Last Date: Friday, December 13, 2024
Supervisors: Dr Kelly Coffey, Dr M Collins, Dr Luke Gaughan, Dr Adam Wollman
Competition Funded PhD Project (Students Worldwide)
Newcastle University MRC DiMeN Doctoral Training Partnership
About the Project
Background: Steroid receptor signalling is critical in hormone driven cancers such as prostate cancer, which accounts for >11,000 deaths annually, in the UK. Characterising androgen receptor (AR) activation consequences in the nucleus have resulted in a number of effective therapies. However, androgen induced rapid signalling in the cytoplasm is still understudied. Early, rapid cytoplasmic signal transduction relies on post-translational protein modification, particularly phosphorylation and palmitoylation, and protein-protein interactions (PPIs) in response to simulation (Mauvais-Jarvis et al., 2022), with HSP27 (Zoubeidi et al., 2007), p38 and Kif5b (Li et al., 2018) being involved in efficient signal transduction. However, there is a significant knowledge gap in understanding rapid, AR driven, cytoplasmic and membranous signalling events and as such a great opportunity exists for therapeutic intervention.
Objectives:
1. Understand rapid cytoplasmic AR signalling and its role in therapeutic resistance
2. Identify novel signalling pathways which facilitate cytoplasmic to nuclear signalling
Experimental Approach:
Established cell line models and molecular biological techniques in the lab of Dr Kelly Coffey (Staff Profile – Kelly Coffey – Newcastle University) will be used to interrogate rapid cytoplasmic AR signalling. CRIPSR-Cas9 technology will be used to generate new cell line models to understand the contribution of novel molecules which facilitate this pathway. Assessment of AR and AR-splice variant transcriptional activity will be carried out using qPCR and chromatin immunoprecipitation assays in collaboration with Dr Luke Gaughan. AR-plasma membrane localisation and palmitoylation will be assessed using membrane isolation experiments, confocal microscopy and specialised single molecule imaging in the lab of Dr Adam Wollman (Staff Profile – Adam Wollman – Newcastle University). Mass spectrometry based-proteomic studies will be carried out in Dr Mark Collins lab (Staff Profile – Mark Collins – University of Sheffield) to inform novel protein-protein interactions and post-translational modifications during AR activation to identify novel therapeutic targets to inhibit AR and AR-splice variant activity.
Impact: This project will reveal new aspects of the AR signalling pathway and identify putative therapeutic targets for further study and clinical development.
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, York 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, training opportunities or internships in science policy, science communication and beyond. Further information on the programme and how to apply can be found on our website:
Funding Notes
Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend (£19,237 for 2024/25) and project costs. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of full studentships to international applicants. Please read additional guidance here: View Website
Studentships commence: 1st October 2025
Good luck!
References
Mauvais-Jarvis et al., 2022
Zoubeidi et al., 2007
Li et al., 2018
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