Date of Award
2006
Degree Type
Thesis
Degree Name
Doctor of Philosophy
Program
Physiology and Pharmacology
Supervisor
Dr. Christopher Pin
Second Advisor
Dr. Kidder
Third Advisor
Dr. Ferguson
Abstract
To identify molecular factors involved in exocrine pancreatic function and disease susceptibility, the role of MistI was examined. Mistl is a basic helix-loop-helix (bHLH) transcription factor expressed in acinar cells of the exocrine pancreas and the absence of Mistl in mice (Mist1k) results in incomplete maturation of acinar cells and premature enzyme activation with no overt phenotypic defect. Therefore, I hypothesize that Mistlκo 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, Mistlκ° mice display higher levels of serum amylase than WT mice suggesting a more severe form of pancreatitis. Histological analysis confirms that Mistlκ° 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, Mistlκ° 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 Mistlκ° mice were subjected to microarray analysis. A number of genes involved in regulated exocytosis were identified to be differentially expressed between WT and Mistlκ° 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 Mistlκ° mice following induction of pancreatitis also revealed a differential molecular response to injuιy and identified a number of factors promoting tissue damage and a block in proper response to iii stress in Mist12 mice. This study therefore indicates that the transcription factor, Mistl, plays a role in dictating severity of pancreatitis making Mist19 mouse a good model for further studying the factors involved in the modulation of the disease process.
Recommended Citation
Kowalik, Agnes S., "IDENTIFYING MOLECULAR FACTORS INVOLVED IN ACINAR CELL FUNCTION AND PANCREATIC DISEASE" (2006). Digitized Theses. 4970.
https://ir.lib.uwo.ca/digitizedtheses/4970