iPSCs to hepatocytes: modelling cholestatic liver disease in East London

The complementary expertise of the supervisory team, supported by a longstanding history of successful collaboration and joint publications, will allow the student to define the effect of mutations in the ABCB4 protein which are unique to the local British South Asian population. The ABCB4 protein functions in the liver to transport lipid into the bile in order to quench the damaging detergent activity of bile acids.

An approach encompassing bioinformatic interrogation of the Genes and Health database, molecular and cellular biology, and human liver sampling will identify new variants and establish their role in liver disease locally. Characterisation of the effect of the mutations at the protein level will establish cause and effect and permit intervention in line with new guidelines developed by the European Association for the Study of the Liver. These data will also open the pathway to personalised medicine; corrector drugs to improve the folding and stability of the mutant protein and potentiator drugs to improve the function of the protein. Such drugs are in the development pipeline of collaborating laboratories in France and will need to be tested for potency and efficacy against the unique mutations found in ABCB4 locally.

The study will offer the student a broad experience in bedside‑to‑bench research, and characterisation of the ABCB4 mutation class will allow the British South Asian population to access new personalised therapies when they become available.

Aim:

We will determine the mutation class for prevalent ABCB4 mutations unique to the local British South Asian population that are associated with liver disease and test the available correctors and potentiators for preclinical treatment efficacy.