AKR1C1 as a therapeutic target in non-alcholoic fatty liver diease and hepatocellular carcinoma

The global epidemic of obesity and metabolic disease, including its hepatic manifestation, non-alcoholic fatty liver disease (NAFLD) has hastened the need to identify pathogenic mechanisms and novel, innovative and efficacious treatments. Within the next 3 years, NAFLD will become the leading cause for liver transplantation. NAFLD is not only assocaited with a signficant increase in liver and cardiovascular morbidity and mortality, but significantly increases the risk of development of hepatocellular carcinoma (HCC).

Our preliminary data, in which we have examined steroid hormone metabolites in clinical samples from more than 250 patients with NAFLD, have demonstrated that the products of a reaction mediated by the enxyme AKR1C1 (20α-hydroxylated steroid metabolites) are highly predictve of the stage of NAFLD and offers the potential as both a biomarker of diease as well as a therapeutic target. Additional work has implicated AKR1C1 in the pathogeneis of ovarian and lung cancer. Despite being highly expressed in hepatocytes, its role in the liver to regulate proliferative and metabolic phenotype remains almost entirely unexplored.

We will test the hypothses that manipulation of AKR1C1 activity and expression using pharmacological approaches as well as genome editing techniques will have a profound impact upon both the metabolic and proliferative phenotype of liver cells and may ultimately represent an entirely novel therapeutic target.

TRAINING OPPORTUNITIES

This project will incorporate the use of cell culture models of human hepatocytes alongside the use of primary cultures of liver cells to define the role of AKR1C1. The project will use many state-of-the-art molecular biology techniques including gene expression by real-time PCR, the use of stable isotopes to track the fat of labelled metabolic substrates as well as genetic manipulation and geneome editing techniques using CRISPR technology. This project will be embedded within the broader research group (including basic scientists and clinicians) providing exposure to metabolic research across the translational spectrum.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.

Generic skills training is offered through the Medical Sciences Division’s Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

The department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.