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Insulin protects pancreatic acinar cells during acute pancreatitis

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  • Full or part time
    Dr Bruce
    Dr Wang
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Acute pancreatitis is a serious and sometimes fatal inflammatory disease whereby the pancreas digests itself. This is caused by bile acids, fatty acid/alcohol metabolites and oxidative stress. Recently, impaired metabolism and cytosolic Ca2+ ([Ca2+]i) overload have been suggested to be the cardinal events that trigger the disease regardless of the causative factor. We have shown that insulin, which is protective in animal models and clinical studies of human pancreatitis, protects pancreatic acinar cells from cytosolic Ca2+ overload, inhibition of the plasma membrane Ca2+ pump (PMCA), ATP depletion and necrotic cell death induced pancreatitis-causing agents. This was due to a metabolic switch from mitochondrial to glycolytic metabolism, sufficient to maintain ATP to fuel PMCA activity and thus prevent Ca2+ overload, even in the face of impaired mitochondrial function. The over-arching aim of this project is to determine the molecular mechanism for this insulin protection and in particular the specific glycolytic enzymes and signalling pathways responsible for the metabolic switch. The successful outcome of this project will further corroborate insulin, and related agents, as possible treatments for acute pancreatitis, regardless of the precise causative factor. It is hoped that this multidisciplinary approach from molecular mechanism to whole organism disease state will have major clinical implications for the treatment of acute pancreatitis. In addition this project may also reveal novel and more specific drug targets for the treatment of acute pancreatitis.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

-Samad A, James A, Wong J, Mankad P, Whitehouse J, Patel W, Alves-Simoes M, Siriwardena AK, Bruce JI (2014) J. Biol Chem. 289 (34), (published online ahead of print July 3rd)

-Mankad P, Siriwardena AK, Elliott AC, Bruce JIE (2012). Insulin protects rat pancreatic acinar cells from oxidant-induced inhibition of the plasma membrane calcium pump. J. Biol Chem. 287, 1823–1836 -Bruce JIE (2010) Plasma membrane calcium pump regulation by metabolic stress World J Biol Chem; 1(7): 221-228.

-Baggaley E, Elliott AC & Bruce JIE (2008) Oxidant-induced inhibition of the plasma membrane Ca2+-ATPase in pancreatic acinar cells: Role of the mitochondria. American Journal of Physiology (Cell Physiology) 295(5): C1247-60.

- Criddle DN, Gerasimenko JV, Baumgartner HK, Jaffar M, Voronina S, Sutton R, Petersen OH, Gerasimenko OV (2007). Calcium signalling and pancreatic cell death: apoptosis or necrosis? Cell Death Differ 14, 1285-1294.

-Voronina SG, Barrow SL, Simpson AW, Gerasimenko OV, da Silva Xavier G, Rutter GA, Petersen OH, Tepikin AV (2010). Dynamic changes in cytosolic and mitochondrial ATP levels in pancreatic acinar cells. Gastroenterology 138: 1976-1987.

- Petersen OH, Tepikin AV, Gerasimenko JV, Gerasimenko OV, Sutton R, Criddle DN. (2009). Fatty acids, alcohol and fatty acid ethyl esters: toxic Ca2+ signal generation and pancreatitis Cell Calcium. 45(6):634-42.

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