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Understanding and Treating Metabolic Liver Disease: Understanding the causes of non-alcoholic fatty liver disease to identify new biomarkers of disease stage as well as trial novel treatments


Project Description

Understanding the causes of non-alcoholic fatty liver disease to identify new biomarkers of disease stage as well as trial novel treatments

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 associated with a significant increase in liver and cardiovascular morbidity and mortality, but significantly increases the risk of development of hepatocellular carcinoma (HCC). Research in our groups seeks to understand the causes of NAFLD, to identify new biomarkers of disease stage as well as trial novel treatments.

We have a long-standing interest in the role of steroid hormones and bile acids to regulate metabolic phenotype. Our recent work has identified specific enzyme targets that appear to be crucial in the development of metabolic liver disease and are potentially amenable to drug targeting. In addition, using gas chromatography mass spectrometry, and working alongside computational scientists, we have been able to develop and entirely novel strategy for staging liver disease without the need for a biopsy.

Adopting a translational approach incorporating both basic science and the use of clinical samples from patients with NAFLD and HCC, we aim to explore the ability of specific steroid hormones and bile acids to regulate multiple aspects of cell biology. Student projects will manipulate the availability of these signalling molecules (genetic and pharmacological) to identify new potential treatment targets.

Within our research group there are specific training opportunities that will include the use of cell culture models of human hepatocytes alongside the use of primary cultures of liver cells. 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 genome editing techniques using CRISPR technology. Students 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 high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

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 build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Funding Notes

Our main deadline for applications for funded places has now passed. Supervisors may still be able to consider applications from students who have alternative means of funding (for example, charitable funding, clinical fellows or applicants with funding from a foreign government or equivalent). Prospective applicants are strongly advised to contact their prospective supervisor in advance of making an application.

Please note that any applications received after the main funding deadline will not be assessed until all applications that were received by the deadline have been processed. This may affect supervisor availability.

References

Prevalence and severity of non-alcoholic fatty liver disease are underestimated in clinical practice: impact of a dedicated screening approach at a large university teaching hospital. Marjot T, Sbardella E, Moolla A, Hazlehurst JM, Tan GD, Ainsworth M, Cobbold JFL, Tomlinson JW. Diabet Med. 2018 Jan;35(1):89-98.
AKR1C3-Mediated Adipose Androgen Generation Drives Lipotoxicity in Women With Polycystic Ovary Syndrome. O'Reilly MW, Kempegowda P, Walsh M, Taylor AE, Manolopoulos KN, Allwood JW, Semple RK, Hebenstreit D, Dunn WB, Tomlinson JW, Arlt W. J Clin Endocrinol Metab. 2017; 102(9):3327-3339
Optimizing human hepatocyte models for metabolic phenotype and function: effects of treatment with dimethyl sulfoxide (DMSO). Nikolaou N, Green CJ, Gunn PJ, Hodson L, Tomlinson JW. Physiol Rep. 2016 Nov;4(21). pii: e12944
Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man. Hazlehurst JM, Oprescu AI, Nikolaou N, Di Guida R, Grinbergs AE, Davies NP, Flintham RB, Armstrong MJ, Taylor AE, Hughes BA, Yu J, Hodson L, Dunn WB, Tomlinson JW. J Clin Endocrinol Metab. 2016 Jan;101(1):103-13
Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. Armstrong MJ, Hull D, Guo K, Barton D, Hazlehurst JM, Gathercole LL, Nasiri M, Yu J, Gough SC, Newsome PN, Tomlinson JW. J Hepatol. 2016 Feb;64(2):399-408

How good is research at University of Oxford in Clinical Medicine?

FTE Category A staff submitted: 238.51

Research output data provided by the Research Excellence Framework (REF)

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