Alternative splicing of precursor-mRNAs is an important gene regulatory mechanism that massively expands proteome complexity and is commonly dysregulated in cancer. The focus of this project is prostate cancer which accounts for >11,000 UK male deaths annually. Dysregulated alternative splicing is critically important in prostate cancer progression, notably evident by the generation of constitutively-active androgen receptor variants in response to hormone ablation therapy.
This project will apply molecular approaches using pre-clinical models to identify candidate alternative splicing events associated with prostate cancer progression to therapy-resistance. We will also interrogate publically-available RNA-sequenced prostate tumours patient cohorts using machine learning tools to identify bio-signatures of alternative splicing events that may predict response to therapy and treatment-resistance. These bio-signatures will be validated using several highly relevant pre-clinical prostate cancer models.
Incorporating established molecular biology techniques, the student will apply siRNA, CRISPR technology and lentiviral infections to modify gene expression in prostate cell lines/ organoids. Experience will be gained in RNA-sequencing and bioinformatics analysis, including machine learning, to identify alternative splicing events associated with cellular sensitivity/resistance to drug treatments. Advanced imaging approaches and multiplex, PCR-based assays will be used in our ex vivo tissue slice model incorporating patient biopsies from treatment-naïve and therapy-resistant tissue exposed to androgen receptor antagonists.
This interdisciplinary translational research project will identify aberrant alternative splicing events associated with prostate tumour progression and the emergence of resistance to current treatments. These changes in alternative splicing have potential utility as biomarkers to determine the aggressiveness of the cancer and/or to predict whether individual patients will respond favourably to current therapies.
Further information on our research interests can be found at:
https://www.ncl.ac.uk/medical-sciences/people/profile/cnrobson.html
https://www.ncl.ac.uk/medical-sciences/people/profile/amirenshaei.html
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, 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 and how to apply can be found on our website:
http://www.dimen.org.uk/how-to-apply/application-overview
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