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EASTBIO Fine tuning of the biomineralisation process: Deciphering the myriad of regulatory procedures


Project Description

Royal (Dick) School of Veterinary Studies / The Roslin Institute

Introduction: Bone is a composite material comprised of collagen and mineral whose combined material properties make bone strong and tough, providing rigidity and resistance to fracture. The initiation of the first mineral crystals within the collagenous extracellular matrix is pivotal for ensuring that mineralisation progresses physiologically but significant gaps exist in our knowledge on how this process occurs and is regulated. Therefore, this inter-disciplinary studentship will use biology, chemistry and imaging approaches to determine how collagen of bone and cartilage is mineralised and what promotes or inhibits this process. Pathological mineralisation can lead to diseases of great public health concern, e.g. osteoarthritis, rickets/osteomalcia and osteoporosis.

Work leading up to this project: By studying skeletal development in embryonic mice we have identified some of the major promotors (e.g. phosphatases – PHOSPHO1 and alkaline phosphatase) and inhibitors (e.g. sibling proteins) of the mineralisation process. We have also studied genetically altered animals such as PHOSPHO1 knockout mice which have bones that are poorly mineralised (osteomalacia) and display spontaneous bone fractures, bowed long bones, and scoliosis in early life. Importantly, ablation of both alkaline phosphatase and PHOSPHO1 function leads to complete absence of skeletal mineralisation (Yadav et al. 2011; Dillon et al. 2019). Gaps in our knowledge however exist and this studentship will help us advance our understanding of this basic process for human and animal health.
Approach: This project will utilise a number of interdisciplinary approaches and will involve the study of genetically modified mice and organ culture models to help answer the research question. The student will characterise the initiation of the mineralisation process in embryonic mice using a range of in vivo methodologies. Intrafibrillar collagen mineralisation will also be studied using cryo transmission (cryoTEM) electron microscopy and focused ion-beam scanning electron microscopy (FIB-SEM), which will show the growth and 3D organisation of the apatite crystals within collagen (Nudelman et al. 2010). Electron diffraction will confirm the presence of apatite. Some post-natal tissues e.g. growth plate cartilage show clear areas of collagen mineralisation (longitudinal septae) juxtaposed to areas on non-mineralisation (transverse septae). What governs this precise spatial control of matrix mineralisation is unknown. Localising the presence of promoters and inhibitors of mineralisation to these locations and identifying the effect of skeletal loading (biomechanics) has the potential to reveal novel insights into the process.

Training: The project is inter-disciplinary, benefiting from supervision by a leading skeletal biologist (Farquharson) and a leading chemist (Nudelman). This project will expose the student to wide-ranging fields of research including: bone development, matrix biology and mineralisation and material science. The University of Edinburgh is an outstanding environment to carry out research into musculoskeletal research with world-leading scientists, excellent support and training opportunities through the Universities generic training programme and EASTBIO’s thematic training. The student will be trained in mouse colony management, imaging, cell and molecular techniques, microscopy, data collection, interpretation and writing papers for publication. The student will engage with other scientists and attend and present their findings at local laboratory meetings as well as UK and international conferences.

Candidates should have or expect to have a minimum of an appropriate upper 2nd class degree. To qualify for full funding students must be UK or EU citizens who have been resident in the UK for 3 years prior to commencement.

Funding Notes

Completed application form along with your supporting documents should be sent to our PGR student team at

Please send the reference request form to two referees. Completed forms for University of Edinburgh, Royal (Dick) School of Veterinary Studies and the Roslin Institute project should be returned to by 5th January 2020.

It is your responsibility to ensure that references are provided by the specified deadline.
Download application and reference forms via:
View Website

References

1. Yadav MC, Simão AM, Narisawa S, Huesa C, McKee MD, Farquharson C, Millán JL. 2011 Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function - A unified model of the mechanisms of initiation of skeletal calcification. J Bone Miner Res. 26:286-297.
2. Dillon S, Staines KA, Millan JL, Farquharson C (2019) How to build a bone: PHOSPHO1, biomineralization and beyond. J Bone Min Res plus 3(7):e10202..
3. Nudelman F, Pieterse K, George A, Bomans PH, Friedrich H, Brylka LJ, Hilbers PA, de With G, Sommerdijk NA. 2010 The role of collagen in bone apatite formation in the presence of hydroxyapatite nucleation inhibitors. Nat Mater. 9:1004-9.

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