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BBSRC CASE MRes/PhD Studentship - Determination of Mechanisms of Flucloxacillin Induced Liver Injury; Translation to Refining Risk Assessment Screening
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| Scholarships or student grants level |
Graduate
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Countries where scholarship
or student grant is applicable |
United Kingdom /
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Universities where scholarships or
student grants are applicable |
University of Newcastle /
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Countries which are eligible
for the scholarhips or student grants |
Austria / Belgium / Bulgaria / Cyprus / Czech Republic / Denmark / Estonia / Finland / France / Germany / Greece / Hungary / Iceland / Ireland / Italy / Latvia / Liechtenstein / Lithuania / Luxembourg / Malta / Netherlands / Norway / Poland / Portugal / Romania / Slovakia / Slovenia / Spain / Sweden / Switzerland / United Kingdom /
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| Scholarships or student grants program description |
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.
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Study fields funded by
the scholarships or student grants |
Medicine, Dentistry And Health / Sciences: Pure And Applied /
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| Official scholarships or student grants website: |
click here to go to the official website
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| Official scholarship or student grants email: |
a.k.daly@ncl.ac.uk
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