(MRC CASE) Understanding the importance of inflammasomes and interleukin-1 to hyper-inflammatory syndromes, including COVID-19

The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused ~900k deaths to date worldwide. The main cause of death in COVID-19 is principally through acute respiratory distress syndrome (ARDS) and a cytokine storm syndrome – a state of hyper-inflammation that results in multi-organ failure.
Over the course of the pandemic there have been multiple clinical trials initiated to treat patients for hyper-inflammation to improve mortality, with promising results to date, though a full randomised Phase 3 trial has yet to be conducted. Cytokine storm complicating macrophage activation syndrome (MAS) associated with rheumatic disease, shares considerable biochemical overlap with the hyper-inflammation observed in patients with COVID-19. Interestingly the drug anakinra, a recombinant interleukin-1 (IL-1) receptor antagonist, is often used off-label in the treatment of MAS, with some success. However, the mechanisms underlying the hyper-inflammation in MAS, COVID-19 and other syndromes remain poorly understood. Better understanding of these mechanisms could therefore reveal more effective therapies and identify those patients that are more likely to respond to a particular treatment, for example anakinra or other immune-modulatory agents.
A mouse model of MAS with characteristics common to human MAS has been described and in this project we aim to utilise this model to determine mechanisms underlying hyper-inflammation as observed in the current COVID-19 pandemic and other syndromes. More specifically we will:
1) Develop a drug testing platform where: a) new interventions providing novel mechanistic insights into MAS (e.g. inflammasome inhibitors, genetic models), and b) existing immunomodulatory therapies including inhibitors of IL-1, IFNγ, TNFα, and IL-6, will be tested against existing and new serological predictors of severity in COVID-19 and MAS, and on overall immunology by immunophenotyping bloods.
2) Determine the effects of age and gender on MAS severity by comparing immune responses in aged animals and male vs female mice.
3) Determine the effects of diabetes, a known risk factor and co-morbidity for COVID-19, on MAS severity by comparing immune responses in control, diabetic and hyperglycaemic mice. Other relevant co-morbidities may also be studied, for example obesity.

The overall outcome of this project will be improved understanding of the regulatory processes driving inflammation in MAS, the identification of new therapeutic strategies, and the biological assessment of the effects of gender and co-morbidity on hyper-inflammation.

https://www.braininflamelab.org/
https://www.sobi.com

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/) .
If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.
Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.
To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website www.manchester.ac.uk/mrcdtpstudentships

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