Structural and functional analysis of the protein complexes which regulate cell fate decisions to identify novel cancer therapies

Whether a cell dies or not has profound consequences on health and disease. In healthy tissue, cells that acquire high levels of genetic damage are safely removed via a process of programmed cell death. This highly controlled process, called apoptosis; is critical in long-lived mammals as it maintains homeostasis during healthy ageing. If it is not executed correctly, it can result in the development and progression of widespread diseases. These include neurodegenerative diseases, where too many cells die when they shouldn't, or cancer, where damaged cells don't die when required.

The commitment to apoptotic cell death therefore must be highly regulated. This regulation is achieved by the formation of multi-protein complexes and specific protein-protein interactions, which either inhibit or initiate the apoptosis pathways. Our ability to manipulate these protein-protein interactions for the treatment of disease has been hindered by a lack of a defined model of the upstream regulatory protein complexes.

This project will build on published work from the lab, which revealed that an inhibitory phosphorylation determines if BAK activation can occur initiating apoptotic cell death. This project will study the mechanism by which the upstream regulatory protein complexes interact with and phosphorylate BAK to control this commitment to apoptosis. To address this question complementary cell biology and structural biology techniques such as NMR, x-ray crystallography and Cryo-electron microscopy will be used to visualise for the first time the key multi-protein complex involved in BAK regulation. The detailed structural insight generated will be used to identify and test, via mutagenesis of critical residues in each protein, key interactions which if disrupted alter the cell fate outcome. These studies will pave the way to develop novel therapeutic strategies to modulate BAK activity to increase levels of apoptosis in cancer models. 

Entry requirements

• Those who have a 1st or a 2.1 undergraduate degree in a relevant field are eligible.
• Evidence of quantitative training is required. For example, AS or A level Maths, IB Standard or Higher Maths, or university level maths/statistics course.
• Those who have a 2.2 and an additional Masters degree in a relevant field may be eligible.
• Those who have a 2.2 and at least three years post-graduate experience in a relevant field may be eligible.
• Those with degrees abroad (perhaps as well as postgraduate experience) may be eligible if their qualifications are deemed equivalent to any of the above.
• University English language requirements apply.

To apply

Carefully read the application advice on our website below and submit your PhD application. 

https://le.ac.uk/study/research-degrees/research-subjects/molecular-and-cell-biology