Funding and Finance

BBSRC CASE MRes/PhD Studentship - Determination of Mechanisms of Flucloxacillin Induced Liver Injury; Translation to Refining Risk Assessment Screening

  • Institute of Cellular Medicine
  • Reference Code: ICM43


Closing Date: 4th June 2009

Details:

Supervisors: Professor Ann Daly, Dr Matthew Wright and Professor Dave Jones. Industrial supervisors will be Dr Martin Armstrong and Dr Gerry Kenna (AstraZeneca)
Institute: Institute of Cellular Medicine
Funded by:  BBSRC with AstraZeneca
Duration of award: 4 years (MRes in Medical and Molecular Biosciences followed by PhD)

Drug induced liver injury (DILI) is the most common cause of death from acute liver failure, the most frequent adverse event to cause attrition in drug development, the most common cause of failure of drug approval and the greatest cause of drug withdrawal and prescribing restrictions. The widely-used antimicrobial agent flucloxacillin is a common cause of DILI. Recent studies at Newcastle have indicated that individuals positive for a particular HLA allele B*5701 and for a common form of the gene encoding the nuclear receptor PXR have an increased risk of DILI development but the underlying mechanism is still unclear. 

This project will explore three potential hypotheses that have arisen from our previous work and integrate the data from all three approaches to better understand human susceptibility to disease. This will involve:

(i) Studies on metabolite mediated toxicity. The possibility that variation in drug metabolism could play a role in susceptibility to flucloxacillin DILI will be further investigated by detailed studies on flucloxacillin metabolism using various in vitro systems including expressed enzymes and liver microsomes.

(ii) PXR regulated responses. Previous observations that the nuclear receptor PXR is relevant to flucloxacillin-induced liver injury will be extended by use of animal model systems.

(iii) Immune mechanisms. In studies on human T cell responses, T cells from individuals positive for HLA B*5701 and from HLA B*5701 negative controls will be collected and in vitro cell stimulation studies will be undertaken with flucloxacillin and its major metabolites. To study antibody responses to flucloxacillin adducts, serum from patients with DILI due to flucloxacillin will be tested by ELISA and by Western blotting for specific antibody response to flucloxacillin modified protein adducts.

Person Specification
Applicants should hold, or expect to obtain, an upper-second-class or first-class degree in any area of biological sciences or a related discipline.

Value of the Award and Eligibility
This award is available to students who have a relevant connection to the UK and meet the BBSRC’s eligibility criteria.  Depending on how you meet the eligibility criteria, you may receive a full award (covers fees and an annual stipend of £13,290) or a partial award (fees only).  The stipend will be supplemented by approximately £4,000 per year by AstraZeneca.

How to Apply
You must complete the University’s postgraduate application form, selecting ‘Master of Research/Doctor of Philosophy - Medical Sciences (Cellular
Medicine)’ as the programme of study and inserting the reference number ICM43. Only mandatory fields need to be completed (no personal statement
required) and a CV, a covering letter and (if English is not your first language) a copy of your English language qualifications must be attached. The covering letter must state the title of the studentship, quote the reference number ICM43 and state how your interests and experience relate to the project.

Closing date for applications: 4 June 2009

Further information
For more details, please contact Professor Ann Daly a.k.daly@ncl.ac.uk