Dissertation
Ductal epithelial plasticity in the cystic fibrosis pancreas
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2020
DOI: 10.17077/etd.005313
Abstract
Cystic Fibrosis (CF) is a multi-organ disease caused by loss of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) function. Impaired CFTR-dependent bicarbonate transport acidifies the pancreatic ductal lumen and prematurely activates secreted digestive enzymes before they exit into the intestine. The subsequent tissue damage leads to pancreatic insufficiency in 85% of CF patients and cystic fibrosis-related diabetes (CFRD) in 50% of adult CF patients. In this study, we characterize the onset and progression of tissue remodeling in the CF pancreas using a ferret CFTR-knockout (KO) model. Key features of tissue remodeling include acinar atrophy, proliferative ducts, and coalesced endocrine mass in the milieu of severe inflammation and fibrosis. Given the developmental potential of the pancreatic ductal cells to generate the acinar and endocrine compartments, we provide evidence for CFTR-dependent cell-autonomous alteration in pancreatic ductal cell plasticity due to altered chromatin accessibility of lineage fate determining genes like PDX1 and PAX6, and altered Wnt, TGF-β, and BMP signaling. We propose a CFTR-dependent mechanism regulating PDX1 expression in the pancreatic ducts that may affect tissue remodeling in response to CF-related pancreatic injury. Overall, our study highlights CF-dependent modification in epithelial fate and its contribution to the development of exocrine and endocrine disorders.
Details
- Title: Subtitle
- Ductal epithelial plasticity in the cystic fibrosis pancreas
- Creators
- Pavana Gururaj Rotti
- Contributors
- John F Engelhardt (Advisor)Andrew Norris (Committee Member)Aliye Uc (Committee Member)Edward Sander (Committee Member)Kristan Worthington (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Engineering
- Date degree season
- Spring 2020
- DOI
- 10.17077/etd.005313
- Publisher
- University of Iowa
- Number of pages
- x, 138 pages
- Copyright
- Copyright 2020 Pavana Gururaj Rotti
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 130-138).
- Public Abstract (ETD)
Cystic Fibrosis (CF) affects 30,000 people in the United States with ~1,000 cases diagnosed every year. Cystic fibrosis-related diabetes (CFRD) is a leading co-morbidity occurring in 50% of the adult CF population. Although terminal changes in the CF pancreas have been characterized, the cause for these alterations and the delayed onset of CFRD is unknown. In this study, we have tried to systematically analyze the onset and progression of CF-related pathology in the pancreas and relate it to systemic changes in glucose tolerance. We report higher ability of CF ductal cells to differentiate into endocrine cells. One therapeutic approach to prevent the decline in endocrine cells that leads to diabetes, is to capitalize on the inherent regenerative potential of pancreatic duct cells. Hence, we characterized the cellular mechanisms promoting the renewal of endocrine cells. Questions arising from this study include whether or not newly born CF endocrine cells are functionally mature and how endocrine cell death may be prevented in the setting of inflammation and fibrosis. Targeting signaling pathways that aid formation of new endocrine cells from the ducts and their functional maturation may reduce the incidence of CFRD.
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Craniofacial Anomalies Research Center
- Record Identifier
- 9983956197302771
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