About the Project
We are seeking enthusiastic candidates for an iCASE PhD project investigating the molecular pathology of COVID-19. The primary aim is to develop a detailed and urgent understanding of the so-called ‘cytokine storm’ which follows persistent SARS-CoV-2 infection and leads to the life-threatening cardiovascular disease. We anticipate that our findings will directly unlock life-saving treatments for patients with either COVID-19 or future variants.
>80% of patients hospitalised due to COVID-10 so far have severe vascular diseases and thrombosis, whilst >40% of autopsies detect myocardial hypertrophy. It is thought that specific cytokines, along with the continued binding of the virus spike protein to the ACE2 receptor over-stimulates the specific cytokine receptors in both the vascular endothelial cells and the myocardium. We will investigate the hypothesis that these events lead to an over-activation of calcium-calmodulin kinase-II (CaMK-II), derailing it from its primary role in cellular homeostasis. We hypothesise that over-stimulated CaMK-II triggers maladaptive protein phosphorylation, remodelling and/or death of these cells, leading to life-threatening acute cardiovascular diseases.
In this project, we will perform novel super-resolution microscopy on tissue samples of lung vasculature and hearts of COVID-19 patients to identify the fine features of the damage caused to the vascular endothelium and heart cells. We will then establish two novel organoid systems (tissue culture assays) – of capillaries and myocardium – to simulate the COVID-19 cardiovascular disease. Coupled with live-cell imaging, these organoids will be subjected to an in vitro version of the ‘cytokine storm’. Based on the pathology and proteins observed in the patient samples, we will use super-resolution microscopy to track the changes in the location and function of CaMK-II. Finally, we will test the effect of a series of pharmacological blockers of the cytokine receptors and CaMK-II to explore strategies to minimise the effect of the ‘cytokine storm’ on the endothelium and myocardium.
As a DiMeN iCASE scholar, you will be eligible for an enhanced stipend (additional £2,500 pa). The project will be primarily based at the Department of Molecular Biology & Biotechnology in the University of Sheffield; in the state-of-the-art laboratory of Dr Izzy Jayasinghe (Twitter: @i_jayas; staff webpage: https://www.sheffield.ac.uk/biosciences/people/mbb-staff/academic/izzy-jayasinghe ; Research webpage: https://appliedbiophotonics.org/). You will join an interdisciplinary team of diverse researchers with a primary expertise in microscopy and cellular cardiology.
The second supervisor is Prof Nikita Gamper (staff website: https://biologicalsciences.leeds.ac.uk/school-biomedical-sciences/staff/70/prof-nikita-gamper), an expert in cytokines, neuroscience and calcium signalling, based in the University of Leeds.
The third supervisor is Dr Jung-uk Shim (website: https://eps.leeds.ac.uk/physics/staff/4132/dr-jung-uk-shim), an expert in microfluidics and their use for tissue culture and organoids. During the studentship, you will spend a 6-month placement with the Leeds-based industrial partner, Badrilla Ltd, one of the UK’s leading producers of antibodies and biochemical analytical tools (https://badrilla.com/). The industrial placement will offer you an opportunity to contribute directly to their core R&D, product development, market operations, research outputs and consortia.
This is an excellent opportunity to work alongside a world-class team of researchers, to learn state-of-the-art technologies and to contribute to a timely research project with high national and international importance.
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:
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.
Miteva & Pedicini et al. J Cell Biol (2019) 218 (7), 2232-2246
Shah et al. Sci Signalling (2020) 13; 7963
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