Analysis of the role of liver sinusoidal endothelial cells in methotrexate-induced liver toxicity

Description

Liver sinusoidal endothelial cells (LSECs) comprise approximately 50% of the non-parenchymal hepatic cells. They play a vital role in hepatic microcirculation and provide a physiological barrier to the movement of xenobiotics from the bloodstream to hepatic tissue. Methotrexate (MTX) is a chemotherapy and immunosuppressive drug, used at a high dose to treat leukaemia, breast cancer, lung cancer and at a lower dose to manage a variety of autoimmune diseases. The most common adverse effects include hepatotoxicity and blood abnormalities with the mechanism of MTX-induced hepatotoxicity obscure.  Our preliminary data from a rat model of MTX injury has shown that MTX can adversely affect liver endothelial cell physiology.

This project will utilise cryopreserved human LSECs to analyse the effect of MTX on endothelial cell physiology, intracellular signalling and gene expression. The project will also utilise a novel 3D multi-cellular liver microtissue composed of primary human hepatocytes, LSECs and human liver fibroblasts to allow analysis of MTX effects on multiple hepatic cells in a more physiologically relevant model. 

By understanding the mechanism of MTX induced liver toxicity we aim to ultimately develop potential diagnostic tests and treatment strategies to alleviate MTX toxicity.

Student experience

The student will be based in a dynamic research environment with modern research laboratories and office space. The student will learn a range of scientific techniques from primary human cell culture, 3D spheroid formation, western blotting, qRT-PCR and immunofluorescence analysis. 

Research Environment

The student will be embedded in a vibrant and well funded research environment. Our research involves collaboration with a range of academic, clinical and industry partners providing a stimulating and supportive research environment.

Applications

Applicant Information: The successful applicant should have an interest in basic biomedical and toxicology research and hold a minimum undergraduate qualification 2:1, or equivalent, in a life science or health-related subject.

Research project related enquiries should be made in the first instance to Dr. Michael Cross (m.j.cross@liverpool.ac.uk).

To apply please send your CV and a covering letter to Dr Michael Cross (m.j.cross@liverpool.ac.uk).

Please note that the application deadline may be subject to change - applications will close once a suitable candidate is found, so you are encouraged to submit yours as soon as possible.