The foundation and downfall of multicellular animals is cell-cell communication. This enables the integration of cellular function necessary for the development of organs and specialised tissues and homeostasis, whereas its disruption results in diseases, e.g, cancers and inflammatory conditions. Central to the regulation of cell-cell communication is the extracellular matrix and its glycosaminoglycans. Glycosaminoglycans are nature’s most complex polymers. They are the key to the extracellular matrix’s regulation of cell communication because of their complexity, size and control of the activity of 100s of extracellular proteins.
While we have good knowledge about the structure of the individual components of extracellular matrix, we know very little about the structure of the ensemble. However, it is clear from numerous studies that the ensemble, so matrix as a whole, has functions that are not described by its individual parts. This is the challenge of the project: establishing the supramolecular structure of extracellular matrix and how this regulates cell function.
This PhD will use complementary bottom-up and top-down approaches. The bottom up approach will be used to produce artificial matrices of defined composition and proteins with designed heparan sulfate binding sites. This will allow the physico-chemical properties of the matrices to be directly related to their components. The top down approach will interrogate real matrices produced by living cells in culture, with the aim of defining key molecular features, such the structure of networks of binding sites of growth factors in glycosaminoglycans. The two approaches will be used in tandem to determine, for example, what aspects of a real matrix should be perturbed to elicit the maximal functional change, for example with respect to growth factor activation of a cell.
A wide range of state-of-the-art techniques will be used. In broad terms these cover the following areas:
Molecular cell biology: recombinant protein production;
Synthetic biology: bottom-up design of a heparin-binding protein;
Bionanotechnology: nanoparticle synthesis;
Proteomics: analysis of protein-glycosaminoglycan interactions by structural proteomics in two and multi component systems;
Chemical biology: conjugation of glycosaminoglycans and proteins to nanoparticles;
Advanced microscopy: single molecule photothermal and fluorescence microscopy, electron microscopy.
This project is open to applicants who are able to obtain their own funding for tuition fee, consumable laboratory costs and living expenses.
A fees bursary may be available for suitably qualified applicants.
The 2016-17 PhD tuition fees are: UK/EU students £4,052.00 p.a.; international students £18,000.00.
In addition fees of between £1,000 and £12,000 per year are required for research costs depending on the type of project. An estimated maintenance allowance of £820 per month is required to cover accommodation, meals, transport etc.
The above figures are for guidance only, details will be provided when an offer is made.
Ori, A., Wilkinson, M.C. and Fernig, D.G. (2011). A systems biology approach for the investigation of the heparin/heparan sulfate interactome. J. Biol. Chem. 286:19892-19904.
Duchesne, L., Octeau, V., Bearon, R.N., Beckett, A., Prior, I.A., Lounis, B., and Fernig, D.G. (2012). Transport of fibroblast growth factor2 in the pericellular matrix is controlled by the spatial distribution of its binding sites in heparan sulfate. PLoS Biol 10: e1001361.
Xu, R., Ori, A., Rudd, T.R., Uniewicz, K.A., Ahmed, Y.A., Guimond, S.E., Skidmore, M.A., Siligardi, G., Yates, E.A. and Fernig, D.G. (2012). Diversification of the structural determinants of fibroblast growth factor-heparin interactions: implications for binding specificity. J. Biol. Chem. 287: 40061-40073.