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MRC Precision Medicine DTP: Characterising the pro-regenerative extracellular matrix in a spinal cord injury site

Project Description

After a spinal cord injury, the lesion site is filled with fibroblasts and extracellular matrix (ECM) material that inhibits regeneration of the spinal cord in mammals. The Becker group (Edinburgh) have recently shown that in zebrafish, which are perfectly capable of functional spinal cord regeneration, the lesion site ECM contains Col XII. Coll XII deposition is controlled by Wnt signalling and is necessary and sufficient to promote axon regeneration across a lesion site (Wehner et al., 2017). This indicates that in the zebrafish model, pro-regenerative ECM components can be identified.

In this collaborative PhD project between the Becker group (Edinburgh) and the Barnett group (Glasgow) the student will elucidate pro-regenerative ECM components, their interplay and regulation. In candidate approaches, the student will localise proteogylcans, such as heparan and chondroitin sulphate proteogylcans (HSPGs, CSPGs) in the lesion site. The Barnett group finds that HSPGs are crucial key players in binding and organising additional components of the ECM (O’Neill et al., 2017). To manipulate their function, the student will use heparin mimetics (present in Barnett group, Higginson et al., 2012) to mimic the HS expression on HSPGs and they will knock out sulfatases that are necessary to control HSPG and CSPG sulfation levels, using CRISPR/Cas9 techniques. As read-outs, axonal regeneration and functional recovery will be assessed. For an unbiased approach, the student will determine expression profiles of spinal injury sites in zebrafish, compared between different regenerating and non-regenerating conditions, e.g. wnt-inhibition or inhibition of immune function. The resulting profiles will be analysed for changes in the expression of ECM-related genes and these will be functionally analysed as above. There is scope to translate verified findings from the fish into the rat spinal cord lesion paradigm in Glasgow.

Hence, this project will identify pro-regenerative components and mechanisms of the ECM in a spinal lesion site in zebrafish and thus provide targets for future manipulations of these molecules in a mammalian system to improve regenerative outcome.

Training outcomes
The student will be trained in complex cloning techniques, in vivo perturbations and analyses using the zebrafish system, confocal imaging techniques and bioinformatics approaches applied to systems biology. This addresses the MRC key priority “Quantitative Skills” as applied to transcriptomics.
This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location:

Please note, you must apply to one of the projects and you should contact the primary supervisor prior to making your application. Additional information on the application process if available from the link above.

For more information about Precision Medicine visit:

Funding Notes

Start: September 2019

Qualifications criteria: Applicants applying for a MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualifications, in an appropriate science/technology area.

Residence criteria: The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £14,777 (RCUK rate 2018/19) for UK and EU nationals that meet all required eligibility criteria.

Full eligibility details are available: View Website

Enquiries regarding programme:


Higginson JR, Thompson SM, Santos-Silva A, Guimond SE, Turnbull JE, Barnett SC. (2012) Differential sulfation remodelling of heparan sulfate by extracellular 6-O-sulfatases regulates fibroblast growth factor-induced boundary formation by glial cells: implications for glial cell transplantation. J Neurosci. b:15902-12.

O'Neill, P., Lindsay, S. L., Pantiru, A., Guimond, S. E., Fagoe, N., Verhaagen, J., Turnbull, J. E., Riddell, J. S. and Barnett, S. C. (2017). Sulfatase-mediated manipulation of the astrocyte-Schwann cell interface. Glia 65, 19-33.

Wehner, D., Tsarouchas, T. M., Michael, A., Haase, C., Weidinger, G., Reimer, M. M., Becker, T. and Becker, C. G. (2017). Wnt signaling controls pro-regenerative Collagen XII in functional spinal cord regeneration in zebrafish. Nat Commun 8, 126.

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