The Bloomsbury Colleges | PhD Studentships | Studentships 2014 | The Molecular Determinants For Fatty Acid Metabolism By Eicosanoid Metabolising Cyp450 Enzymes
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The Molecular Determinants For Fatty Acid Metabolism By Eicosanoid Metabolising Cyp450 Enzymes

Principal Supervisor: Dr David Bishop-Bailey (Royal Veterinary College, University of London)

Co- Supervisor: Dr Irilenia Nobeli (Birkbeck, University of London)

The dietary intake of polyunsaturated fish oils is considered beneficial for long and healthy life. The mechanisms by which these fish oils/ fatty acids exert their benefits are far from clear. We are interested in a group of cytochrome  (CYP)450 enzymes that metabolize fatty acids in to a series of biologically active mediators that regulate both physiological and patho-physiological processes. These CYPs metabolize arachidonic acid and related fatty acids in to a series of hydroxy- and epoxy-fatty acid metabolites. Lipidomic mass spectroscopy analysis shows all these pathways exist in physiological and patho-physiological processes.

For many of these lipid metabolizing CYPs there is little structural (crystal) information available, although mutants or polymorphisms have been identified which lack enzymic activity.

The aims of this project are:

  • To produce computer models of the active site of the lipid metabolising CYP2J2, CYP2B2 and CYP2C23 enzymes.
  • To compare the active sites of these enzymes to start to hypothesise how CYPs bind different fatty acids and produce different regio- and stereo-isomer products.
  • Use this information for mutation analysis to engineer enzymes to test these predictions, and change the products formed; and
  • Test the function of these different mutant enzymes in vitro on endothelial cells function to include proliferation, migration, angiogenesis, and inflammatory responses. 

This collaboration combines cutting edge molecular modelling with molecular and cell biology techniques to answer the questions posed and therefore represents a unique opportunity for candidates to undertake cross-cutting research. The student will join the 2014-15 BBSRC DTP cohort for training and monitoring.

Candidate Requirements

Good first degree or equivalent  in a related subject.

Opportunities for Research/ Training

The student will participate in Ph.D. training programmes at both institutes. At the RVC, the student will undertake a statistics course, induction in laboratory safety, IT skills and have the opportunity to supervise an undergraduate laboratory project. The student will participate in lab meetings, journal clubs and presenting data at both institutes. In addition the student will be specifically trained in methods of modelling structures (BBK), molecular cloning expression and mutagenesis, cell biological assays, and analytical techniques such as capillarly electrophoresis, and LC/MS/MS (RVC). There will also be opportunities to work with external collaborators in London, the UK and the USA.

These two unique research environments will provide the student with a far broader perspective and transform the student into a truly interdisciplinary scientist.

Key References:

  1. Askari A, Thomson SJ, Edin ML, Zeldin DC, Bishop-Bailey D. Roles of the epoxygenase CYP2J2 in the endothelium. Prostaglandins Other Lipid Mediat. 2013. doi:pii: S1098-8823(13)00009-9.
  2. Patschull, A.O.M., Gooptu, B., Ashford, P., Daviter, T., Nobeli, I. (2012). In Silico Assessment of Potential Druggable Pockets on the Surface of a1-Antitrypsin Conformers. PLoS ONE 7: e36612. doi:10.1371/journal.pone.0036612.
  3. VanRollins M, VanderNoot VA. Simultaneous resolution of underivatized regioisomers and stereoisomers of arachidonate epoxides by capillary electrophoresis. Anal Biochem. 2003 Feb 1;313(1):106-16.
  4. Bystrom, J., Thomson, S., Johansson, J., Edin, M.L., Zeldin, D.C., Gilroy, D.W., Smith, A., Bihop-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 10.1371/journal.pone.0075107
  5. Lafite P, André F, Zeldin DC, Dansette PM, Mansuy D. Unusual regioselectivity and active site topology of human cytochrome P450 2J2. Biochemistry. 2007 Sep 11;46(36):10237-47.

Further details about the project may be obtained from:

Principal Supervisor: Dr David Bishop-Bailey, dbishopbailey@rvc.ac.uk; http://scholar.google.co.uk/citations?user=cAXYCSgAAAAJ&hl=en;

Co- Supervisor: Irilenia Nobeli, i.nobeli@mail.cryst.bbk.ac.uk, http://www.bbk.ac.uk/biology/our-staff/academic/irilenia-nobeli

Further information about PhDs at Royal Veterinary College is available from:

http://www.rvc.ac.uk/Postgraduate/Research/PhD/Index.cfm

Application forms and details about how to apply are available from:

http://www.rvc.ac.uk/postgraduate/info/howtoapply.cfm#research

researchdegrees@rvc.ac.uk

In addition to the standard application form, applicants will need:

  1. A CV
  2. A personal statement explaining why you would like to undertake this particular project
  3. A copy of your degree certificate(s)
  4. A transcript of your degree(s) - this must be a certified translation if the original was not issued in English
  5. Two confidential references

Closing date for applications is 21st February 2014