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ExomiR resetting of the energy profile in Hepatocellular Cancer (HCC) via the mitochondrial proteome

Project Description

Project description
The issue/problem
Hepatocellular cancer (HCC) is a primary liver cancer and one of the commonest cancers in the world. It is the third cause of cancer related death in developed countries and the second most common cancer death worldwide. Overall the prognosis is poor with most cases being diagnosed at an advanced stage of disease when curative options cannot be considered and with no treatment, 80% of patients will be dead at one year after diagnosis.

Dysregulation of cellular metabolism (how the cell produces energy) has been accepted as a hallmark of cancer thereby producing distinctive patterns of mitochondrial dysfunction. From a pilot study we have demonstrated that there are widespread changes in the mitochondrial proteome of HCC that would be predicted to alter the way in which the cell generates energy. We want to explore the metabolic network of HCC that captures the multiple events that define liver carcinogenesis and by understanding this “energy threshold” find a way to reset the system.

In recent years, exosomes have emerged as a new player in cell communication and in regulating physiological as well as pathological processes. Identification of microRNAs (miRNAs) inside exosomes has revolutionized the field. The characterization of exosome encapsulated miRNAs (exomiRs) holds the potential of providing a mechanistical insight into cancer driven alteration of the mitochondrial proteome as well as enable therapeutic manipulation of the system.

The approach/experimental plan
The student will work with primary hepatocytes and hepatocellular cancer cell lines, as well as patient samples. The main aims of the project is to isolate and characterize hepatocyte specific exosomes. Analytical techniques employed will encompass next generation sequencing, nanoparticle tracking analysis, flow cytometry and mass spectrometry. Further mechanistical work will involve high resolution respirometry (Oroboros/Seahorse) to assess functional effect of characterized liver ExomiR on mitochondria function in hepatocytes and hepatocellular cancer. The translational longterm goal of this research is to use the data to design therapeutic exosomes that can be used in patients with liver cancer. 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, 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 on going collaboration with John’s Hopkins Hospital, USA and Barts Cancer Institute, Queen Mary Univesity, London. The data generated will add to the Primary Liver Cancer Computational Pipeline that is being developed at Kings. The student will also be supported by the Hepatocyte Biology and Transplantation Group established at King’s.

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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