The proposed training in the K08 application outlines an integrated plan of mentored research and career development activities as well as a specific strategy for this pediatric gastroenterologist to pursue an independent research career as a physician scientist. This award will allow her to refine existing and gain additional skills with te guidance of her mentors Drs. Rustgi and Nakagawa. She will pursue formal coursework as well as seminars in career development, bioethics, grant writing, and laboratory management. Eosinophilic esophagitis (EoE) is an allergic disease characterized by esophageal infiltration of eosinophils. Esophageal fibrosis is the most serious complication of EoE, leading to dysphagia, food bolus impaction, and esophageal stricture. Fibrosis is defined as excess deposition of collagen leading to tissue stiffness. However, the quality of the collagen, meaning the extent of collagen cross-linking, may be just as important as the amount of collagen. Collagen cross-linking by the enzyme lysyl oxidase (LOX) enhances stiffness within the tissue. Increased tissue stiffness may support a positive feedback loop that increases fibrosis, since fibroblasts are known to transdifferentiate into activated myofibroblasts upon contact with a stiff matrix. Preliminary data suggest that cross-talk between esophageal epithelial cells and esophageal fibroblasts, specifically through the cytokine TNFa, enhances expression of LOX. In addition, LOX expression is upregulated in patients with active EoE in biopsy samples. Based on these findings, the overall hypothesis is that LOX is a critical modulator of fibrosis in EoE and that it functional properties are mediated in part through specific epithelial-fibroblast interactions. Using an established organotypic culture model system, the investigator will define how epithelial derived LOX enhances myofibroblast activation and increases tissue stiffness (Aim 1). She will determine the mechanism in which TNFa induces LOX expression utilizing genetic and chemical inhibition. She will further delve into the signaling pathway of TNFa and determine the mechanism of signaling that ultimately results in LOX expression (Aim 2). Lastly, we will look in vivo at the role of LOX in a chronic mouse model of EoE. Through chemical inhibition, she will determine the effect of LOX inhibition on fibroblast activation and function (Aim 3). She anticipates that results from these studies will define LOX's role in EoE fibrosis and will provide the foundation for future studies with translational applications in the management and therapy of EoE. These studies will elucidate novel mechanisms of LOX in EoE and have the potential to contribute significantly to understanding of fibrosis.
Eosinophilic esophagitis (EoE) is a chronic disease in which allergic inflammation and tissue damage eventually lead to scarring and fibrosis of the esophagus. This proposal seeks to elucidate the role of epithelial derived lysyl oxidase (LOX) in collagen cross- linking in esophageal fibrosis. Results from this study will lead to a more precise understanding of esophageal epithelial and stromal cross-talk and will provide the basis for future work targeting the prevention and reversal of fibrosis in EoE.
| Kasagi, Yuta; Chandramouleeswaran, Prasanna M; Whelan, Kelly A et al. (2018) The Esophageal Organoid System Reveals Functional Interplay Between Notch and Cytokines in Reactive Epithelial Changes. Cell Mol Gastroenterol Hepatol 5:333-352 |
| Whelan, Kelly A; Muir, Amanda B; Nakagawa, Hiroshi (2018) Esophageal 3D Culture Systems as Modeling Tools in Esophageal Epithelial Pathobiology and Personalized Medicine. Cell Mol Gastroenterol Hepatol 5:461-478 |
| Cianferoni, Antonella; Ruffner, Melanie A; Guzek, Ryan et al. (2018) Elevated expression of activated TH2 cells and milk-specific TH2 cells in milk-induced eosinophilic esophagitis. Ann Allergy Asthma Immunol 120:177-183.e2 |
| Muir, Amanda; Moore, Hillary; Spergel, Jonathan (2018) To treat or not to treat: The minimally symptomatic EoE patient. Ann Allergy Asthma Immunol : |
| Ruffner, Melanie A; Brown-Whitehorn, Terri F; Verma, Ritu et al. (2018) Clinical tolerance in eosinophilic esophagitis. J Allergy Clin Immunol Pract 6:661-663 |
| Muir, Amanda B; Wang, Mei-Lun; Metz, David et al. (2017) Proton pump inhibitor-responsive oesophageal eosinophilia: too early to change clinical practice. Gut 66:979-980 |
| Whelan, Kelly A; Merves, Jamie F; Giroux, Veronique et al. (2017) Autophagy mediates epithelial cytoprotection in eosinophilic oesophagitis. Gut 66:1197-1207 |
| Menard-Katcher, Calies; Benitez, Alain J; Pan, Zhaoxing et al. (2017) Influence of Age and Eosinophilic Esophagitis on Esophageal Distensibility in a Pediatric Cohort. Am J Gastroenterol 112:1466-1473 |
| Merves, Jamie F; Whelan, Kelly A; Benitez, Alain J et al. (2016) ATG7 Gene Expression as a Novel Tissue Biomarker in Eosinophilic Esophagitis. Am J Gastroenterol 111:151-3 |
| Muir, Amanda B; Dods, Kara; Henry, Steven J et al. (2016) Eosinophilic Esophagitis-Associated Chemical and Mechanical Microenvironment Shapes Esophageal Fibroblast Behavior. J Pediatr Gastroenterol Nutr 63:200-9 |
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