Development of novel mass spectrometry approaches to study the dynamics subcellular localisation upon post translational modification associated with disease and therapeutic intervention

Department name: Cambridge Centre for Proteomics (CCP), University of Cambridge (http://proteomics.bio.cam.ac.uk/) Supervisors: Primary: Professor Kathryn Lilley (University of Cambridge) and Derek Barratt (https://www.astrazeneca.co.uk/)

As a key mediator of cellular signalling, phosphorylation remains a principal target for biological question. Identifying and quantifying the phosphorylation state of proteins involved in cell progression, metabolism, growth and disease is critical for the elucidation of cellular function. The initial aim of the project with be to extend recent developments that have demonstrated that the combination of phospho-peptides enrichment using titanium matrices and isobaric chemical labelling (TMT) allows the identification of 10,000 to 15,000 phosphopeptides from total cell lysate (1, 2). This coupled with the hyperLOPIT methodology (Localisation of Organelle proteins by isotope tagging, (3-5), which combines a biochemical organelle fractionation with a quantitative mass spectrometry analysis, will enable proteomic analysis at the organelle level. Whilst scientifically and experimentally challenging it is realistic to envisage the combination of these methods to deliver a novel approach which will add cellular resolution to phosphoproteomic analysis.

The second goal of the research will be the application of these methods to probe disease relevant cell types and response to compound treatment. This will leverage AstraZeneca's disease expertise and wealth of annotated probe compounds. Hypotheses generated from these analyses with be further tested by, targeted proteomic strategies (Selected Reaction Monitoring) and antibody methods to directly characterise the phosphorylation state of the protein candidates and their localisation within the cell using fluorescence microscopy. Finally, exploiting AstraZeneca's access to disease relevant tissues the expression of targeted protein candidates can be validated on mouse/human samples.

The successful candidate will be jointly supervised by Prof. Kathryn Lilley of the Cambridge Centre for Proteomics which is located in the Department of Biochemistry, University of Cambridge and Discovery Sciences Labs at the Darwin Building on the Cambridge Science Park, working alongside a team delivering Mechanistic Biology support to Oncology Drug Discovery Projects.

Applications should be sent to Prof. Kathryn Lilley ([Email Address Removed]), by midnight on Friday 8th July 2017, enclosing a cover letter, a detailed curriculum vitae (both in PDF format) and the names and contact details of two academic referees.

Please quote reference PH11837 on your application and in any correspondence about this vacancy.

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For Literature please see the following link:
http://www.jobs.cam.ac.uk/job/13335/file/References.docx