Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.770519
Title: CFTR regulation of islet morphology and function
Author: Koivula, Fiona Manderson
ISNI:       0000 0004 7653 0868
Awarding Body: Ulster University
Current Institution: Ulster University
Date of Award: 2017
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Abstract:
Cystic Fibrosis-related Diabetes (CFRD) is the largest extra-pulmonary co­morbidity in Cystic Fibrosis (CF), and while there have been many studies investigating the role of the Cystic Fibrosis Transmembrane-conductance Regulator (CFTR) in the lung, little is known regarding the role of CFTR in the endocrine pancreas. Using a combination of cellular and molecular techniques, this study investigated the role of CFTR in the morphology and function of the endocrine pancreas in islet cell lines and primary islets. We have confirmed the presence of CFTR in the beta cell and identified a role for CFTR in the maintenance of islet architecture via gap junction activity. Pseudoislet morphology is significantly altered following CFTR inhibition and is associated with reduced expression of genes associated with cell-cell contact. Islet function is also impaired whereby acute glucose-stimulated insulin secretion is reduced following cAMP activation and treatment with CFTR inhibitors. This was coupled with decrease in expression of common beta cell markers associated with insulin secretion. Ca2+ plays an important role in the insulin secretion pathway in the beta cell, and we demonstrated altered [Ca2+]Cyt flux and impaired Ca2+ uptake into the mitochondria in CFTR inhibited cells. Additionally, we have shown that activation of the unfolded protein response (UPR) induces CFTR stress and that this is associated with a reduction in GLP-l-stimulated insulin secretion. Collectively, this project confirms a role for CFTR in the morphology and function of the pancreatic islet in rodent cell lines and primary islets. This work will contribute to a growing body of evidence for the role of CFTR and chloride channels in the development of CFRD with the aim of developing new therapeutic targets in these patients. Future work will focus on the role of specific CFTR mutations in the structure and function of the pancreatic islet.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.770519  DOI: Not available
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