Project: MRC CASE Studentship in collaboration with AstraZeneca, including up to six months in the AstraZeneca laboratories, Maccesfield, Cheshire
Supervisors: Dr David Meredith, Oxford Brookes University; Dr Sarah Kelly, AstraZeneca
Start date: 15 September 2008
Value p.a. £16,542 & fees
Closing Date: 30 April 2008
The organic anion transporting polypeptide superfamily of transporters (e.g. OATP1A2, OATP1B1, OATP1B3 and OATP2B1) are key membrane transporters for which crystal structures are not currently available. They are expressed at the interface of hepatocytes, renal tubular cells, enterocytes, and the choroid plexus, display broad substrate specificity, are highly divergent across species and have been implicated in drug-drug interactions. The relative importance of individual members of the OATP family in the hepatic uptake process depends on the drug of interest, even if they belong to the same class of drugs (e.g. statins). Understanding the key molecular features for substrate-transporter interactions (i.e. developing a structure activity relationship) of relevant hepatic isoforms will facilitate a better understanding of the pharmacokinetics (PK) of compounds that are known to be substrates for these transporters and their potential involvement in drug-drug interactions.
The aims if this project are to understand better the structure-function relationships of the OATPs, including to identify residues likely to be important in substrate binding in members of the OATP family of transporters expressed in hepatic tissue across multiple species. In addition, experiments will compare expression levels of OATP transporters between hepatocytes from pre-clinical species and human donors and attempt to co-express the relevant isoforms from a particular species in Xenopus oocytes at a ratio comparable to the native cells. Co-expression of hepatic isoforms in this manner will permit comparisons to be made between the native cells and the expression system, and allow evaluation of the Xenopus oocyte expression system as a predictive assay for hepatic uptake through the OATPs.
Informal enquiries and further information about this project can be obtained at www.brookes.ac.uk/lifesci/research/studentshipmeredith or from Dr David Meredith
Applications should be posted to:
Ms Angela Robinson
Research Administrator
School of Life Sciences
Oxford Brookes University
Headington
Oxford
OX3 0BP
Please email Ms Angela Robinson if you have any enquiries in relation to the application procedure
