This project will investigate the fundamental mechanisms which regulate bone mineralisation through extracellular vesicles. A deeper understanding of this process will expose new therapeutic targets for the treatment of bone disorders.
Background: Bone is a composite tissue formed from two phases; an organic collagen I protein matrix and the inorganic calcium phosphate mineral hydroxyapatite. The relationship between collagen and mineral in bone is crucial to its remarkable properties and render it both flexible and strong enough to resist fracture under load. During skeletal development in the embryo, osteoblasts release nanoscale extracellular vesicles known as matrix vesicles (MVs) into the collagenous matrix. These vesicles are posited to accumulate calcium and phosphate in an amorphous (i.e. non-crystalline) state through the action of proteins and deliver this amorphous calcium phosphate (ACP) to the collagen matrix before mineral nucleation. This process is critical for healthy bone mineralisation, however there are significant gaps in our understanding around the relationship between MVs and collagen fibrils and how ACP is delivered to the fibril. This studentship will employ a combination of advanced cryo-electron microscopy and molecular biology to advance our understanding of the role of MVs in bone mineralisation.
Work leading to the project: The Farquharson lab discovered the PHOSPHO1 phosphatase which plays a major role in bone mineralisation. PHOSPHO1 has been localised to MVs and its absence causes a huge loss of bone in the embryonic skeleton. Our data support the hypothesis that PHOSPHO1 scavenges phosphate from the MV membrane to facilitate accumulation of ACP.
Experimental approach: We will use state-of-the-art 3D cryo-focussed ion beam scanning electron microscopy (cryoFIB-SEM) to image mineralising embryonic bone at the nanoscale in a native hydrated state to establish the presence of amorphous phases within MVs and their spatial relationship with collagen. Embryos genetically modified to knock-out PHOSPHO1 will also be used to study its role in ACP accumulation. The student will furthermore work with our collaborators at University of Cambridge employing correlative light-electron microscopy and nuclear magnetic resonance to characterise the intimate relationship between nucleating mineral crystals and the collagen fibril.
Application Process:
To apply for an EASTBIO PhD studentship, follow the instructions below:
1) Informal enquiries should be addressed to Dr Fabio Nudelman in the first instance. To apply, please send a cover letter outlining your previous research experience and reasons for applying, alongside an up-to-date CV to [Email Address Removed]
2) After you have discussed the projects of interest to you with Dr Nudelman, download and complete our Equality, Diversity and Inclusion survey and then fill in the EASTBIO Application Form and submit this to Dr Fabio Nudelman.
3) Send the EASTBIO Reference Form to your two academic/professional referees and ask your referees to submit your references directly to Dr Fabio Nudelman, [Email Address Removed]
4) If you are nominated by the supervisor(s) of the EASTBIO PhD project they will provide a Supervisor Support Statement for your application.
We anticipate that our first set of interviews will be held 7th – 11th February 2022 with awards made in the following week.
If you have further queries about the application/recruitment process please contact EASTBIO
The successful applicant will be advised how to apply for admission to the PhD programme via EUCLID in due course.
The School of Chemistry holds a Silver Athena SWAN award in recognition of our commitment to advance gender equality in higher education. The University is a member of the Race Equality Charter and is a Stonewall Scotland Diversity Champion, actively promoting LGBT equality. The University has a range of initiatives to support a family friendly working environment. See our University Initiatives website for further information. University Initiatives website: https://www.ed.ac.uk/equality-diversity/help-advice/family-friendly
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