How and when do amyloid proteins cause cellular toxicity and disease? And how can we prevent their formation?
Using a C. elegans Alzheimer’s Disease model, we have recently shown that activation of Hsp90 expression via Transcellular Chaperone Signalling prevents the formation of toxic amyloid protein deposits in the animal throughout aging (O’Brien et al, Cell Reports 2018). The activation of protective chaperone expression such as Hsp90 from one tissue to another via Transcellular Chaperone Signalling is a novel concept in biology that allows for the development of original therapeutic strategies against age-related protein misfolding diseases.
This project aims to understand how and when amyloid disease proteins become disruptive to cells in vivo in an aging organism and how this is prevented by the increased expression of a protective chaperone. For this, we combine the strength of an in vivo Alzheimer’s disease model system (C. elegans) with Cryo-EM and biochemical approaches. The project will allow for a highly interdisciplinary training for the PhD student and will result in unprecedented knowledge that can have a translational impact.
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:
Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Stipend at national UKRI standard rate
Research training and support grant (RTSG)
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: https://goo.gl/8YfJf8
O’Brien, D., Jones, L., Good, S., Miles, J., Aston, R., Smith, C., Vijayabaskar, S., Westhead, D., and van Oosten-Hawle, P. A PQM-1-mediated response mediates transcellular chaperone signaling and organismal proteostasis. Cell Reports. 2018 Jun 26;23(13):3905-3919.
van Oosten-Hawle, P., Porter, R.S., and Morimoto, R. I. (2013). Regulation of organismal proteostasis by transcellular chaperone signaling. Cell 153, 1366-1378.
Iadanza, M.G., Silvers, R., Boardman, J., Smith, H., Karamanos, T., Griffin, R.G., Ranson, N.A. and Radford, S.E.. (2018). The cryo-EM structure of a b-2-microglobulin fibril shows the molecular basis of a common amyloid architecture. Nature Communications, (2018) 9, 2369.
Iadanza, M.G., Jackson, M., Hewitt, E.W., Ranson, N.A. & Radford, S.E. (2018). A new era for understanding amyloid structures and disease. Nat Rev Mol Cell Biol. DOI:10.1038/s41580-018-0060-8