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The role of CRAC channel inhibitor CM4620 in pancreatic acinar cells as a potential therapy for acute pancreatitis

Lewis, Sian 2020. The role of CRAC channel inhibitor CM4620 in pancreatic acinar cells as a potential therapy for acute pancreatitis. MPhil Thesis, Cardiff University.
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Abstract

Introduction. Acute pancreatitis (AP) is a life-threatening disorder with significant morbidity, mortality and no specific therapy available in the clinic. Excessive alcohol consumption and gallstone biliary disease are the leading causative factors of AP. Excessive release of Ca2+ from intracellular stores and subsequent activation of Ca2+ release-activated Ca2+ (CRAC) channels instigates cytosolic Ca2+ overload, mitochondrial dysfunction, necrosis and premature activation of digestive enzymes. Currently, a novel selective CRAC channel inhibitor CM4620 (developed by CalciMedica) has reached phase III human trials. However, this inhibitor has a very short therapeutic window due to its profound effects on immune cells. Recently, another approach has emerged where cells are supplied with energy supplement galactose, reducing AP effects in vitro and in vivo. This thesis aimed to combine these two approaches in vitro and in vivo. Methods. The effect of 1 μM and 10 μM CM4620 on calcium entry was recorded, using fluorescence imaging, by depleting intracellular calcium stores and activating calcium influx. Different concentrations of CM4620 (100 nM, 50 nM, 10 nM, 1 nM, 200 pM) were administered in the presence or absence of galactose (1 mM) and the effects on cellular necrosis levels, elicited by AP-inducing agents, was also measured using confocal microscopy. Additionally, the effect of nanomolar concentrations of CM4620 in alcohol-induced in vivo models of AP was investigated. Results. The data presented in this thesis shows that CM4620 markedly protects against acinar cell necrosis in vitro at much lower concentrations (100 nM, 50 nM, 10 nM, 1 nM, 200 pM) than reported previously, following exposure to bile acids, alcohol metabolites and asparaginase. Combining CM4620 and galactose (1 mM) provided a higher degree of protection, reducing the extent of necrosis to near-control levels. Administering 0.1 mg/kg CM4620 significantly diminished pancreatic histopathology in alcoholinduced in vivo mouse models of AP. Conclusions. As a potential therapy for the incurable disease AP, the protective capability of low concentrations of CM4620 could also diminish side effects resulting from CRAC channel inhibition. The novel combination of CM4620 with galactose increases the effectiveness

Item Type: Thesis (MPhil)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Date of First Compliant Deposit: 18 May 2020
Last Modified: 13 Mar 2021 02:25
URI: https://orca.cardiff.ac.uk/id/eprint/131766

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