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The pathological role of bcl-2 family proteins and the protective role of calcium regulator calmodulin in pancreatic acinar cells

Peng, Shuang 2013. The pathological role of bcl-2 family proteins and the protective role of calcium regulator calmodulin in pancreatic acinar cells. MPhil Thesis, Cardiff University.
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Acute pancreatitis is a life threatening illness characterized by premature activation of digestive enzymes inside pancreatic acinar cells. This leads to necrosis and digestion of the pancreatic tissue and its surroundings. As of yet, no specific therapy to treat acute pancreatitis has been found. The physiological and pathological processes are controlled to a large extent by calcium signalling in pancreatic acinar cells. Intracellular calcium signalling not only regulates the expression and secretion of digestive enzymes but also contributes to the activation of trypsinogen, which eventually leads to pancreatitis and causes necrosis of pancreatic tissue. The Bcl-2 protein is a member of Bcl-2 family proteins that regulate programmed cell death. It has been shown that Bcl-2 proteins are engaged in the regulation of cellular calcium homeostasis. One aim of this study was to investigate the effects of the anti-apoptotic Bcl-2 protein on intracellular calcium fluxes. Another goal was to study the effects of calmodulin activators (calcium-like peptides) on pathophysiological processes in pancreatic acinar cells. Our data showed that thapsigargin and acetylcholine-induced cytosolic calcium release was quicker in pancreatic acinar cells lacking Bcl-2 protein than in wild type cells. We blocked the endoplasmic reticulum Ca2+ pumps by thapsigargin and removed the external Ca2+, therefore, Ca2+ extrusion was the only process restoring the basal cytosolic Ca2+ level. Our results show that cells lacking Bcl-2 extrudes Ca2+ more efficiently than the wild type cells. Furthermore, Ca2+ extrusion was decreased in the pancreatic cancer cell line AR42J which has overexpression of Bcl-2. This effect can be explained by the increased activity of plasma membrane calcium-activated ATPase (PMCA) which was blocked by Caloxin 3A1, which in turn promotes necrosis in pancreatic acinar cells. In addition, the data presented here showed that the calmodulin activators CALP-3 and CALP-1 did not affect the physiological calcium signalling in pancreatic acinar cells but instead contributed to either increasing the cell survival rate or causing apoptosis. CALPs were applied to specifically activate calmodulin which reduced the toxic effects of pancreatic acinar cells challenged with alcohol or the oxidant menadione. This study shows that the inhibition of calcium recovery mechanisms by Bcl-2 is significantly pathological. The study also proposes that calcium-like peptides could potentially be developed as therapeutic agents for acute pancreatitis.

Item Type: Thesis (MPhil)
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > QP Physiology
Uncontrolled Keywords: Acute Pancreatitis, CALP, alcohol
Funders: Medical Research Council
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 04:58

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