Cholangiocarcinoma (CCA) arises from the transformation of cholangiocytes of the epithelial bile duct/ductules within the liver. The incidence and mortality rates for CCA are increasing worldwide and a better understanding of how CCA develops and new treatment options are urgently needed.
Inflammation is a major contributor to CCA and can lead to the dysregulation of intracellular signalling pathways and the activation of dormant embryonic developmental signalling pathways in adult bile ducts.
The PRH transcription factor has been identified by our group as being an important hitherto unrecognized driver of CCA tumour growth and tumour invasion. PRH can change normal bile duct cells towards a tumour-like phenotype in the laboratory. We want to be able to either block PRH itself or block the pathways that PRH promotes in CCA in order to inhibit tumour growth and progression. We know that PRH controls embryonic pathways including Notch3 signalling and Wnt signalling through our current work; but these are well known pathways which are being targeted by treatments already. Instead we will identify mechanisms that can control PRH activity or PRH-regulated pathways.
This work will help to identify new treatments for patients with CCA and for patients who have inflammatory diseases of the bile duct that could progress to CCA. In this project we will explore the following:
1. Determine whether inflammation controls CCA tumour growth and spread by activating PRH expression and whether anti-inflammatory molecules will alter the expression of PRH. We will examine whether immune signals regulate PRH expression in CCA cells to reveal new approaches to the treatment of inflammatory conditions that lead to CCA.
2. We will establish how PRH is regulated by signalling pathways such as the Wnt and Notch pathways. We will determine which sequences in the HHEX gene encoding PRH mediate regulation by Notch3 using deletion mutagenesis in vitro and CRISPR. This will test a new approach to the treatment of CCA.
3. We will use an unbiased (non-targeted) approach to identify drugs from a drug repurposing library that can decrease CCA tumour cell proliferation and reduce PRH protein expression and alter the expression of PRH target genes. This will identify candidate drugs that could be used to treat CCA.
Start dates are October, December, February and April each year.
How to apply
We will consider applications from prospective students with:
• a good biomedical or related degree, with interests in any of the areas outlined above,
• a good command of the English language (written and spoken) as outlined in the postgraduate prospectus,
• competence with computers and data handling,
To be considered for this studentship, please apply online at: https://www.nottingham.ac.uk/pgstudy/course/research/Medicine-PhD
Please include in your application:
• A detailed CV;
• Names and addresses of three referees;
• A covering letter highlighting your research experience/capabilities;
• At the top of your covering letter please put the name of your proposed supervisor and the title of the research