Item – Theses Canada

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OCLC number
471036382
Link(s) to full text
LAC copy
LAC copy
Author
Kowalik, Agnes S.
Title
Identifying molecular factors involved in acinar cell function and pancreatic disease.
Degree
Ph. D. -- University of Western Ontario, 2007
Publisher
Ottawa : Library and Archives Canada = Bibliothèque et Archives Canada, [2008]
Description
4 microfiches
Notes
Includes bibliographical references.
Abstract
To identify molecular factors involved in exocrine pancreatic function and disease susceptibility, the role of 'Mist1' was examined. ' Mist1' is a basic helix-loop-helix (bHLH) transcription factor expressed in acinar cells of the exocrine pancreas and the absence of 'Mist1 ' in mice ('Mist1KO') results in incomplete maturation of acinar cells and premature enzyme activation with no overt phenotypic defect. Therefore, I hypothesize that 'Mist1KO' mice will develop more severe pancreatitis than wild type (WT) littermates. To address this hypothesis, mice were injected with supramaximal amounts of caerulein, a cholecystokinin analogue, which induces acute and chronic pancreatitis. Following caerulein injection, 'Mist1KO' mice display higher levels of serum amylase than WT mice suggesting a more severe form of pancreatitis. Histological analysis confirms that 'Mist1 KO' pancreatic tissue exhibits a progressive degeneration of pancreatic tissue characterized by distended duct formation, vacuolization, pronounced fibrosis and a decrease in the number of cells undergoing apoptosis. Additionally, 'Mist1KO' pancreas exhibits formation of focal metaplastic lesions characteristic of pre-neoplastic lesions. To identify molecular factors that may play a role in pancreatic function and disease susceptibility, pancreata of WT and 'Mist1KO' mice were subjected to in croarray analysis. A number of genes involved in regulated exocytosis were identified to be differentially expressed between WT and 'Mist1KO' mice, including 'Cx32, Rab3D, Cabp2, Fxyd3.' In addition, a novel, pancreas specific calcium ATPase was identified ('SPCA2'). Comparison of expression of molecular factors between WT and 'Mist1KO' mice following induction of pancreatitis also revealed a differential molecular response to injury and identified a number of factors promoting tissue damage and a block in proper response to stress in 'Mist1KO' mice. This study therefore indicates that the transcription factor, ' Mist1,' plays a role in dictating severity of pancreatitis making ' Mist1KO' mouse a good model for further studying the factors involved in the modulation of the disease process. Keywords: pancreas, microarray, pancreatitis, transcription factor, regulated exocytosis, stress response
ISBN
9780494308264
0494308265