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Elucidating Disease Mechanisms using New Approaches to Capture Transient Protein Complexes in the Mitochondria


Institute of Integrative Biology

Prof L-Y Lian Applications accepted all year round Self-Funded PhD Students Only

About the Project

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. We have shown, using modern multiomics techniques to show that CypD plays a key role metabolism, cellular function and is important for maintaining metabolic homeostasis. We also know that CypD binds weakly to target proteins to prime them into conformations that are favourable for multi-protein complex assembly.

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. 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.

Funding Notes

The project is open to both European/UK and International students. It is UNFUNDED and applicants are encouraged to contact the Principal Supervisor directly to discuss their application and the project.

Assistance will be given to those who are applying to international funding schemes.

The successful applicant will be expected to provide the funding for tuition fees and living expenses as well as research costs of £7000 per year.

A fee bursary may be available for well qualified and motivated applicants.

Details of costs can be found on the University website:
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References

1. 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

2. 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., 57:16688–1669

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