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Quantitative Allele-Specific Proteomics in Drug Metabolism and Disposition


Project Description

The effective dose of a drug is subject to considerable inter-individual variation because the enzymes that metabolise drugs and the proteins that transport them in and out of cells exist, in many cases, in different polymorphic forms and are expressed in varying concentration. This one person’s effective drug dose can be ineffective in another person, and toxic in a third person. Studies of the nature and abundance of the proteins involved in drug metabolism and transport can lead to so-called “precision dosing” which is used increasingly to deliver the correct dose of drugs to particular patient groups.
In this project we will:
* Survey the different polymorphic forms of the enzymes and transporters important in drug metabolism and disposition
* Design standards (QconCATs) to monitor both the polymorphism and the concentration of each of these proteins by tandem mass spectrometry.
* Determine the inter-individual variation of polymorph and concentration of enzymes and transporters in representative sets of human samples (liver, kidney, intestine) using targeted mass spectrometry-based proteomic measurements.
* Model the effect of polymorphic and abundance variation in silico. Such models can be used by the pharmaceutical industry to indicate optimum drug doses for groups of patients.

The student will therefore receive a thorough training in mass spectrometry-based proteomics and quantitative systems pharmacology modelling, and will have the opportunity to contribute to models that will be used for patient benefit.

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in biochemistry, chemistry, pharmacology or another laboratory-based science subject. Confidence in the used of Microsoft Excel is highly desirable. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor.”

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Identification and Quantification of Blood-Brain Barrier Transporters in Isolated Rat Brain Microvessels
H Al Feteisi, ZM Al-Majdoub, B Achour, N Couto, A Rostami-Hodjegan, J Barber
J Neurochemistry, 2018, 146: 670-685.

Quantitative Characterization of Major Hepatic UDP-Glucuronosyltransferase Enzymes in Human Liver Microsomes: Comparison of Two Proteomic Methods and Correlation with Catalytic Activity
B Achour, A Dantonio, M Niosi, JJ Novak, JK Fallon, J Barber, PC Smith, A Rostami-Hodjegan, TC Goosen
Drug Metab. Disposit. 2017, 45, 1102-1112.

GASP and FASP are Complementary for LC–MS/MS Proteomic Analysis of Drug‐Metabolizing Enzymes and Transporters in Pig Liver
M Howard, B Achour, Z Al‐Majdoub, A Rostami‐Hodjegan, J Barber
Proteomics, 2018, https://doi.org/10.1002/pmic.201800200

Proteomic Quantification of Human Blood-Brain Barrier SLC and ABC Transporters in Healthy Individuals and Dementia Patients
ZM. Al-Majdoub, H Al Feteisi, B Achour, S Warwood, S Neuhoff, A Rostami-Hodjegan, J Barber
Accepted for publication, available to short-listed candidates on request.

Quantitative Allele Specific Proteomics (Q-ASP) of a Clinically Significant Cytochrome P450 2B6 Polymorphism using a QconCAT Standard
J Barber, M Russell, A Rostami-Hodjegan, B Achour
Submitted for publication, available to short-listed candidates on request.

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