Ion channels and pumps in secretory cells: pancreatic acinar physiology and pathology

Lead Research Organisation: University of Liverpool
Department Name: Biomedical Sciences

Abstract

The pancreas is the organ in our body producing and secreting the enzymes that are essential for the normal digestion of food in the gut. When these enzymes are inappropriately activated inside the cells of the pancreas (breaking down this organ and its surroundings) we have the disease Acute Pancreatitis. About 20000 people in the UK develop pancreatitis every year, and currently there is no known cure. Life-threatening complications occur in about 25% of the cases and the mortality is about 10%. We have recently shown that abnormal changes in the calcium concentration inside the pancreatic cells causes activation inside these cells of the digestive enzymes. It is therefore essential now to understand how the abnormal Ca2+ signals can be generated in order to prevent this happening. Pancreatitis is often triggered by bile flowing back into the pancreas or by alcohol. We plan to investigate the mechanism by which pancreatitis is initiated by these agents through the use of realistic models. We shall study both the intact pancreas from normal and genetically modified mice and rats as well as isolated human pancreatic acinar cells obtained from surgical procedures for cancer.

Technical Summary

Acute pancreatitis is an important (and often life-threatening) human disease in which the pancreatic digestive enzymes, normally engaged in the digestion of food in the gut, break down the pancreatic acinar cells and their surroundings. The pathophysiology of acute pancreatitis is far from fully understood, but we have recently established that excessive flow of Ca2+ into the acinar cells is an important early event in the activation of digestive enzymes inside the acinar granules. We have also shown very recently that bile acids, which are known to be able to trigger acute pancreatitis, can evoke excessive cytosolic Ca2+ signals in the acinar cells. Our research plan is aimed at understanding how the physiological local Ca2+ signals, needed for the precise control of normal secretion, can be transformed into global sustained Ca2+ elevations causing intracellular protease activation. We plan to employ realistic models for acute pancreatitis in both isolated acinar cells from mice and humans as well as in the intact mouse or rat pancreas. One of the major specific aims is to establish the mechanism(s) by which bile acids and ethanol, agents implicated in the development of acute pancreatitis, generate abnormal cytosolic Ca2+ signals. We shall explore the relationships between these Ca2+ signals and activation of trypsin and the transcription factor NFkB, both of which are important for the pathogenesis of acute pancreatitis. Intracellular Ca2+ handling under conditions relevant to disease states will be explored also with regard to testing possible means of interfering with excessive flow of Ca2+ into the cells. This could be important for development of new therapies.

Publications

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Criddle DN (2007) Calcium signalling and pancreatic cell death: apoptosis or necrosis? in Cell death and differentiation

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Criddle DN (2006) Role of Ca2+ in pancreatic cell death induced by alcohol metabolites. in Journal of gastroenterology and hepatology

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Gerasimenko J (2010) Inhibitors of Bcl-2 protein family deplete ER Ca2+ stores in pancreatic acinar cells in Pflügers Archiv - European Journal of Physiology

 
Description MRC Grant
Amount £1,000,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2009 
End 04/2012
 
Description Characterization of the actions of CRAC channel blockers on pancreatic acinar cells 
Organisation GlaxoSmithKline (GSK)
Department GlaxoSmithKline Medicines Research Centre
Country United Kingdom 
Sector Private 
PI Contribution We are characterizing the actions and investigating the mechanisms of action of GSK-identified molecules on the functional properties of pancreatic acinar cells (Calcium signalling, intracellular protease activation, cell death). We are particularly interested in potential protective effects against agents indicing pancreatitis
Collaborator Contribution GSK are supplying us with GSK-identified molecules as well as information about their chemical properties and their whole-body handling
Impact A manuscript is being prepared
Start Year 2012
 
Description Identification of IP3 receptor subtypes involved in initiation of alcohol-related pancreatitis 
Organisation RIKEN
Department RIKEN Brain Science Institute
Country Japan 
Sector Public 
PI Contribution The principal experimental work measuring changes in intracellular calcium stores
Collaborator Contribution Supply of transgenic mice with deleted specific IP3 receptor subtypes
Impact Gerasimenko et al PNAS 106, 10758-10763, 2009
Start Year 2008
 
Description Knock-out of IP3 receptors 
Organisation RIKEN
Department RIKEN Brain Science Institute
Country Japan 
Sector Public 
PI Contribution We showed the importance of functonal IP3 receptors for induction of pancreatitis by fatty acid ethyl esters or alcohol
Collaborator Contribution Provision of transgenic mice
Impact Two papers, both published in PNAS (Gerasimnko et al 2009, 2011 - listed uner publications) have so far appeared in he scienif literature
Start Year 2008
 
Description A Pancreas-protecting protein 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Many requests for interviews with different media (incl BBC, magazines and newspapers)

Difficult to evaluate. Certainly increased awareness nationally and internationally of our work. May have contributed to increasing number of invitations to speak
Year(s) Of Engagement Activity 2011
 
Description BBC Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact Following Press Release by MRC and Cardiff University, interviewed live by BBC Wales

Coverage of press release and ineview in several newspapers
Year(s) Of Engagement Activity 2011
 
Description British Association Annual Meeting Liverpool 2008 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact Ole H Petersen chaired and gave introductory talk in session on Cystic Fibrosis organized by The Physiological Society. The new findings from MRC supported research on human pancreatic acinar cells published shortly before the meeting in the top-rated journal Gastroenterology (PMID: 18555802) were highlighted.

University of Liverpool issued Press release about our work, which resulted in Newspaper articles
Year(s) Of Engagement Activity 2008
 
Description Inteview published in THE 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact Interview published in THE describing my research following Life Time Achievement Award fromThe European Pancreatic Club (EPC).

Invited Award Lecture at EPC Annual Meeting in Stockholm 2010
Year(s) Of Engagement Activity 2010
 
Description Invted talk at British Association Annual Meeting in Liverpool 2008 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact Ole H Petersen chaired and gave introductory talk in session on Cystic Fibrosis organized by The Physiological Society. The new findings from MRC supported research on human pancreatic acinar cells published shortly before the meeting in the top-rated journal Gastroenterology (PMID: 18555802) were highlighted.

The University of Liverpool issued a Press Release, which gave rise to reports in Newspapers.
Year(s) Of Engagement Activity 2008
 
Description Research described in MRC Annual Review 2009/2010 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact Brief description of results from our PNAS 2009 article

So far none
Year(s) Of Engagement Activity 2010