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MRC DiMeN Doctoral Training Partnership: Elucidating Disease Mechanisms using New Approaches to Capture Transient Protein Complexes in the Mitochondria

  • Full or part time
    Prof L-Y Lian
  • Application Deadline
    Monday, January 06, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

The mitochondria is the powerhouse of the cell. Its malfunction is the cause of many diseases, ranging from cancer to heart and neurological diseases, which become more prevalent with age. Stress on the mitochondria can arise when there is a calcium insult, causing Ca2+ overload. This leads to opening of the mitochondrial permeability transition pore (MPTP). Unregulated opening of the MPTP is linked to many mitochondrial diseases; hence, understanding the generic mechanism of MPTP regulation could ultimately lead to identification of drug targets and drug discovery programs for multiple diseases. As the nature of the MPTP remains elusive, effective targeting of the MPTP cannot yet be achieved. We have shown, using modern multiomics techniques that CRISPR/CAS9 knock-out of Cyclophilin D (CypD) – a key regulator of MPTP – affects metabolism and cellular function, thus demonstrating that the protein is important for maintaining metabolic homeostasis. We now need to understand how Cyp D regulates metabolism and hypothesise that CypD binds weakly to target proteins to prime them into conformations that are favourable for multi-protein complex assembly.

To test this hypothesis, the objectives of the project are to: (i) develop novel photo-crosslinkers, and use these to (ii) map the CypD interactome. State-of-the-art techniques to be used include chemical tag-transfer photo-crosslinking, proteins bearing unnatural amino acids which are introduced using recombinant methods; mass spectrometry proteomics, very high field nuclear magnetic resonance spectroscopy and confocal imaging. This project is designed to closely integrate Life Sciences with Chemistry and will be carried out on split sites between the Universities of Liverpool and Leeds. The student will exploit preliminary Systems Biology (Multiomics) data and develop interdisciplinary skills in Biochemistry, Biophysics and Chemical Biology to address the project objectives.

The project will suit students with a strong organic chemistry, chemical biology or biochemistry background who are interested in applying their skills to address challenging biological problems that will lead to the elucidation of basic mechanisms and enable drug discovery. This project is part of a larger research programme where clinicians, chemists and biochemists are already working together to develop new inhibitors of Cyclophilin D.

Web links:
Professor Lu-Yun Lian: https://www.liverpool.ac.uk/integrative-biology/facilities-and-services/nmr-centre-for-structural-biology/about-nmr-centre/
Professor Andrew Wilson: https://wilson.leeds.ac.uk/

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 2020.

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

Shore E, Awais M, Kershaw N, Gibson R, Pandalaneni S, Latawiec D, Wen Li, Javed M, Criddle DN, Berry N, O'Neill Lian, P, Lian LY and Sutton R (2016) Small Molecule Inhibitors of Cyclophilin D to Protect Mitochondrial Function as a Potential Treatment for Acute Pancreatitis, J. Med. Chem. 59:2596-2611

Horne JE, Walko M, Calabrese AN, Levenstein MA, Brockwell DJ, Kapur N, Wilson AJ, Radford SE (2018) Rapid Mapping of Protein Interactions Using Tag-Transfer Photocrosslinkers, Angew. Chemie. Int. Ed., 57:16688–16692

Ibarra AA, Bartlett GJ, Hegedüs Z, Dutt S, Hobor F, Horner KA, Hetherington K, Spence K, Nelson A, Edwards TA, Woolfson DN, Sessions RB, Wilson AJ (2019) Predicting and Experimentally Validating Hot-spot Residues at Protein-Protein Interfaces, ACS Chem. Biol., 14:2252-2263

How good is research at University of Liverpool in Chemistry?

FTE Category A staff submitted: 34.00

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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