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Title: The role of Orai inhibition in acute pancreatitis
Author: Wen, Li
ISNI:       0000 0004 5369 021X
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2015
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Background and aims: Prolonged elevation of cytosolic Ca2+ concentration is the key trigger of pancreatic damage and acute pancreatitis (AP). Ca2+ release-activated Ca2+ modulator Orai1 channel is the most abundant store-operated Ca2+ entry (SOCE) channel in pancreatic acinar cells; it sustains calcium overload in mice exposed to toxins that induce AP. The studies in this thesis investigated the roles of Orai1channel in pancreatic acinar cell injury and the development of AP in mice. Methods: Freshly isolated mouse and human acinar cells were hyper-stimulated or incubated with human bile acid orthapsigargin to induce Ca2+ entry. Effects of GSK-7975A or CM_128 on Ca2+ entry and necrotic cell death pathway activation were analysed by confocal and video microscopy. Experimental acute pancreatitis was induced in C57BL/6J mice by 1) ductal injections of taurolithocholic acid 3-sulphate (TLCS-AP); 2) intraperitoneal (IP) administration of caerulein (CER-AP) or 3) a combined IP administration of ethanol and palmitoleic acid (FAEE-AP). Two Orai1 inhibitors were administrated at different time points and the disease severity was assessed by various local and systemic parameters, including pancreatic trypsin and myeloperoxidase (MPO) activity, serum interleukin (IL)-6 and lung MPO activityas well as blinded histopathology. Results: GSK-7975A and CM_128 each separately inhibited toxin-induced activation of SOCE via Orai1 channels in a concentration dependent manner, in mouse and human pancreatic acinar cells (inhibition > 90% the levels observed in control cells). GSK-7975A and CM_128 each inhibited all local and systemic features of AP in all three representative models, in dose- and time-dependent manners. The agents were significantly more effective, in a range of parameters, when given early versus late after induction of AP. Conclusion: Cytosolic Ca2+ overload mediated via Orai1 plays a pivotal role in the pathogenesis of AP. Inhibition of Orai1 channel is a useful therapeutic approach for human acute pancreatitis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: RM Therapeutics. Pharmacology