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MRC DiMeN Doctoral Training Partnership: Effects of SARS-CoV-2 on blood vessels


MRC DiMeN Doctoral Training Partnership

, Wednesday, January 27, 2021 Competition Funded PhD Project (Students Worldwide)
Newcastle United Kingdom Biochemistry Cell Biology Immunology Molecular Biology Pathology Virology

About the Project

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) has led to a global pandemic of disease termed COVID-19. Although the virus uses ACE2 receptor expressed by pneumocytes to infect the host, thereby causing lung injury, the ACE2 receptor is also widely expressed on endothelial cells. COVID-19-associated tissue injury is not primarily mediated by viral infection, but rather is a result of the inflammatory host immune response and microthrombosis. The leukocyte LTB4, and its receptor, orchestrate the recruitment of neutrophils into the area of inflammation.  Furthermore, coronaviruses activate multiple complement pathways. Our understanding of the mechanisms involved in the activation of complement pathways and dysregulated neutrophil recruitment in the presence of SARS-CoV2 infection and how this leads to organ dysfunction is very limited. 

We aim to use an in-vitro model with human pulmonary microvascular endothelial cells (HPMEC) and airway epithelial cells to assess the effect of SARS-CoV-2 infection in presence of complement, on the expression of activation markers, membrane integrity, leukocyte adhesion and migration. Additionally, we will use complement and neutrophil inhibitors to ameliorate the process.

Our approach is multi-disciplinary and brings together well-established clinical expertise (Prof A Fisher, Dr C Duncan) with basic science (Profs S Ali & C Harris), access to containment level 3 facilities (Dr C Duncan) and industry collaboration (Akari Therapeutics). Our Industry collaborators will provide a secondment opportunity, during which the student will gain experience of working across the sector.  Newcastle University co-hosts MRC UK Coronavirus Immunology Consortium. Through this consortium we will have access to COVID-19 patient serum and expertise. 

This project will utilise core research skills in cell biology, virology, immunology, cell migration, flow based adhesion, RNA Seq etc. In the proposed project we will specifically assess the effect of infection by SARS-CoV-2 in presence of complement using primary lung derived endothelial and epithelial cells (unused donor lungs). A better understanding of the mechanism can lead to tailored therapies. This fully funded studentship is available for outstanding candidates aiming to obtain high quality research training in an exciting and very translational subject area.

https://www.ncl.ac.uk/medical-sciences/people/profile/claireharris.html

https://www.ncl.ac.uk/medical-sciences/people/profile/christopherduncan.html

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

Funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner.

Funding will cover UK tuition fees and an enhanced stipend (around £17,785) only. We aim to support the most outstanding applicants from outside the UK. We 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

Barker CE, Thompson S, O'Boyle G, Lortat-Jacob H, Sheerin NS, Ali S, Kirby JA. CCL2 nitration is a negative regulator of chemokine-mediated inflammation. Scientific Reports 2017, 7, 44384.
Calippe B, Augustin S, Beguier F, Charles-Messance H, Poupel L, Conart J-B, Hu SJ, Lavalette S, Fauvet A, Rayes J, Levy O, Raoul W, Fitting C, Denefle T, Pickering MC, Harris C, Jorieux S, Sullivan PM, Sahel J-A, Karoyan P, Sapieha P, Guillonneau X, Gautier EL, Sennlaub F. Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation. Immunity 2017, 46(2), 261-272.
Andreasson ASI, Borthwick LA, Gillespie C, Jiwa K, Scott J, Henderson P, Mayes J, Romano R, Roman M, Ali S, Fildes JE, Marczin N, Dark JH, Fisher AJ, on behalf of the DEVELOP-UK Investigators. The role of interleukin-1β as a predictive biomarker and potential therapeutic target during clinical ex vivo lung perfusion. Journal of Heart and Lung Transplantation 2017, 36(9), 985-995.

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