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MRC DiMeN Doctoral Training Partnership: The in situ 3D molecular structure of Alzheimer’s disease-associated pathology


Project Description

Synapses are the microprocessors of the mind that encode and store memories. In Alzheimer’s disease (AD), synapses are damaged by the constituents of abnormal beta-amyloid plaques that accumulate in the brain. Indeed, the loss of synapses correlates most closely with cognitive decline in people with AD. Currently, no treatments are available to prevent or slow the progression of AD.

Research in the Frank group is aimed at determining the in situ 3D molecular structures associated with AD to understand disease mechanisms and molecular pathways that can lead to the rational design of a mechanism-based therapy. To this end, we have developed methods combining mouse genetics and cryo-electron microscopy (cryoEM).

The methods used will include: i) Electron tomography and computational image processing. ii) experiments with mouse models of Alzheimer’s disease iii) Biochemical and genetic labelling. Applicants from all backgrounds, including physical, chemical and biological sciences, are encouraged to apply. Some experience with programming (e.g. Python, Matlab or similar) will be highly advantageous.

This project will generate information-rich molecular structures of the mammalian brain that are expected to provide new insights into disease mechanisms. Thus, the student undertaking this research will receive an interdisciplinary training at the cutting edge of structural biology, neuroscience, and dementia research.

Prospective PhD students are encouraged to send an informal email enquiry to in the first instance with a summary of what interests you about our research and any laboratory or computational experience to date.
Please also attach your CV.


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 can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2019.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website
Good luck!

References

Almeida-Souza L., Frank R.A.W, Garcia-Nafria J., Colussi A., Gunawardana N., Johnson C.M., Yu M., Howard G., Andrews B., Vallis Y., McMahon H.T. A flat BAR protein promotes actin polymerisation at the base of clathrin-coated pits.
Cell 74, 325 (2018) PubMed DOI: 10.1016/j.cell.2018.05.020

Fernandez, E, Collins, M.O., Frank, R.A.W., Zhu, F., Kopanitsa, M.V., Nithianantharajah, J., Lempriere, S.A., Fricker, D., Elsegood, K.A., McLaughlin, C.L., Croning, M.D.R., Mclean, C., Armstrong, J.D., Hill, W.D., Deary, I.J., Cencelli, G., Bagni, C., Fromer, M., Purcell, S.M., Pocklington A.J., Choudhary, J.S., Komiyama, N.H., Grant, S.G.N. (2017). Arc Requires PSD95 for Assembly into Postsynaptic Complexes Involved with Neural Dysfunction and Intelligence.
Cell Reports 45, 139-147 (2017) PubMed DOI: 10.1016/j.celrep.2017.09.045

Frank R.A.W., Grant S.G.N. (2017). Supramolecular organisation of NMDA receptors and the postsynaptic density.
Current Opinions in Neurobiology 142, 139-147 (2017) PubMed DOI: 10.1016/j.conb.2017.05.019

Frank R.A.W., Komiyama N.H., Grant S.G.N. Hierarchical organisation and genetically separable subfamilies of PSD95 postsynaptic supercomplexes.
Journal of Neurochemistry 142, 504-511 (2017) PubMed DOI: 10.1111/jnc.14056

Frank R.A.W., Komiyama N.H., Ryan T.J., Zhu F., O’Dell T., Grant S.G.N. (2016). NMDA receptors are selectively partitioned into complexes and supercomplexes during synapse maturation.
Nature Communications 7, 11624 (2016) PubMed DOI: 10.1038/ncomms11264

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