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EXPLORING THE MECHANISMS OF ESOPHAGEAL KERATINOCYTE HOMEOSTASIS IN THE CONTEXT OF EOSINOPHILIC ESOPHAGITIS
Hall, Timothy Michael
Hall, Timothy Michael
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Thesis/Dissertation
Date
2019
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Biomedical Sciences
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http://dx.doi.org/10.34944/dspace/2951
Abstract
Eosinophilic esophagitis (EoE) is a chronic allergic pathology of the esophagus characterized by infiltration of eosinophils into the esophageal mucosa. EoE results in considerable impact on patient quality of life, substantiating the need to better understand the pathobiology of the disease in order to define novel approaches to diagnosis, monitoring and therapy. Our previous studies indicate an increase in circulating mitochondrial DNA in patients with active EoE and extracellular structures consistent with mitochondria in esophageal epithelium of patients with active EoE inflammation. While published studies provide evidence of a genetic link between mitochondrial dysfunction and development of EoE, the functional role of mitochondria in EoE pathophysiology remains unclear. In this thesis, we use immunohistochemistry on human patient biopsies, mouse models of EoE-like inflammation, and complementary in vitro and ex vivo models to explore the effects of the EoE inflammatory milieu on mitochondria in esophageal keratinocytes. We report that mitochondrial content is increased in human patients and mice with EoE inflammation. We also provide evidence that the EoE-associated cytokine, interleukin-13 increases mitochondrial DNA level and mitochondrial activity in vitro. To explore the role of autophagy in mitochondrial regulation in esophageal keratinocytes, we began generation of an autophagy-deficient cell line. This thesis provides foundation for further studies evaluating the role and mechanisms of mitochondrial regulation in the context of eosinophilic esophagitis.
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