ABSTRACT/PROJECT SUMMARY Eosinophilic Esophagitis (EoE) is a chronic allergic disease of the esophagus clinically characterized by symptoms including difficulty swallowing, food impaction, and decreased quality of life. Histopathological features of EoE include esophageal eosinophilia (EOS/HPF) and epithelial remodeling, including dilated intercellular spaces (DIS) and basal zone hyperplasia (BZH). BZH has been linked with a fibrostenotic phenotype and clinical outcomes such as esophageal stiffness and dysfunction, food impaction and stricture [1]. The underlying immune/inflammatory responses that drive EoE pathogenesis have been extensively studied; however, studies defining the molecular basis of esophageal epithelial proliferation and BZH in EoE are sparse. Herein, we identified a critical role Secreted Frizzled-Related Protein 1 (SFRP1) in driving esophageal epithelial proliferation in EoE. A major gap in our knowledge is the molecular basis of SFRP1 regulation in Interleukin-13 (IL-13)- induced esophageal epithelial proliferation and BZH in EoE. EoE disease pathogenesis is largely driven by the cytokine IL-13, which is upregulated in esophageal biopsies of EoE patients and is sufficient to alter gene expression in esophageal epithelial cells in vitro and in vivo. In preliminary studies we show that IL-13 induces a time-dependent increase in p-STAT3 (Y705 and S727) and p-STAT6 (Y641) in esophageal epithelial cells (EPC2-ALI) and in 3D primary esophageal cell cultures; however, IL-13-induced esophageal epithelial proliferation is STAT3-dependent. Differentially expressed genes (DEGs) derived from RNAseq analyses of esophageal biopsy samples from EoE individuals and IL-13-induced EPC2-ALI cells are enrichment for genes that contain putative STAT3 binding motifs and are enriched for genes involved in epithelial proliferation and are pro-survival pathways. We identified Secreted Frizzled Related Protein 1 (SFRP1), a soluble modulator of Wnt signaling and cellular proliferation as a common STAT3 putative target and DEG in esophageal epithelial cells. We will test the central hypothesis that IL-13-STAT3-dependent regulation of esophageal epithelial proliferation is mediated by SFRP1. The specific aims (SA) will SA1) Define the requirement of STAT3 in IL-13-induced SFRP1 expression in esophageal epithelial cells and SA2) Define the role of SFRP1 in IL-13-induced esophageal epithelial cell proliferation. My long-term career goal is to become an independent investigator in an academic setting. I will be immersed in an academically rich research training environment with access to world-class facilities, equipment, and basic / clinical / translational research programs. The proposed research will be supervised by a multidisciplinary team of expert scientists and clinicians, who have the experience and expertise to mentor me and assure successful completion of the proposed studies and provide an excellent foundation training to pursue a career in medical research.

NARRATIVE Eosinophilic Esophagitis (EoE) is a debilitating chronic allergic disease of the esophagus characterized by esophageal eosinophilia and epithelial remodeling (BZH and DIS), for which there is a large, unmet clinical need. The observed esophageal epithelial proliferation in BZH drives esophageal remodeling and contributes to disease chronicity, and its underlying molecular basis remains unclear. In this proposal we will define the requirement of STAT3 in IL-13-induced SFRP1 expression in the regulation of esophageal epithelial proliferation in EoE; successful completion of the specific aims will lead to identification of novel therapeutics which target SFRP1 in the treatment of BZH in EoE.