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MRC DiMeN Doctoral Training Partnership: Caught in the act. Protease capture technologies to understand immune cell function in inflammatory disease.


MRC DiMeN Doctoral Training Partnership

Sheffield United Kingdom Cell Biology Immunology Molecular Biology Organic Chemistry Pharmaceutical Chemistry Synthetic Chemistry

About the Project

The challenge of understanding uncontrolled inflammation has never been more timely. Inflammation is now known to be a key driver of many acute and chronic pathologies including rheumatoid arthritis and most recently, COVID-19. The neutrophil is a key effector cell of inflammation. Is it the most abundant white blood cell in mammals and a critical component of the innate immune system, responsible for phagocytosis and killing of bacterial and fungal threats. Neutrophils can cause devastating tissue damage during inflammation, yet remain poorly understood compared to other cells of the immune system, largely because the neutrophil is difficult to manipulate experimentally. If we could better understand how neutrophils function, we could tune inflammation to prevent harmful outcomes while maintaining host-defence against infection.

Neutrophil function is highly dependent on protease activity. Proteases aid digestion of ingested pathogens and break down tissue matrix. This project will investigate how neutrophil behaviour is regulated by intracellular protease activity and how this determines the outcome of inflammation. The interdisciplinary supervisory team is uniquely skilled to build chemical probes to capture activated proteases in the cell and to use these to determine which proteases are activated during inflammation and pathogen killing. The knowledge gained will inform treatment of infection and inflammation - critical to dealing with the most important diseases of today.

Project outline: We have developed innovative SNAP-tagged protease capture ligands based on defined protease substrates. These will be built using synthetic chemistry expertise, then tested in human neutrophils purified from blood. Proteases captured in this way will be subjected to mass spectrometry to identify the exact protease captured, and the regulatory complexes associated with it.

You will target 3 principal groups of proteases: (1) caspases, (2) serine proteases including neutrophil elastase, and (3) aspartyl proteases such as cathepsin D. Caspases are critical regulators of cell death and are activated in caspase-activating platforms (CAPs). We have previously shown that neutrophil lifespan is determined by a novel CAP, and you will aim to identify this CAP, allowing us the potential to fine tune rates of neutrophil survival. Neutrophil elastase is a principal protein in neutrophil immune function, while also being the cause of tissue damage in disease. Cathepsins such as CatD are also key proteases in bacterial killing and in triggering intracellular events. Using capture ligands you will profile the timing and regulation of elastase and cathepsin activity, in well-established models of infection and inflammation.

These objectives will form the basis of a novel cell biology project to understand the regulation of neutrophil protease activity during inflammation.

The successful student will benefit from high quality doctoral level training in thriving chemistry and biology labs, in a friendly and encouraging environment comprised of other PhD students, technicians and post-docs. We will support the student in publishing their work in respected journals, and encourage attendance at national and international conferences. Many of our previous students have gone on to secure excellent first positions in academia and industry.

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 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: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:

https://bit.ly/3lQXR8A 


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2021
Good luck!

References

eLife (2018), 7:e32057
eLife (2019) 8:e50990
Science Advances (2018) 4(9):eaar8320;

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