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MRC DiMeN Doctoral Training Partnership: Visualising the molecular assembly of perineuronal nets by super-resolution microscopy in ageing brains


MRC DiMeN Doctoral Training Partnership

Leeds United Kingdom Biochemistry Biophysics Neuroscience

About the Project

Perineuronal nets (PNNs) are specialised extracellular matrix structures that ensheath selected neurons in the brain. PNNs are important in regulating plasticity which is crucial for regeneration and memory acquisition in the central nervous system (CNS). We have previously demonstrated that, in the adult CNS, modulation of PNN composition enhances axonal sprouting and promotes recovery in a wide range of neurodegenerative and injury models.

PNNs are assembled from four types of extracellular matrix molecules: the polysaccharide hyaluronan (HA), link proteins, chondroitin sulphate proteoglycans (CSPGs) and tenascin-R (Tn-R). This composition is dynamic and changes during ageing. Interrogating the spatial organisation and dynamics of PNN molecules in the PNN, and how PNNs interact with neighbouring synapses in situ, will be essential for understanding the molecular mechanisms underpinning PNN-mediated neuronal plasticity important in a variety of neurological disorders, such as Alzheimer’s and Parkinson’s diseases.

In this project, we shall investigate the spatial organisation and dynamics of PNN molecules in the PNNs, and their interplay with synapses, using advanced imaging techniques including super-resolution expansion microscopy (ExM). ExM at a resolution of 15 nm will be employed to study the spatial relationship of PNN molecules and synapses in situ. Multiplex labelling of PNNs with markers against selective PNN binding proteins and synapses, in combination with biophysical and dynamic analysis of PNN molecular assembly on neuronal surfaces, will provide valuable evidence for the question.

This project combines super-resolution imaging and biophysics to understand the role of PNNs in neuroplasticity. Training of individual techniques will be provided and regular meetings will be held with the supervisory team to ensure progress.

To date, there is no direct evidence demonstrating the hierarchical assembly of PNN molecules and their localisation in relation to synapses on the neuronal surface. Obtaining in situ information of PNN arrangement in adult and ageing brains will provide an in depth understanding of how synaptic plasticity could be controlled via PNN manipulation.

More information can be found in:
https://biologicalsciences.leeds.ac.uk/school-biomedical-sciences/staff/99/dr-jessica-cf-kwok
https://www.sheffield.ac.uk/biosciences/people/mbb-staff/academic/izzy-jayasinghe
https://biologicalsciences.leeds.ac.uk/school-biomedical-sciences/staff/129/dr-ralf-richter

Alternatively, you can learn about our research focus in the Twitters pages: @KwokLab, @i_jayas and @LabRichter.

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:
https://bit.ly/3lQXR8A


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website

Studentships commence: 1st October 2021

Good luck!

References

1) Carulli D et al. (2010) Animals lacking link protein have attenuated perineuronal nets and persistent plasticity. Brain 133(Pt 8):2331-47.

2) Jayasinghe I et al. (2018) True molecular scale visualization of variable clustering properties of ryanodine receptors. Cell Rep 22(2):557-567.

3) Richter RP et al. (2018) Glycosaminoglycans in extracellular matrix organisation: are concepts from soft matter physics key to understanding the formation of perineuronal nets? Curr Opin Struct Biol 50:65-74.

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