Many diseases, including cancer and neurological disease, stem from mitochondrial dysfunctions often triggered by sudden elevation of agents such as calcium and reactive oxygen species. Central to this is the membrane permeability transition pore (MPTP) whose molecular nature remains a mystery. Opening of the pore under stress conditions is believed to lead to many diseases including cancer, cardiovascular and neurological diseases. Much effort is devoted to elucidate how the MPTP is regulated with the hope that the pore itself, or the proteins or pathways that regulate its function, will become therapeutic targets for diseases where mitochondrial function is pivotal. In addition, knowing how the MPTP is regulated will lead to an understanding of comorbidity, where a patient suffers from more than one disease, a very common feature, especially as a person ages. It has been suggested that protein folding has a role in the MPTP, encompassing concepts such as the pore being the aggregation of unfolded proteins to the regulatory proteins providing a house-keeping function to ensure folded protein homeostasis for proper functioning of the mitochondria.
The major mitochondrial folding chaperones HSP 90 and 60 work in concert with small helper proteins, with the latter ensuring that the final hurdles to attain the fully folded state are overcome. This project aims to understand the role played by small helper proteins in regulating the MPTP.
This project will have access to clinical collaborators who will help define the disease states to study. The student will develop excellent skills in cell biology, omics techniques, biochemistry and chemical/structural biology with access to state-of-the art equipment.
The project is suited to a student with at least a good B.Sc. Upper Second degree in chemical or biological sciences and an interest in understanding the molecular mechanisms of mitochondrial diseases.
Funding Notes
The project is open to both European/UK and International students. The successful applicant will be expected to provide the funding for tuition fees and living expenses as well as research costs. A fee bursary may be available for well qualified and motivated applicants.
Applicants are encouraged to contact the Principal Supervisor directly at an early stage to discuss their application and the project. Assistance will be given to those who are applying to international funding schemes.
Details of costs can be found on the University website: View Website
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. 59:2596-611
2. Baines CP and Gutiérrez-Aguilard M (2018) The still uncertain identity of the channel-forming unit(s) of the mitochondrial permeability transition pore, Cell Calcium, 73: 121-130.
3. Jane A Armstrong… Criddle DN (2018) Oxidative stress alters mitochondrial bioenergetics and modifies pancreatic cell death independently of cyclophilin D, resulting in an apoptosis-to-necrosis shift, J. Biol. Chem. doi: 10.1074/jbc.RA118.003200.
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