Applications are invited to work on a project to develop novel biomaterials based on liposomes and hydrogels to tackle an outstanding question in biology; how fibrillar assemblies interacts with cell membranes.
Our research team
The successful applicant will have the opportunity to work in a truly multidisciplinary project and take advantage of Dr Milanesi, Prof. CH Hunter and M.P Philpott expertise in organic synthesis, biophysical and structural characterisation of higher order assemblies (proteins and gel fibrils), 1,2 fundamental investigations of non-covalent interactions (molecular design and computer modelling of biomolecular interactions)3 and in cell-biology techniques for the analysis of cell response to synthetic materials.4
The extracellular matrix (ECM) and the cytoskeleton are networks of fibres that support cells morphologies and tissues structure. Tissue engineering aims to produce artificial materials that are capable of replicating the structure and function of the ECM. Efforts to generate materials that are capable of this function and also to support cell differentiation would benefit from an optimal understanding of how the cell membrane and the ECM interact with each other. However, the molecular details of the interaction of cell membranes and ECM fibres or more generally, nanosized fibrillar structures, are poorly understood. Part of the problem is that the direct study of cell-fibres interaction is hampered by the complexity of the cell system.5 A way around this problem is to use simplified chemical models of fibres and cells.
The AIM of the project is to develop novel biomaterials composed of liposomes (as a model of cell membrane) and small molecules based hydrogels (as a model of ECM fibres) to characterize the interaction of self-assembled fibres and lipid membranes.
This research will contribute to our understanding of the molecular basis of fibrils-cell membrane interactions and provide tools to manipulate such interactions for biomedical applications. This knowledge will pave the way for the engineering of novel materials that interact with cell membranes in a controllable fashion for application in tissue engineering, bio-sensing and cell signalling.
What you will do
Workplan milestones, non-exhaustive and adjustable based on project progress and candidate research interests, will include:
1. Synthesis of low molecular weight hydrogelators which will build upon recently published work by Dr Milanesi and C. A. Hunter.1, 6 Compounds bearing bis-maleimide groups will be functionalised with peptides present in the ECM. The candidate will receive training in the following techniques: (i) Organic synthesis and purification, including HPLC, (ii) structural analysis of organic molecules (NMR, MS).
2. Characterisation of the interaction hydrogel-lipid membrane will include the biophysical and structural analysis of the interaction fibrils-liposomes using, isothermal titration calorimetry (ITC), UV-visible and fluorescence spectroscopy. NMR and computer modelling will be used to characterise the assembly mechanism of the hydrogelators whilst transmission electron microscopy (TEM) will be used to determine the structure of the liposome-hydrogel fibrils. 1-3
3. Characterisation of the interaction hydrogel-cell membrane
The hydrogels will be evaluated as synthetic ECMs for the growth of cell cultures in collaboration with Mike Philpott team. The candidate will use and adjust if necessary protocols that we have already established to measure biocompatibility of bis-maleimides with cells. Biochemical analysis of cells that growth within the newly synthetized hydrogels will be use to understand what metabolic pathways are affected by the gelators.
These studies will help to understand the role that the chemical and mechanical properties of the hydrogels play on the structure of the fibrils-cell membrane adhesion zones.
The structure of the adhesive contacts between biocompatible hydrogel fibrils and the cells membrane will be analysed using TEM whilst techniques for cell cultures, analysis of cell viability, cell morphology and phenotype (biochemical assays, fluorescence and optical microscopy, flow cytometry) will be used to determine the impact of the hydrogels on the cell-life cycle and the candidates will be train in these techniques by M. Philpott team.7
We are seeking a highly motivated and enthusiastic individual willing to work as part of a multidisciplinary team and holding, or expected to receive, a First or Upper Second Class Honours, MSc/MRes, MSci degree or equivalent.
Applications for PhD funding through Ciência sem Fronteiras, CONACYT, the China Scholarship Council or the Higher Education Commission of Pakistan are welcomed, as are those applicants who can self-fund.
Applicants should be able to demonstrate that they can cover the cost of living expenses and tuition fees for a minimum of 3.5 years. However, the School does offer a limited number of tuition fee only scholarships for excellent applicants and if you wish to apply for these you should discuss this with your potential supervisor.
1. L. Milanesi, C. A. Hunter, N. Tzokova, J.P. Waltho, S.Tomas (2011), Chem. Eur. J, 17, 9753-9761
2. L. Milanesi, W.F. Xue, T. Sheynis, E. V. Orlova, A. L. Hellewell, R. Jelinek, E. W. Hewitt, S. E. Radford and H. Saibil (2012), Proc Natl Acad Sci U S A, 109: 20455-20460.
3. a) W Cullen, S Turega, C.A. Hunter, MD Ward – Chem. Sci. (2015) 6, 2790
(DOI: 10.1039/c5sc00534e); b) Busuttil, K.; Geoghegan, M.; Hunter, C. A.; Leggett, G. J., J. Am. Chem. Soc. 2011, 133, 8625-8632. doi:10.1021/ja2011143
4. Harrison WJ, Cochrane B, Neill GW and Philpott MP (2014), Oncogene 2014 May 8;33(19):2432-40
5. Christina J. Newcomb, Shantanu Sur2, Julia H. Ortony, One-Sun Lee, John Matson, Job Boekhoven, Jeong Min Yu, George C. Schatz & Samuel I. Stupp, (2014),Nature Communications, DOI: 10.1038/ncomms4321
6. L. Milanesi, J. P. Waltho, C. A. Hunter, D. J. Shaw, G. S. Beddard, G. D. Reid, S. Dev , Martin Volk,(2012), Proc Natl Acad Sci U S A, 109, 19563-19568.
7. Nadendla SK, Hazan A, Ward M, Harper LJ, Moutasim K, Bianchi LS, Naase M, Ghali L, Thomas GJ, Prowse DM, Philpott MP, Neill GW, PLoS One. 2011: 6(5): e20271.
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