PhD, University of Cincinnati, 2018, 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 ( (open full item for complete abstract)

Committee: 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) Subjects: Pharmacology

Master of Science (MS), Ohio University, 2014, Biological Sciences (Arts and Sciences)

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and renal failure in humans. The molecular pathways that lead to DN are not well known. This research investigates possible roles of several signal transducers and activators of transcription (STAT) proteins in this disease using a STAT5A/B knockout (SKO) mouse model. Based on previous observations of increased inflammation-related gene expression in the kidneys of diabetic SKO mice, the hypothesis of the current project was that the combination of the loss of STAT5 repression and increase of STAT3 activity escalates inflammation-related gene expression in the kidneys of diabetic SKO mice. In support of this hypothesis, an increase of IRF-1 RNA expression, reflective of the loss of STAT5 repression, was observed in the kidneys of diabetic SKO mice. Levels of phosphorylated STAT3 were also increased in the kidneys of diabetic SKO mice. These results suggest that STAT5 acts as a repressor of inflammation-related genes in DN and, in its absence, expression of these genes is no longer repressed, either due to direct loss of the STAT5 repression or due to increased STAT3 activity which could potentially increase their expression.

Committee: Karen Coschigano PhD (Advisor); Calvin James PhD (Committee Member); Ramiro Malgor MD (Committee Member) Subjects: Animals; Biology; Biomedical Research; Immunology; Molecular Biology

PhD, University of Cincinnati, 2012, Medicine: Cell and Molecular Biology

Significance: Signal Transducer and Activator of Transcription 3 (STAT3) is crucial for both innate and adaptive mucosal immune responses in human inflammatory bowel disease (IBD) and murine models of colitis. Background: Our lab has reported up-regulation of IL-6:STAT3–dependent biological networks in colonic mucosal biopsies from IBD patients. We identified increased frequency of STAT3 activated lamina propria and epithelial cells that correlated with histologic disease severity and epithelial injury. Recent genome-wide association studies (GWAS) have associated genetic variants in STAT3 with risk for IBD. Goals: Goals that are met in this dissertation are as follows: (1) Determine the functional effect of rs744166 STAT3 IBD risk SNP (STAT3 “A” risk allele) in pediatric Crohn's disease phenotype, leukocyte recruitment to the gut, peripheral T lymphocyte and granulocyte STAT3 activation, and STAT3 signaling. (2) As no suitable mode for the study of in-vivo epithelial STAT3 specific affects exits, create and characterize an epithelial Stat3 deficient murine model (3) and determine if the loss of STAT3 in the epithelial compartment would promote the development of chronic colitis following acute dextran sodium sulfate (DSS) injury. Results: (1)The STAT3 “A” risk allele is associated with colonic up-regulation of chemokines IL-8, CXCL1, and CXCL3, which promote CXCR2+ neutrophil recruitment to the gut, and the neutrophil activation products, calprotectin (S100A8/S100A9) and S100A12. The frequency of neutrophils expressing CXCR2 was increased, and the frequency of pSTAT3+ or CXCR2+ neutrophils correlated with histologic severity in colonic biopsies from patients carrying the risk allele. Peripheral blood frequency of basal CD4+ lymphocytes and basal and IL-6/IL-6R stimulated granulocytes expressing pSTAT3 was increased in patients carrying the STAT3”A” risk allele. EBV-transformed lymphocytes from patients carrying the STAT3”A” risk allele exhibited increased basal and (open full item for complete abstract)

Committee: Lee Denson MD (Committee Chair); David Hildeman PhD (Committee Member); Nelson Horseman PhD (Committee Member); Marshall Montrose PhD (Committee Member); Yi Zheng PhD (Committee Member) Subjects: Cellular Biology