esophagitis (EoE) is a chronic allergen mediated inflammatory esophageal disease with substantial and increasing burden in children and adults. Chronic inflammation classically leads to dysphagia. Mounting evidence identifies a subset of patients who develop clinically significant fibrosis and esophageal stricture, a phenotype identified to have more severe symptoms and worse treatment response. Termed fibrostenotic EoE (FS-EoE), this phenotype can be defined by partially occlusive stricture formation. Identifying those patients at greatest risk of fibrosis; determining optimal management strategies; and closing gaps in our understanding of the cellular pathways involved in the development of fibrotic disease are all needed to help provide tailored approach to therapy. Supported by Dr. Menard-Katcher?s K23, we evaluated and characterized over 110 pediatric EoE patients based on clinical outcomes, symptoms, endoscopic appearance, histology and esophageal function (ie distensibility). RNASeq analysis from a subset of these patients identified genes with altered expression that could define a FS-EoE phenotype. Gene pathway analysis identified SMAD protein phosphorylation pathways to be differentially expressed between fibrotic (with stricture) and non-fibrotic (without stricture) EoE subjects and specifically identified connective tissue growth factor (CTGF/CCN2) overexpression in the FS-EoE phenotype. CTGF (or CCN2) is a secreted regulatory matricellular protein involved in promoting fibrosis often through TGF /SMAD in response to injury. CTGF is implicated in the progression of fibrosis in the kidney, lung and skin and it may be an amenable target for treatment. We hypothesize CTGF is involved in promoting fibrotic remodeling in EoE and that evaluation of the EoE proteome will identify novel proteins implicated in a more severe fibrotic phenotype. To address this overarching hypothesis, we propose two related but independent aims. As CTGF has not yet been explored in EoE or the esophagus, in Aim 1 we will determine CTGF expression in in vitro and in a novel in vivo model of EoE.
In Aim 2 we will evaluate the esophageal mucosal proteome to identify targets and pathways implicated in the fibrostenotic phenotype. Results from the proposed Aims will elucidate if the CTGF pathway is implicated in EoE and use multi- omic data to identify novel pathways and targets for next step research in the pathogenesis and possible treatment of FS-EoE. This will provide novel evidence to support a successful R01 or similar application that will investigate biomechanisms of disease and innovative approaches to management of FS-EoE.
Substantial fibrotic narrowing occurs in the esophagus in a subset of patients with a severe phenotype of Eosinophilic Esophagitis (EoE), a chronic allergen disease of the esophagus. Gene expression data resulting from the applicant?s K23 Career Development Award implicates novel genes and pathways in promoting the fibrotic remodeling seen in severe EoE. This R03 application proposes to clarify the role of one of these promising targets not yet investigated in EoE and analyze the proteome of fibrotic EoE to further elucidate novel pathways critical for progression of this disease.
