Cellular Biology of the Gastrointestinal Tract and Pancreas in Health and Disease

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

Abstract

Gastrointestinal disease is a significant cause of early mortality and places a heavy financial burden on the National Health Service. For example, colorectal, stomach, oesophageal and pancreatic cancers are the 2nd, 5th, 6th and 7th commonest causes of cancer death in the UK. The NHS costs for treating GI disease is #3.03 billion per year. One fifth of short-term absence from work is as a result of gastrointestinal disease, which costs the country #2 billion per year (Gastroenterology in the UK: Burden of Disease. Prism Project 9608. The Wellcome Trust http://www.bsg.org.uk/burden.html).

The University of Liverpool has a long and distinguished history in gastrointestinal research and currently has nie research groups that focus on the science underlying a number of common gastrointestinal diseases. Specific questions being addressed are as follows. What are the mechanisms of calcium signalling in health and pancreatitis? How is gastric structure and function regulated in health, peptic ulcer disease and gastric cancer? How is apoptosis (programmed cell death) initiated in colorectal cancer by anticancer drugs? How do dietary lectins regulate proliferation in the normal and cancerous bowel? What are the genes that cause oesophageal cancer? How does dietary fibre maintain the health of colonic epithelium? How do abnormalities of calcium cause pancreatitis? Out of these questions come a number of shared intellectual and experimental themes such as mechanisms of signalling within and between GI epithelial cells, the causes of cancer in the GI tract and mechanisms by which epithelial cells develop specific functions in health and disease.

The component groups in this proposal already work together to some extent but added value would be given to each group if they were formally brought together into an MRC Co-operative Group. This would facilitate the purchase and sharing of expensive items of equipment and provide a framework to allow fast and efficient flow of ideas and expertise between the component groups. This grant application has two purposes: first to retain MRC Co-operative status; and secondly, the salary for a technician to work with transgenic animals together with modest running expenses.

Technical Summary

Abstract of Research
Gastrointestinal (GI) disease is a major cause of morbidity, mortality, and time off work in the UK, and is also associated with a high consumption of resources. The University of Liverpool has a strong research record in gastrointestinal science, which is currently sustained by 8 independent research groups including one MRC Research Professorship, 2 MRC Programme Grants and 2 MRC component grants. These research groups investigate complimentary aspects of the regulation of epithelial cell function in the gastrointestinal tract and pancreas and have already a published record of joint research in 36 papers. It is therefore logical to enhance further the productivity of the research environment by bringing these groups together into a co-operative group. Component projects cover the research areas of calcium signalling, the biological effects of gastrin on the stomach, regulation of apoptosis in the pancreas, effects of dietary lectins on intestinal epithelial metabolism and proliferation, identification of the tylosis oesophageal cancer gene, regulation of the butyrate transporter in the colonic epithelium, the role of calcium in pancreatitis, gene therapy for pancreatic cancer and cell cycle regulation. Externally peer-reviewed funding with more than 18 months to run already supports each component project. Participation in this co-operative gives added value to each project in terms of shared intellectual interaction, joint projects and shared equipment and expertise. Common research themes between the component projects are intracellular signal transduction in GI and pancreatic epithelium, regulation of proliferation and apoptosis, identification of genes regulating epithelial function and the investigation of the pathogenesis of pancreatitis and gastrointestinal neoplasia. Shared experimental techniques include state-of-the-art imaging, generation of transgenic knockout animals. Support is requested for a technician to maintain transgenic animal colonies and equipment for our multiphoton microscopy facility.

Publications

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Almeida-Vega S (2009) Gastrin activates paracrine networks leading to induction of PAI-2 via MAZ and ASC-1. in American journal of physiology. Gastrointestinal and liver physiology

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Boyd MT (2008) MDM2 polymorphisms and cancer risk in basal cell carcinoma. in The British journal of dermatology

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Burdyga G (2008) Cholecystokinin regulates expression of Y2 receptors in vagal afferent neurons serving the stomach. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description BBSRC fudning (The potential role of soluble plantain fibre and its components in preventing colonisation and invasion of the intestinal mucosa by S.Typhimurium)
Amount £450,000 (GBP)
Funding ID BB/G01969X/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start  
 
Description NIHR Biomedical Research Centre
Amount £3,500,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Liverpool Pancreatic Biomedical Research Unit
Sector Academic/University
Country United Kingdom
Start  
 
Description NIHR Centre for Pancreatic Digestive Disease
Amount £3,750,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start  
 
Description Phenotypic analysis of the MTBP knockout mouse and investigation of the role of MTBP in the p53/MDM2 pathway
Amount £207,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Wellcome Trust Project Grant (The role of NF-kB and cell shedding in Inflammatory Bowel Disease)
Amount £405,072 (GBP)
Funding ID 087768 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2009 
End 05/2012
 
Title Murine trangenesis 
Description Establishment of a range of transgenesis skills ES cell culture and gene targeting and pronuclear microinjection to generate plasmid and YAC transgenic strains 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact The creation of a fully functional transgenesis unit at the University of Liverpool 
 
Title Myofibroblast culture 
Description We developed methods for long term culturing of myofibroblasts from gastric cancer and adjacent normal tissue 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact Several groups, including our own, now recognise this method as key to studying the role of stromal cells in oncogenesis 
 
Description Control of gastrin secretion 
Organisation Syntaxin
Country United Kingdom 
Sector Private 
PI Contribution The student worked in our labs.
Collaborator Contribution Syntaxin have fully supported a post grad studentship. The support allows us to study gastrin cell function in more detail and seek novel ways to inhibit gastrn secretion.
Impact Syntaxin have fully supported a post grad studentship. The support allows us to study gastrin cell function in more detail and seek novel ways to inhibit gastrn secretion.
Start Year 2006
 
Description Control of gastrin secretion 
Organisation Syntaxin
Country United Kingdom 
Sector Private 
PI Contribution The student worked in our labs.
Collaborator Contribution Syntaxin have fully supported a post grad studentship. The support allows us to study gastrin cell function in more detail and seek novel ways to inhibit gastrn secretion.
Impact Syntaxin have fully supported a post grad studentship. The support allows us to study gastrin cell function in more detail and seek novel ways to inhibit gastrn secretion.
Start Year 2006
 
Description Developing a molecular epidemiological risk prediction model 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact NCRI conference

A couple of publications
Year(s) Of Engagement Activity 2006
 
Description Mechanisms of epithelial cell shedding 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Tight junction meeting in Berlin

Made useful contacts for further research
Year(s) Of Engagement Activity 2008
 
Description Pathobiology of MDM2 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact MDM2 meeting in Woods Hole

Increased visibility in field
Year(s) Of Engagement Activity 2007
 
Description Physiology Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact 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.
Year(s) Of Engagement Activity 2007