Understanding receptor clustering via multivalent ligand display
Extracellular signalling is a vital means for cells to communicate with each other, respond to their environment, and ultimately form functioning tissues. Signalling proteins bind to cell-surface receptors triggering cascades that lead to changes in cell behaviour. Critically, this signalling is concentration dependent with the clustering of receptors increasing signal potency. In this project, we will design new chemical techniques to probe this clustering process in precise detail, by creating polymer-protein conjugates that present multiple protein ligands in defined architectures to cells. By doing so, we will be able to identify the optimal orientation, arrangement, and valency of ligands needed to activate signalling, providing unprecedented understanding of this key biological phenomena.
i) Develop new protein modification chemistries that target protein N-termini irreversibly; ii) Synthesise polymer-protein arrays via controlled radical polymerisations; iii) Correlate polymer architecture to intracellular signalling activation and persistence;
This highly interdisciplinary project will combine elements of organic synthesis, polymer chemistry, biochemistry, and mechanistic biology. To do this, we have brought together a collaborative team across the Chemistry and Biology departments in York and the industry partner Qkine.
We will first use small molecule model systems, using aromatic and peptide chemistries, to identify reactions that can irreversibly modify polypeptide N-termini. We will use a combination of NMR and fluorescence studies to characterise these reactions, before applying them to protein modification, with characterisation through mass spectrometry and biochemical assays.
We will go on to conjugate the important signalling proteins FGF-2 and BMP-2 to precisely defined polymer arrays, synthesised via RAFT polymerisation. These polymers will then be screened for their ability to induce receptor activation, using reporter mesenchymal stem cell lines to provide a direct fluorescent readout of signalling.
Though the key role played by receptor clustering in controlling cell signalling is widely known, our mechanistic understanding of this process is limited. Little is known about the optimal orientation and valency of protein presentation for downstream signalling. This project directly addresses this challenge by exploiting cutting-edge technologies in chemical protein modification, low-volume polymer synthesis, and recombinant growth factor protein expression.
Training: This project is highly interdisciplinary in nature and will provide applicants with a diverse range of skills across chemistry and biology. The student will join the Spicer Group in the Molecular Materials Division at York, which specialises in the design and synthesis of polymers and materials for next-generation biotechnologies. They will receive specific training in advanced organic chemistry, protein modification, and polymer synthesis. They will also join the Genever Group in the Department of Biology at York, where they will be trained in mammalian cell culture, imaging, and genetic engineering. As part of the placement, the student will undertake a 3 month placement with our industrial partner Qkine in Cambridge, where they will learn to recombinantly express growth factor proteins and will be fully exposed to commercial research and business development.
The student will be fully integrated into the White Rose Mechanistic Biology DTP, joining a cohort of PhD students from across York, Leeds, and Sheffield exploring important questions in the biosciences. This programme will provide the student with key training in both research and professional skills throughout their PhD, as well as enabling them to build strong professional networks that will benefit their future career.
Additionally, all Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/idtc/
The Departments of Chemistry and Biology hold Athena SWAN Gold Award and are committed to supporting equality and diversity for all staff and students. The Chemistry Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/. This PhD project is available to study full-time or part-time (50%).
This PhD will formally start on 1 October 2020. Induction activities will start on 28 September.
This is a BBSRC White Rose DTP iCASE studentship fully funded for four years and covers: (i) a tax-free annual stipend at the standard Research Council rate (£15,009 estimated for 2020 entry), (ii) research costs, and (iii) tuition fees at the UK/EU rate. It is available to those who are eligible for research council studentships: https://www.findaphd.com/funding/guides/research-council-studentships.aspx
Entry requirements: Students with, or expecting to gain, at least an upper second class honours degree, or equivalent, are invited to apply. The interdisciplinary nature of this research project means that we welcome applications from students with backgrounds in any biological, chemical, and/or physical science, or students with mathematical backgrounds who are interested in using their skills in addressing biological questions.
Deadline: Sunday 5 January 2020
To apply press this link: https://www.york.ac.uk/study/postgraduate/courses/apply?course=DRPBIOSCHE4