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An organotypic model of the bone remodelling process


Project Description

Project Background:
Maintenance of bone integrity is a key medical challenge, especially in our ageing population. Bone tissue is actively produced, remodelled and repaired throughout life and disruption of this process causes fragility and disability. Novel treatments are needed to restore bone integrity in patients with conditions that include osteoporosis, inflammatory arthritis, non-union fracture.
Bone remodelling requires coordination between three cell-types: Osteoclasts, osteoblasts and osteocytes. Osteocytes are entombed within mineralised bone and have a network of microscopic cellular extensions (canaliculi) to communicate with and control osteoblast/osteoclast activity at the bone surface. Existing in vitro models of bone remodelling comprise only osteoblasts and osteocytes and, therefore, do not accurately recapitulate the bone remodelling process, leading researchers to use in vivo (animal) models instead.
Work undertaken by our previous NC3Rs-funded PhD student resulted in development of a self-structuring bone model that allows us to “grow” bones in culture. These cultured bones successfully recapitulate the osteocyte organisation and composition of mature bone (see reference below). The osteocytes living within these bone structures survive and thrive for more than one year, whilst in 2D culture they de-differentiate within a week of isolation. This ability to maintain osteocytes in culture represents a substantial breakthrough for the bone research field and allows us the opportunity to develop novel bone remodelling assays containing primary human cells to replace some of the currently used animal models.

The aim of this PhD project is to use this novel, ground-breaking technology to develop an in vitro model that will replace animal models of the bone remodelling process and that can be used for screening of drug candidates for efficacy.

Supervision:
This project sits at the interface between chemical engineering and cell biology, offering excellent training in cutting edge techniques. The student will be co-supervised by Dr Amy Naylor (Rheumatology Research Group) and Professor Liam Grover (Healthcare Technology Institute) and will have access to the laboratory facilities of both. The student will also be part of the wider MRC Centre for Musculoskeletal Ageing Research, giving access to the facilities within the Centre which include FACS sorting, confocal and fluorescence microscopy, tissue sectioning, cell culture, proteomics and genomics capabilities. The Centre provides an extremely supportive and collaborative environment of PhD students and postdoctoral researchers. The student will also work with Professor Grover’s research group and will have access to all of the physical and chemical analysis methods that he has previously used to characterise bone (Raman microscopy, microCT, nanoindentation, AFM). The two research groups that the student will interact strongly with are located on hospital premises and are less than a five-minute walk apart.
The expectation is that, upon completion of the PhD, the student will have acquired a highly competitive skill set on which to base their future career.

Why do an NC3Rs-funded PhD?
• Gain a solid introduction to research that aims to replace, reduce and refine the use of animals in science.
• Undertake scientific training with a prestigious university committed to 3Rs research.
• Join the UK’s growing 3Rs research community and participate in our studentship summer school.
• Contribute to research that advances the boundaries of how science is conducted.


Funding Notes

Candidates should hold, or expect to obtain, at least an Upper Second Class Honours degree or equivalent, with a strong academic background in the biological sciences.
Open to UK nationals. EU nationals, who have spent at least three years prior to the application resident in the UK, are also eligible to apply. Non-UK residents can only be considered if the Research Organisation can demonstrate a shortage of high-quality UK candidates, and must be approved by the NC3Rs prior to appointment.
Funding provides full support for tuition fees for the three-year duration, associated project costs, and an annual tax-free stipend.

References

Iordachescu et al. An in vitro model for the development of mature bone containing an osteocyte network. Advanced Biosystems. 2017.

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