Understanding the role of TNFRSF11B polymorphisms in osteoprotegerin bioavailability and bone metabolism

Description

This project will focus on determining the effect of the polymorphisms of the TNFRSF11B gene, which encodes osteoprotegerin (OPG), on bone metabolism.

Age-related bone loss leading to osteoporosis and fractures is predicted to rise as the world population ages. The current treatments are time-limited and not without side-effects. Thus, better understanding of bone metabolism is key for development of new strategies to preserve bone in the quest for ‘healthy ageing’.

Bone renewal is driven by bone remodelling, which depends on the interplay of two main molecules: the receptor-activator-of-nuclear-factor-kappa-B-ligand (RANKL), which induces bone resorption and OPG, an endogenous decoy-receptor for RANKL, which blocks bone resorption. This effect has been exploited in the development of a fully human RANKL antibody, denosumab, which is used for treatment of osteoporosis. OPG is encoded by the TNFRSF11B gene and secreted by osteocytes and osteoblasts. Lack, or deficiency in OPG causes a high bone turnover state (severe osteoporosis in mice and Juvenile Paget’s Disease in humans). Several TNFRSF11B polymorphisms are associated with the two most common late onset metabolic bone diseases: postmenopausal osteoporosis and adult onset Paget’s Disease (Daroszewska et al 2004; Beyens, Daroszewska et al, 2007) however the underlying mechanism for this association is unclear. Understanding of the functional effect of these polymorphisms on the bioavailability of OPG would provide much needed information for the development of targeted management of individuals at high risk of bone loss.

We have generated modified TNFRSF11B-reporter constructs in order to study the TNFRSF11B polymorphism in detail and in pilot experiments found that some of the polymorphisms were functional. The aim of this PhD project is to determine how a spectrum of polymorphisms affects the function of the TNFRSF11B gene, the secretion of the OPG protein, and bone resorption. The understanding of these processes will allow for application of gained knowledge in personalised medicine, as prophylactic and therapeutic strategies could be developed for individuals at high risk of developing osteoporosis or other metabolic bone diseases due to their genetic make-up. Results generated using cell lines will be replicated in primary human cells obtained from patients with osteoporosis or other metabolic bone disorders.

The successful candidate will use state-of-the-art molecular biology techniques, including tissue culture with microscopy, confocal microscopy, electron microscopy, cloning, luciferase reporter assays, PCR, qPCR, Western Blotting, ELISA and epigenetic techniques as required during the project. Laboratory training in all required techniques will be provided. The PhD student will work closely with Dr Anna Daroszewska, Clinical Senior Lecturer in Musculoskeletal Biology, expert in bone cell signalling, who was first to identify the association of OPG polymorphisms with Paget’s disease and as a Clinical Scientist bridges the bench-to-bedside research, and Prof Rob van ‘t Hof, expert in molecular biology of bone and bone imaging.

The project will be undertaken at the University of Liverpool, within the Institute of Ageing and Chronic Disease and the Paget’s Association of Centre of Excellence, of which Dr Anna Daroszewska and Prof Rob van ‘t Hof are co-directors. The IACD has state-of-the-art molecular and cellular biology laboratories, and imaging facilities, with close proximity to the Royal Liverpool University Hospital.

The Institute of Ageing and Chronic Disease is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.

To apply please send

• A detailed CV with names and addresses of two referees
• A covering letter highlighting your research experience and capabilities
• Copies of degree certificates with transcripts
• Evidence of proficiency in English, if applicable

to Dr Daroszewska with a copy to

Availability

Open to students worldwide

Funding information

Self-funded project

We welcome applications from self-funding candidates and candidates who can source their own funding. Tuition costs can be found on the University website View Website and the research support fees/consumables cost is £12,000 per year.

We are seeking a committed candidate with a sound knowledge of biology, molecular biology and English. Applicants should have a commitment to research in metabolic bone disorders / bone pathophysiology, hold at least an Upper Second Class Honours Degree in a relevant subject and hold a Masters Degree in a relevant subject.

Supervisors

References

Daroszewska et al 2004. Susceptibility to Paget’s disease of bone is influenced by a common polymorphic variant of Osteoprotegerin. J Bone Miner Res Sep;19(9):1506-11

Beyens, Daroszewska et al 2007. Identification of Gender-Specific Association Between Polymorphisms of the Osteoprotegerin Gene, TNFRSF11B, and Paget’s Disease of Bone. J Bone Miner Res Jul;22(7):1062-71 

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