Microtubules are long polymers important for cell division, intracellular transport and polarity. Many isotypes of microtubules co-exist in human cells and levels of expression vary with the cell type. Growing evidence shows different isotypes have different properties, leading to potentially distinct functions of tubulin in cells. This gives rise to a “tubulin code” hypothesis [1] and raises many questions about tubulin biology but also in the specificity of microtubule cytoskeleton drug targeting to disrupt cellular processes and for therapeutic purposes. Recent synthetic progress in the Hulme group [2], means that we can now readily design new macrocycles targeting the maytansine sub-site on tubulin, to use as tools to selectively target specific tubulin isotypes. In this project, the student will use a combination of computational, synthetic organic, cell biology and biophysical approaches, to design and optimise new isotype-specific tools.
In a design-synthesis-test approach, the student will make full use of the expertise of two labs in Edinburgh. Using computational approaches, novel disorazole and nocodazole analogues will be designed. These chemical tools will then be synthesised by the student, making use of world-leading expertise of the Hulme group in the construction of macrocycles. Working in the Welburn labs, the student will use a recombinant system to generate isotype-pure tubulins. The sensitivity and affinity of these tubulins to the new chemical tools will be assessed using in vitro reconstitution and a series of biophysical assays, including microtubule dynamics and assembly assays and fluorescence anisotropy [3]. From this work, the student will be able to hypothesize how drugs may fail to work in certain cell types, while the results will offer them opportunities to improve small molecule inhibitors based on isotype specificity and expression patterns. These results will have strong implications for our understanding of cytoskeleton biology and the synthesis and optimization of macrocyclic drugs for personalized medicine.
[1] The Tubulin Code in Microtubule Dynamics and Information Encoding: A. Roll-Mecak. Dev Cell. 2020. 54:7-20.
[2] An Alkyne Metathesis Based Approach to the Synthesis of the Anti-malarial Macrodiolide Samroiyotmycin A: E. Yiannakas, M. I. Grimes, J. T. Whitelegge, A. Fürstner, A. N. Hulme, Angew. Chem. Int. Ed. 2021. 60:18504-18508.
[3] A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin: G. Menchon, A. E. Prota, D. Lucena-Agell, P. Bucher, R. Jansen, H. Irschik, R. Müller, I. Paterson, J. F. Díaz, K.-H. Altmann, M. O. Steinmetz, Nature Commun. 2018. 9: 2106.
Application Process:
To apply for an EASTBIO PhD studentship, follow the instructions below:
1) Informal enquiries should be addressed to Professor Hulme in the first instance. To apply, please send a cover letter outlining your previous research experience and reasons for applying, alongside an up-to-date CV to [Email Address Removed]
2) After you have discussed the projects of interest to you with Professor Hulme, download and complete our Equality, Diversity and Inclusion survey and then fill in the EASTBIO Application Form and submit this to Professor Hulme.
3) Send the EASTBIO Reference Form to your two academic/professional referees. Please ask your referees to submit your references directly to Professor Hulme [Email Address Removed]
4) If you are nominated by the supervisor(s) of the EASTBIO PhD project , they will provide a Supervisor Support Statement for your application.
We anticipate that our first set of interviews will be held 7th – 11th February 2022 with awards made in the following week.
If you have further queries about the application/recruitment process please contact EASTBIO
The successful applicant will be advised how to apply for admission to the PhD programme via EUCLID in due course.
The School of Chemistry holds a Silver Athena SWAN award in recognition of our commitment to advance gender equality in higher education. The University is a member of the Race Equality Charter and is a Stonewall Scotland Diversity Champion, actively promoting LGBT equality. The University has a range of initiatives to support a family friendly working environment. See our University Initiatives website for further information. University Initiatives website: https://www.ed.ac.uk/equality-diversity/help-advice/family-friendly
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