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Roles of epoxy-oxylipins in the human acute inflammatory response

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  • Full or part time
    Dr Bishop-Bailey
  • Application Deadline
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  • Funded PhD Project (UK Students Only)
    Funded PhD Project (UK Students Only)

Project Description

Supervisors: Dr David Bishop-Bailey, Professor Derek Gilroy University of London and Dr Carolyn Hyde Bioanalytical Lab

Department: Comparative Biomedical Sciences

Epoxygenases are cytochrome P450 enzymes that metabolise arachidonic acid (AA) into epoxy-eicosatrienoic acids (EETs). In addition to AA, epoxygenases also metabolise fish oil docosahexaenoic acid and eicosapentaenoic acid as well as linoleic acid into biologically related mediators called epoxy-oxylipins. Both EETs and epoxylipins are rapidly metabolised into inactive diols by soluble epoxide hydrolase (sEH). While convincing in vitro and rodent-derived data is building to show that epoxy-oxylipins possess profound anti-inflammatory properties, a convenient and rapid method for their measurement is lacking. Moreover, their anti-inflammatory effects in humans are unknown.

This training has 3 components:

- Develop LC/MS/MS to measure epoxy-oxylipins from biological samples. With the Bioanalytical lab we have developed an LC/MS/MS assay to measure 7 eicosanoid and epoxy-oxylipins. Using authentic standards we will expand this analysis to measure an extended panel of epoxy-oxylipins and their metabolites. In addition, the Bioanalytical Lab has considerable expertise in high performance capillary electrophoresis (HPCE). An HPCE approach could dramatically reduce cost per sample. The student will therefore compare LC/MS/M to HPCE to measure epoxy-oxylipins.
- Human blood cones will be obtained from the NHS Blood bank. Whole blood will be treated with bacterial products, and the production of and effects of epoxylipins measured in monocytes, neutrophils, and lymphoyctes cell populations.
- Human volunteer study: We will elicit blisters on the forearm of volunteers, de-roof these blisters and isolate the exposed sub-dermal connective tissue with a newly developed “Exudate Collection Chamber” into which test compounds can be examined. Inflammation is characterised by the immediate influx of PMNs, which peak in number at 4h. At 4h cells will be collected and counted to determine inflammation severity. The production of and effects of epoxylipins will be tested in this new model.
The studentship will commence at the beginning of October 2016.

Interviews for studentships - will be held on 16th March or in the w/c 21st March 2016 at the RVC’s Camden or Hawkshead Campuses

http://www.rvc.ac.uk/study/postgraduate/phd

Funding Notes

This is a three year fully funded studentship supported by the Medical Research Council. Candidates must meet the MRC eligibility criteria.

References

Bystrom J, Thomson SJ, Johansson J, Edin ML, Zeldin DC, Gilroy DW, Smith AM, Bishop-Bailey D. Inducible CYP2J2 and its product 11,12-EET promotes bacterial phagocytosis: a role for CYP2J2 deficiency in the pathogenesis of Crohn's disease? PLoS One. 2013 Sep 13;8(9):e75107.
Jenner W, Motwani M, Veighey K, Newson J, Audzevich T, Nicolaou A, Murphy S, Macallister R, Gilroy DW. Characterisation of leukocytes in a human skin blister model of acute inflammation and resolution. PLoS One. 2014 Mar 6;9(3):e89375.
Bishop-Bailey D, Thomson S, Askari A, Faulkner A, Wheeler-Jones C. Lipid-metabolizing CYPs in the regulation and dysregulation of metabolism. Annu Rev Nutr. 2014;34:261-79.

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