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Stratification of clinical risk in Primary Sclerosing Cholangitis (PSC)

Project Description

Project description
The issue/problem
Primary Sclerosing Cholangitis (PSC) is classified as a rare liver disease with an incidence of 0.77 per 100,000 person-years and compared to the general population, PSC mortality is 3 x higher. PSC is associated with an increased risk of cancer development, mainly cholangiocarcinoma, gallbladder carcinoma and hepatocellular carcinoma, with nearly 50% of deaths in patients with PSC being due to cancer. Treatment options are limited and outcome remains poor.

The approach/experimental plan
The project will focus on modelling PSC risk for the development of cholangiocarcinoma. The main phases of work will be divided into analysis of archival clinical samples ie formalin fixed and paraffin embedded (FFPE) and Kings biobank samples (blood, bile, tissue). Generated biological data will be associated with clinical metadata for further computational modelling. Analytical techniques utilized will be related to profiling DNA (tissue and circulating), phosphoproteomics (tissue), biliary single cell analysis and biliary nanoparticle (exosome) quantification.

The clinical utility of calculating a polygenic risk score (PRS) for cholangiocarcinoma in PSC and measuring circulating DNA (ddPCR) for diagnostics will be explored. Similarly, the functionality of single cell analysis (Fluidigm C1) and nanoparticle diagnostics of bile will be investigated. Differential phosphoproteomic profile of malignant versus non-malignant PSC tissue (explant/resected specimen) will be data mined for carcinogenesis mechanism and modelled for informing chemotherapy decision making using an in house algorithm. The work is intended to improve diagnostics in this patient cohort that will assist in clinical decision making during surveillance and guide in the timing of therapies to improve survival. The emphasis of the project will be on translational science in order to change clinical practice and the skill set that the student acquires during the project will assist in their post doctoral career.

The infrastructure/support
The location of this work will be in the Institute of Liver Studies at Kings College Hospital (KCH), where scientists work in parallel with clinicians. The Unit has an established track record in liver research in both adult and paediatric practice. The proposed research will build on an ongoing collaboration with Barts Cancer Institute, Queen Mary’s University London (QMUL) where we have demonstrated that an algorithm can recommend Kinase Inhibitor therapeutic combinations based on the phosphoproteomic profile of cholangiocarcinoma. As well as be supported by the Liver Molecular Genetics Group that are clinically established within the Institute of Liver Studies, Kings College Hospital. The data generated from the proposed work will add to the Primary Liver Cancer Computational Pipeline that is being developed by KCH/QMUL. On a national level this project will supplement the ongoing genetic study of UK-PSC as part of the NIHR Rare Disease Research collaboration.

Eligibility Criteria
Applicants should have a BSc Honours degree (First or Upper Second) or MSc (Distinction or Merit) in a biomedical science. The applicant needs to demonstrate a strong interest and self motivation, good computational skills, ability to think analytically and creatively. Good verbal and writing skills in English are required. Previous experience in a research laboratory would be advantageous.

The supervisor track record
Professor Nigel Heaton has led the liver transplant programme at King’s College Hospital for the past 25 years. Pioneering liver transplantation in adult and paediatrics, as well as establishing nationally recognised programmes for islet, hepatocyte and small bowel transplantation. He has over 400 published papers in peer reviewed journals.

Funding Notes

This studentship is fully funded by King's College Hospital Charity (View Website). The scholarship is for 3 years. The student will receive a stipend of £19,000 per year. The scholarship includes payment of Home/EU tuition fees to King’s College London for the 3 year period.

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