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Effects of gastrin receptor antagonists and proton pump inhibitors on osteoblast function and bone quality


   College of Medicine and Veterinary Medicine

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  Prof C Farquharson, Dr G McLachlan, Dr AJ Stewart  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

Background: Proton pump inhibitors (PPIs) are amongst the most commonly prescribed drugs and are used in the treatment of gastroesophageal reflux disease, peptic ulcer disease and indigestion. The safety records of PPI’s are generally favourable, but pharmaco-epidemiological evidence has consistently shown a positive association between PPI use and bone fractures (1). The mechanism of this association is poorly understood but may involve PPIs ability to inhibit the activity of the phosphatase, PHOSPHO1, which has a critical role in bone mineralisation (2). Alternatively, the high gastrin levels that occur with PPI use may act negatively on the skeleton via the gastrin receptor (CCK2) to cause the poor bone health (3). This Industry funded studentship will investigate the mechanism(s) by which PPI use results in poor bone health and whether alternative treatment strategies can alleviate and reduce the risk of bone fracture whilst still providing effective acid-suppressive medication.

Experimental Approach: This project will use a combination of laboratory approaches to answer our research question. This will include human osteoblast cell culture, human recombinant phosphatase assays and in vivo murine studies.

Training: This inter-disciplinary studentship will benefit from supervision from leading experts in skeletal biology (Farquharson) and protein biochemistry (Stewart). The student will join an established research group and be trained in all laboratory techniques required including cell culture, protein biochemistry, imaging, gene and protein expression, micro-computed tomography, in vivo studies and statistical analysis. 

Facilities: The student will benefit from two world-class research environments at the University of Edinburgh and the University of St Andrews. The student will be based in the Roslin Institute of the University of Edinburgh. The research of the School aims to enhance the life of animals and humans through world class research in animal biology. The School has approximately 160 PhD students and over 1000 staff forming a vibrant research community. The Roslin Institute is a modern facility and compromises fully equipped molecular, histopathology and cell culture laboratories, with access to standard laboratory equipment for molecular and biochemical analysis, including quantitative real-time PCR and LICOR image analysis of western blots. The imaging suite offers access to a range of flow cytometry and light sheet, electron and confocal microscopy. The student will also spend some time at The University of St Andrews. Throughout the project, the student will be fully supported, trained and mentored by the supervisors.

A statement of interest and full CV with names and addresses (including email addresses) of two academic referees, should be emailed to [Email Address Removed].

When applying for the studentship please state clearly the project title and the supervisor in your covering letter.

For informal enquiries, please contact Professor Colin Farquharson ([Email Address Removed])


References

1. Poly TN et al., Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies. Osteoporos Int. 2019 30:103-114. doi: 10.1007/s00198-018-4788-y.
2. Staines KA et al., Proton pump inhibitors inhibit PHOSPHO1 activity and matrix mineralisation in vitro. Calcif Tissue Int. 2021, 109:696-705. doi: 10.1007/s00223-021-00882-9.
3. Aasarød KM et al., Skeletal effects of a gastrin receptor antagonist in H+/K+ATPase beta subunit KO mice. J Endocrinol. 2016 230:251-62. doi: 10.1530/JOE-16-0017.
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