Funded PhD Opportunity Development of a pharmacogenomic model to predict efficacy or adverse events to cannabidiol treatment of arthritic pain.

This opportunity is now closed.

Subject: Biomedical Sciences

Summary

The endogenous cannabinoid system modulates neuronal and immune cell function, both of which play key roles in Osteoarthritis (OA) and rheumatoid arthritis (RA) pain. Cannabidiol (CBD) is a non-psychoactive compound extracted from cannabis. CBD binding of endogenous receptors can produce reliable anti-nociceptive effects in preclinical inflammatory and neuropathic pain models. However cannabidiol’s safety and efficacy have not yet been studied independently by clinical trial for pain in arthritis. The ESCAPe (CHITIN) study proposed would be the first of its kind to investigate the safety profile and pain effects of CBD, in these conditions. CBD is metabolized in the liver by cytochrome P450 enzymes CYP2C and CYP3A converting it into 7-OH-CBD and 6-OH-CBD.

Of particular relevance to safety, CBD has potential to block cytochrome P450 metabolism of other co-medications in the liver, such as NSAID and opioid co-medications in arthritis patients. Therefore pharmacogenomic and pharmacokinetic studies will be conducted in parallel, to identify variants of cannabidiol metabolising enzymes and receptors which in combination could be carried by individuals more likely to respond or at higher risk of adverse events.

Aim: Discover genomic variant data that to stratify patients achieving pain reduction or at risk of adverse events, when treated with cannabidiol.

Objectives:

1. Perform pharmacokinetic analysis of CBD, NSAID and opioid metabolites in patients to measure any changes in metabolism attributable to CBD.

2. Data from a pharmacogenomic screen of CBD metabolising enzymes will be analysed for associations with CBD reduction in pain scores or adverse events.

Methods:

a)Genomic analyses: DNA will be extracted from whole blood samples and targeted gene sequencing and variant calling will performed using TruSeq custom amplicon kits and an Illumina MiSeq instrument at NI Centre for Stratified Medicine (NICSM).  Analysis of single nucleotide polymorphisms (SNPs) with functional consequences for CBD metabolism or signalling will be focussed on CYP2C19 and CYP3A4 genes. The strength of associations between individual SNPs and drug levels or pain response scores will be assessed by multivariate regression modelling.

b)Pharmacokinetics: the metabolism of CBD and its metabolites will be analysed in blood plasma and urine samples for both Stage 1 and 2 studies. Samples will be centrifuged to remove cellular material and frozen at the recruitment site, sent to NICSM for analyses at the Mass Spectrometry Core Technology Unit at Ulster University. CBD, 7-OH-CBD and 6-OH-CBD, NSAID and opioid plasma and urine concentrations will be ascertained by a liquid extraction surface analysis (LESA)-nano electrospray ionisation triple quadrupole mass spectrometry method (ESI-QQQ MS) using.

c)Bioinformatic analyses:  Statistical analysis will be performed by SPSS (version 24.0). Pre- and post-treatment outcome data will be will be analysed to examine any relationships between the specific genotype/drug meatbolite profile of a patient with their disease activity, demographics and clinically determined response to therapy. A patient stratification algorithm and model will be designed to detect associations between specific gene variants CBD pain response or adverse event.

Essential Criteria

  • Upper Second Class Honours (2:1) Degree from a UK institution (or overseas award deemed equivalent via UK NARIC)
  • Sound understanding of subject area as evidenced by a comprehensive research proposal
  • A comprehensive and articulate personal statement

Desirable Criteria

If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.

  • First Class Honours (1st) Degree
  • Masters at 65%
  • Completion of Masters at a level equivalent to commendation or distinction at Ulster
  • Research project completion within taught Masters degree or MRES
  • Experience using research methods or other approaches relevant to the subject domain
  • Work experience relevant to the proposed project
  • Publications - peer-reviewed
  • Experience of presentation of research findings

Funding

    Vice Chancellors Research Scholarships (VCRS)

    The scholarships will cover tuition fees and a maintenance award of £14,777 per annum for three years (subject to satisfactory academic performance). Applications are invited from UK, European Union and overseas students.

    DFE

    The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £ 14,777 per annum for three years. EU applicants will only be eligible for the fees component of the studentship (no maintenance award is provided).  For Non EU nationals the candidate must be "settled" in the UK.

Other information

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Key Dates

Submission Deadline
Monday 19 February 2018
Interview Date
6, 7 and 8 March 2018

Contact Supervisor

Dr David Gibson

Other Supervisors

Apply online

Visit https://www.ulster.ac.uk/applyonline and quote reference number #238115 when applying for this PhD opportunity