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Title: The involvement of Receptor Interacting Protein Kinase 1 (RIPK1) in the pathogenesis of acute pancreatitis
Author: Ouyang, Y.
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2017
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Acute pancreatitis (AP) is a severe and potentially fatal human disease characterized by parenchymal necrosis with associated inflammation. Necroptosis is a form of controlled necrosis which is mediated through receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL) as a regulated cell death pathway. Accumulating studies have demonstrated that necroptosis plays an important role in the pathogenesis of AP related to RIPK3 and MLKL. However, the function of RIPK1 in the pancreas, especially under pathological conditions, has remained unclear. The aims of this study were to investigate the effects of RIPK1 kinase activity, using gene modification and pharmacological inhibition, on in vitro cell death, reactive oxygen species (ROS) production, and Ca2+ signalling and in vivo using three experimental AP models, to further understand the role of RIPK1 in AP. Both genetic modification and pharmacological inhibition led to significant reductions of acinar cell necrosis. In addition, chemical inhibitors were also found to reduce TLCS-induced apoptosis, ROS production and CCK-induced sustained Ca2+ elevations. The severity of experimental pancreatitis in TLCS- , FAEE- and CER-AP was only partially protected in Ripk1K45A mice compared to strain-matched controls. Application of Nec-1 (56 mg/kg) through a mini pump as a treatment markedly reduced the severity of AP in all three experimental models. In addition, inhibition of indoleamine 2, 3-dioxygenase (IDO), another reported target of Nec-1, caused partial protection in TLCS-AP. In conclusion, RIPK1 kinase activity may play a role in the pathogenesis of AP, however, the results indicated that it would not be an appropriate target for drug development. In contrast, Nec-1 significantly ameliorated AP in all experimental models tested, likely through multiple pathways, suggesting further elucidation of its effects might assist the development of novel therapies.
Supervisor: Criddle, D. C. ; Sutton, R. S. ; Mukherjee, R. M. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral