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MRC DiMeN Doctoral Training Partnership: Chemical probes for real-time visualisation of calcium-sensing receptor trafficking during inflammation


   MRC DiMeN Doctoral Training Partnership

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  Dr Megan Wright, Dr Polina Yarova, Prof John Simpson  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

This fully-funded MRC studentship is an opportunity to perform exciting research across chemistry, biology and medicine. You will develop tools to study the expression and localisation of a protein involved in signalling and inflammation in living cells and patient samples, paving the way for better treatments and diagnostics for a range of diseases.

 Calcium-sensing receptor (CaSR), the body’s master controller of calcium homeostasis, has recently emerged as a key player in the development of pro-inflammatory diseases, including asthma, rheumatoid arthritis and cardiovascular disease. CaSR responds to ligands released during inflammation, altering cellular signalling. There are currently no tools to measure CaSR expression levels in real time and visualise its trafficking in its native environment. In this project you will design and apply chemical probes to track CaSR in living cells, leading to new insights into the biology of this receptor. Further, you will develop this approach into a new diagnostic tool for detecting inflammation in patients.

This interdisciplinary project will span chemistry, chemical biology, cell biology and imaging, and provide high quality training in all these areas. You will design and synthesise chemical probes, based on known CaSR-targeting drugs, that deliver a fluorophore onto the receptor. You will show that these tools work on cells expressing CaSR and use them in high resolution imaging experiments to track the receptor’s movement in response to various stimuli. Finally, you will apply your tools to image receptor expression levels and trafficking in primary lung epithelial and endothelial cells, or from in patients with pneumonia or sepsis.

This project is a collaboration between the Universities of Leeds and Newcastle. You will be primarily based at the University of Leeds and supervised by Dr Megan Wright, a chemical biologist with expertise in protein labelling. The second supervisor is Dr Polina Yarova (Newcastle), who is an expert in CaSR, physiology and imaging, and will host you for secondments to apply the synthesised chemical probes to understand CaSR biology in complex settings. Prof. John Simpson (Newcastle) will provide supervision in the handling and analysis of primary cells and patient samples to investigate the potential of the new probes for profling and diagnosis of inflammatory disease.

We are looking for a student with chemistry experience who is motivated by the application of chemistry to biological questions. We encourage informal enquiries to Dr Megan Wright ([Email Address Removed]). 

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog

Further information on the programme and how to apply can be found on our website: https://www.dimen.org.uk/how-to-apply


Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend and project costs. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of full studentships to international applicants. Please read additional guidance here: https://www.dimen.org.uk/eligibility-criteria
Studentships commence: 1st October 2023
Good luck!

References

D. H. Field, S. L. Warriner, M. H. Wright*: A fluorescent photoaffinity probe for formyl peptide receptor 1 labelling in living cells, ChemRxiv 2022.
C. C. Bauer, A. Minard, I. B. Pickles, K. J. Simmons, E. Chuntharpursat-Bon, M. P. Burnham, N. Kapur, D. J. Beech, S. P. Muench, M. H. Wright, S. P. Warriner, R. S. Bon*: Xanthine-based photoaffinity probes allow assessment of ligand engagement by TRPC5 channels, RSC Chem Biol 2020, 1, 436.
M. H. Wright, Y. Tao, J. Drechsel, J. Krysiak, S. Chamni, A. Weigert-Munoz, N. L. Harvey, D. Romo* and S. A. Sieber,* Quantitative chemoproteomic profiling reveals multiple target interactions of spongiolactone derivatives in leukemia cells, Chem. Commun., 2017, 53, 12818.
P. Yarova et al.: Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma, Science Translational Medicine, 2015, 7, 284.
M. Schepelmann et al. Impaired mineral ion metabolism in a mouse model of targeted CaSR deletion from vascular smooth muscle cells, JASN, 2022, 33, 1323.
P. Yarova et al. Characterisation of negative allosteric modulators of the calcium-sensing receptor, CaSR, for repurposing as a treatment for asthma, JPET, 2021, 383.
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