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MRC DiMeN DTP: Dissecting INPP5K function: cell biology, structural determination by X-ray crystallography and enzymology of a key protein implicated in muscular dystrophy, insulin signalling, spastic paraplegias and Parkinsonism

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  • Full or part time
    Dr L Swan
    Dr S Antonyuk
    Dr M Stagi
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

The Swan laboratory (https://www.researchgate.net/profile/Laura_Swan), specialists in phosphoinositide lipid biology and the cell biology of membrane trafficking, in collaboration with international teams of clinicians and scientists, have recently discovered that mutations in a specific phosphatase cause a congenital muscular dystrophy with short stature, brain and eye manifestations (papers: https://www.sciencedirect.com/science/article/pii/S0002929717300198?via%3Dihub and https://www.sciencedirect.com/science/article/pii/S0002929717300241). This protein is part of a critical network that regulates cell function, with effects of INPP5K expression found in neurological disorders, Parkinsonism, insulin signalling and cancers.

The enzyme is strongly recruited to the endoplasmatic reticulum (ER), where it may regulate contacts between the ER and other membranes in the cell. ER-membrane contacts are dysfunctional in several disorders, notably Hereditary Spastic Paraplegias (HSPs)
The primary supervisor has identified a new ligand for INPP5K. We will study this complex by X-ray protein crystallography in the laboratory of Dr Antonyuk (https://www.researchgate.net/profile/Svetlana_Antonyuk), an expert structural biologist. Effects of this ligand binding interface will be assessed in cell culture by live imaging and enzymology before examining neuronal physiology in cultures overexpressing INPP5K and INPP5K knockout neurons in the laboratory of Dr Stagi (https://www.researchgate.net/profile/Massimiliano_Stagi/research), a specialist in live-imaging neurophysiology.

We are looking for highly motivated students interested in cell biology and neuroscience. Your project will include cell biology, molecular biology and structural biology/biophysical experiments, as well as primary neuronal culture and live imaging. You will be a part of a team of three labs at the University of Liverpool with ongoing projects/expertise in each field, as well as part of a wider clinical/biological network of collaborations in UK, USA and Germany.

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: https://goo.gl/8YfJf8
Good luck!

References

Pirruccello, M.*, Swan, L. E.*, Folta-Stogniew, E., & De Camilli, P. Recognition of the F&H motif by the Lowe syndrome protein OCRL (2011). NATURE STRUCTURAL & MOLECULAR BIOLOGY, 18(7), 789-U63. doi:10.1038/nsmb.2071

Klein, Z. A., Takahashi, H., Ma, M., Stagi, M., Zhou, M., Lam, T. T., & Strittmatter, S. M. Loss of TMEM106B Ameliorates Lysosomal and Frontotemporal Dementia-Related Phenotypes in Progranulin-Deficient Mice (2017). NEURON, 95(2), 281-+. doi:10.1016/j.neuron.2017.06.026

Amporndanai,K.; Johnson, R.M.; O’Neill, P.M.; Fishwick,C.W.G; Jamson,H.; Rawson,S.; Muench, S.P.; Hasnain, S.S; Antonyuk, S.V. X-ray and cryo-EM structures of inhibitor-bound cytochrome bc1 complex for structure-based drug discovery (2018) IUCRJ v5(2) 200-210 doi; 10.1107/S205225251800161



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