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MRC DiMeN Doctoral Training Partnership: Dysregulation of non-coding RNAs in the development of Hepatocellular carcinoma


MRC DiMeN Doctoral Training Partnership

Leeds United Kingdom Biochemistry Bioinformatics Cancer Biology Cell Biology Genetics Immunology Microbiology Molecular Biology Other

About the Project

Hepatocellular carcinoma (HCC) is one of the most common malignant tumours and the second highest cause of cancer-related deaths worldwide. Like many cancers, HCC is characterised by the involvement of multiple gene networks and the imbalance of signalling pathways. Various non-coding RNA (ncRNA) species have been implicated in HCC development and progression. However to date, research has focused on the unidirectional ncRNA-mediated regulation of target protein-coding transcripts by miRNAs. Emerging evidence now suggests the existence of an unexpected interplay between distinct ncRNA species that influences how gene expression is regulated. This hidden cross-talk of ncRNA:ncRNA interactions, results in ncRNAs competing for binding to mRNAs, thereby functioning in a ncRNA regulatory network. We aim to determine how dysregulation of this intricate network of ncRNA:ncRNA interactions impacts on HCC proliferation and growth.

This project will identify ncRNA species (circRNAs, miRNAs, lncRNAs, tRFs) that are dysregulated in matched HCC and background non-malignant tissue from the same patient. Once characterised we will identify essential ncRNA:ncRNA interactions which dysregulate mRNA expression in HCC. Finally, the role of these target mRNAs controlled by dysregulated ncRNA networks will be examined in HCC development and progression.

This project is highly novel and very timely as molecular crosstalk between ncRNA species is an emerging regulatory layer of gene expression. ncRNA networks pervade and define the correct functioning of canonical protein-coding pathways involved in many cellular processes, consequently dysregulation of these networks is implicated in a wide range of human diseases, particularly cancers. Importantly, development of applied NGS-based technologies now allows the identification of dysregulated ncRNA species in cancerous versus non-malignant tissue. These dysregulated ncRNAs in HCC may provide potential prognostic or diagnostic biomarkers and may have future potential applications in RNA-targeting therapeutics, such as ASO and RNAi-based approaches.

This project is highly interdisciplinary drawing on the expertise of supervisors in RNA biology, cancer research and bioinformatics. The project will utilise a range of cutting-edge techniques including: NGS-based approaches (CircSeq, Small RNA-Seq and RNA-seq) established in the primary supervisor’s laboratory. Once identified the roles of these ncRNA network-regulated mRNAs will be examined in HCC proliferation and growth assays using depletion/overexpression studies. Finally, the effect of reversing the dysregulation of ncRNAs will be examined on HCC proliferation and growth, using virus-based delivery of LNA-oligonucleotides or ncRNA mimics.

More information of supervisors research expertise can be found at :
http://www.fbs.leeds.ac.uk/staff/Whitehouse_A/
https://medicinehealth.leeds.ac.uk/medicine/staff/735/dr-adel-samson
https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/154/professor-david-r-westhead

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 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:
https://bit.ly/3lQXR8A

Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website

Studentships commence: 1st October 2021

Good luck!

References

Harper, K.L., McDonnell, E. & Whitehouse, A. (2019). CircRNAs: from anonymity to novel regulators of gene expression in cancer. International Journal of Oncology, 55, 183-193.
Anastasiadou, E., Jacob, L. & Slack, F. Non-coding RNA networks in cancer. Nat Rev Cancer 18, 5–18 (2018).
Yang, J.D., Hainaut, P., Gores, G.J. et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 16, 589–604 (2019)

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