Exploiting state of the art mass spectrometry for understanding cellular glycosylation processes

Glycans are carbohydrate polymers, which with proteins, DNA and RNA are one of the four biopolymers essential for life. Yet our understanding of glycan biosynthesis remains rudimentary compared with that of proteins and nucleotides. This is a significant drawback given the well documented importance of glycans in mammalian development, pathology, efficacy of therapeutic proteins (biologics), and longevity. For example, most biologics (such as antibodies, follicle stimulating hormone and erythropoietin) are currently expressed in cultured mammalian cells as a mixture of different ‘glycoforms’ (the same protein backbone bearing a range of different glycan structures). While it is well documented that glycosylation state is critical for the effectiveness of glycoprotein therapeutics, our current knowledge of glycan biosynthesis does not allow the tailoring of glycans on biologics; this means that a significant fraction of every biologic product on the market could potentially have low efficacy. Better understanding of glycan biosynthesis would allow tailoring of glycosylation and thus the production of cheaper and more efficient drugs. Similarly, despite the clear importance of glycans during early mammalian development and cellular differentiation, our lack of knowledge about how glycan biosynthesis is regulated limits our ability to clarify the distinct roles of specific glycan structures in these important physiological processes.

This PhD project will exploit the outstanding instrumentation available in the York Centre of Excellence in Mass Spectrometry to establish, evaluate, and exploit a range of new mass spectrometric approaches for glycan structural analysis and quantification. We have developed (Abdul Rahman et al) and recently significantly extended a miniaturised method for glycan release and isolation from cells in culture. Using model cell culture systems which replicate known human mutations or that undergo cellular differentiation and development, the student will release the glycans, and then use the mass spectrometric approaches they establish to determine the structures of those glycans, and to quantify them. They will use this information to determine the effects of the cellular changes on the glycan structures expressed by those cells (an example of this sort of work is described in Abdul Rahman et al). The successful candidate will receive training in both cellular and analytical glycobiology, splitting their work between the labs of the two collaborating supervisors. In Biology, the student will learn cell culture, tissue differentiation, molecular biology and glycobiology. In Chemistry the student will establish and then apply the range of new mass spectrometric structural analysis approaches to glycan analysis and quantification, of the glycans they release and isolate from the experimental cellular systems. They will learn to interpret and evaluate their results both as analytical chemists but also in terms of the broader cellular biology questions we are looking to address.

Abdul Rahman, S., Bergström, E., Watson, C.J., Wilson, K.M., Ashford, D.A., Thomas, J. R., Ungar, D., Thomas-Oates, J.E., (2014) Filter-Aided N-Glycan Separation (FANGS): a Convenient Sample Preparation Method for Mass Spectrometric N-Glycan Profiling. J. Proteome Res., 13: 1167-1176.

Shortlisted applicants will be invited for an interview to take place at the University of York on Wednesday 15 February 2017. Candidates will be asked to give a 5 minute presentation as part of their interview by an academic panel. Applicants shortlisted for interview will be notified by 1 February 2017. All research students follow our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills.

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