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Regulation of Esophageal Epithelial Function in Eosinophilic Esophagitis

Zeng, Chang
http://orcid.org/0000-0002-8348-3903
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1530797729542185

Abstract Details

2018, PhD, University of Cincinnati, Medicine: Molecular, Cellular and Biochemical Pharmacology.
Eosinophilic Esophagitis (EoE) is an allergic inflammatory disorder with increasing prevalence in the western world. Patients with EoE demonstrate symptoms including vomiting, dysphagia and food impaction which decreased the quality of life. One of the histopathological features of EoE is esophageal tissue remodeling, including dilated intercellular spaces (DIS) and basal zone hyperplasia (BZH). However, the underlying molecular s that drive these features is largely unknown. Here, we investigate the 1) involvement of sodium-hydrogen exchanger 3 (NHE3) in esophageal epithelium remodeling and 2) the role of the transcription factors, signal transducer and activator of transcription (STAT), in the regulation of gene networks that control esophageal epithelial proliferation and histopathological features of EoE. By analyzing RNA sequencing comparing transcriptome difference in esophageal biopsies from normal control (NL) and EoE patients, we identified NHE3 as the most upregulated transmembrane transporters in patients with active EoE. We found that the expression pattern of NHE3 closely correlated with the disease severity and DIS. Functional analyses demonstrated that NHE3 activity is upregulated in IL-13 treated primary esophageal epithelial cells derived from EoE patients, as well as in IL-13-induced stratified squamous epithelium generated by the air-liquid interface (EPC2-ALI). Pharmacological Inhibition of NHE3 activity protected from IL-13 induced DIS in esophageal epithelium. Thus, we concluded that NHE3 plays a functional role in DIS formation and pharmacologic interventions targeting SLC9A3 function may suppress the histopathologic manifestations in EoE IL-13 has previously been shown to activate STAT proteins, particularly STAT3 and STAT6 and regulate the transcriptome changes in EoE patients. Using transcription factor binding site (TFBS) analysis, we identified STAT protein binding motif is one of the most enriched transcription factor binding site (TFBS) in the dysregulated genes in both EoE biopsies and IL-13 treated EPC2-ALI cultures. In particular, we identified the STAT3 binding site as the most enriched TFBS in IL-13 induced upregulated genes in EPC-ALI. By knocking down STAT3 in EPC2 cells, we revealed a role for STAT3 in the regulation of epithelium barrier function and IL-13-induced proliferation. In contrast, we show that STAT6 plays a pro-inflammatory role regulating cytokine and chemokine production in esophageal epithelium. Together, we identified several molecular targets in the esophageal epithelium that are important in modulating the esophageal epithelium remodeling in EoE. This dissertation, for the first time, uncovers the role of transmembrane transporters in the pathogenesis of EoE. Also, we provide valuable information on the two distinct divergent pathways regulated by STAT3 and STAT6 driving IL-13-mediated transcriptome changes in EoE. Further investigations into the contribution of these mechanisms in the clinical manifestations of EoE will facilitate the evolvement of new therapeutic approaches in EoE treatment.
Anjaparavanda Naren, Ph.D. (Committee Chair)
Simon Hogan, Ph.D. (Committee Member)
Marshall Montrose, Ph.D. (Committee Member)
Robert Rapoport, Ph.D. (Committee Member)
Gary Edward Shull, Ph.D. (Committee Member)
Hongsheng Wang, Ph.D. (Committee Member)
194 p.
Pharmacology
Eosinophilic Esophagitis; SLC9A3; IL-13; Dilated Intercellular Spaces; signal transducer and activator of transcription

Recommended Citations

Citations

  • Zeng, C. (2018). Regulation of Esophageal Epithelial Function in Eosinophilic Esophagitis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1530797729542185

    APA Style (7th edition)

  • Zeng, Chang. Regulation of Esophageal Epithelial Function in Eosinophilic Esophagitis. 2018. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1530797729542185.

    MLA Style (8th edition)

  • Zeng, Chang. "Regulation of Esophageal Epithelial Function in Eosinophilic Esophagitis." Doctoral dissertation, University of Cincinnati, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1530797729542185

    Chicago Manual of Style (17th edition)

ucin1530797729542185
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This open access ETD is published by University of Cincinnati and OhioLINK.