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Understanding and manipulating our immune system to protect against ageing

Ageing is the most important non-modifiable risk factor for a number of diseases and conditions of the immune system including ischaemia reperfusion injury (e.g. myocardial infarction and stroke), cancer, infections, wound healing, degenerative diseases (e.g. vascular dementia, Alzheimer’s disease) and cardiovascular diseases. Ageing is also associated with several morbidities that finally lead to organ failure and death.

As we age, our immune system undergoes a dynamic change characterised by low-grade chronic inflammation and involving a number of immune cells (e.g. neutrophils, platelets and endothelial cells) and pro-inflammatory cytokines e.g. tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. This chronic activation of inflammation associated with ageing has been termed ‘inflammaging’ and although the detrimental effects of ageing are well defined, mechanisms contributing to poor outcomes following many morbidities remain unknown. In addition, these effects may also be compounded by additional co-morbidities including environmental factors (e.g. stressful environments, alcohol consumption, smoking).

Multimorbidity (i.e. two or more long-term health conditions) is prevalent as we age, with 75% of adults by the age of 70 having multimorbidities. These effects increase the risk of infections in the elderly and are at greater risk for infections (e.g. COVID-19), with worse outcomes. Additionally, inflammageing affects immune responses to illness, infections and vaccines, which may lead vaccination against e.g. SARS-CoV-2 being less effective, or not lasting as long as in younger patient cohorts. How inflammageing affects COVID-19 risk and poor outcome in the elderly remains unknown and is of great unmet clinical need to help identify potential novel disease biomarkers for future clinical trials.

In summary, we are particularly interested in the mode, dynamics and mechanisms of inflammaging that occur in the microcirculation (both in the brain and systemic organs).1-8 As such, this project area gives rise to a number of PhD opportunities aiming to provide a greater understanding of the complex haemodynamic responses of the immune system as we age in order to drive drug discovery programmes aimed at manipulating our immune system to protect against ageing and help solutions to key global challenges.

Training/techniques to be provided

As multiple PhD opportunities are available, the training and skills sets will be tailored to each individual project. However, training could include

  • In vivo skills e.g. animal handling and maintenance, animal anaesthesia, in vivo ageing models and surgery -
  • Novel in vivo imaging techniques e.g. intravital microscopy, IVIS, Magnetic Resonance Imaging
  • In vitro methodologies which may include histology, immunohistology, electron microscopy, immune cell functional assays (e.g. chemotaxis, transmigration, granule release assays, NETosis), molecular biology, flow cytometry and flow chamber systems.
  • Modern mathematical approaches for the analysis of immune cell function.
  • Metabololipidomics and genetic profiling

Students will have the opportunity to collaborate and work with a number of groups based both in the UK and globally during their PhD.

These PhD projects will be supervised by Professor Felicity Gavins. If you are interested in applying for a PhD project in this area or if you prefer a one-year MPhil on a similar topic, contact Professor Gavins to discuss your interest and discover whether you would be suitable.

Entry Requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject (e.g. physiology, pharmacology, biomedical sciences). Candidates with experience in in-vivo pharmacology and immune-histochemistry are encouraged to apply. The duration of this PhD project is three years.

References

  1. Vital SA, Senchenkova EY, Ansari J, Gavins FNE. Targeting AnxA1/Formyl Peptide Receptor 2 Pathway Affords Protection against Pathological Thrombo-Inflammation. Cells. 2020;9:2473. 2
  2. Senchenkova EY, Ansari J, Becker F, Vital SA, Al-Yafeai Z, Sparkenbaugh EM, Pawlinski R, Stokes KY, Carroll JL, Dragoi AM, Qin CX, Ritchie RH, Sun H, Cuellar-Saenz HH, Rubinstein MR, Han YW, Orr AW, Perretti M, Granger DN, Gavins FNE. Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation. Circulation. 2019;140:319-335.
  3. Senchenkova EY, Russell J, Yildirim A, Granger DN, Gavins FNE. Novel Role of T Cells and IL-6 (Interleukin-6) in Angiotensin II-Induced Microvascular Dysfunction. Hypertension. 2019;73:829-838.
  4. Gillespie S, Holloway PM, Becker F, Rauzi F, Vital SA, Taylor KA, Stokes KY, Emerson M, Gavins FNE. The Isothiocyanate Sulforaphane Modulates Platelet Function and Protects Against Cerebral Thrombotic Dysfunction. Br J Pharmacol. 2018;175:3333-3346.
  5. Vital S, Becker F, Holloway PM, Perretti M, Granger DN, Gavins FNE. Fpr2/ALX Regulates Neutrophil-Platelet Aggregation and Attenuates Cerebral Inflammation. Impact For Therapy in Cardiovascular Disease. Circulation, 2016;133:2169-2179.
  6. Holloway PM, Durrenberger PF, Trutschl M, Cvek U, Cooper D, Orr AW, Perretti M, Getting SJ, Gavins FN. Both MC1 and MC3 Receptors Provide Protection From Cerebral Ischemia-Reperfusion-Induced Neutrophil Recruitment. Arterioscler Thromb Vasc Biol. 2015;35:1936-1944.
  7. Hughes EL, Cover PO, Buckingham JC, Gavins FN. Role and Interactions of Annexin A1 and Oestrogens in The Manifestation of Sexual Dimorphisms in Cerebral and Systemic Inflammation. Br J Pharmacol. 2013;169:539-553.
  8. Gavins FN, Hughes EL, Buss NA, Holloway PM, Getting SJ, Buckingham JC. Leukocyte recruitment in the brain in sepsis: involvement of the annexin 1-FPR2/ALX anti-inflammatory system. FASEB J. 2012;26:4977-4989

How to apply

If you are interested in applying for the above PhD topic please follow the steps below:

  1. Contact the supervisor by email or phone to discuss your interest and find out if you woold be suitable. Supervisor details can be found on this topic page. The supervisor will guide you in developing the topic-specific research proposal, which will form part of your application.
  2. Click on the 'Apply here' button on this page and you will be taken to the relevant PhD course page, where you can apply using an online application.
  3. Complete the online application indicating your selected supervisor and include the research proposal for the topic you have selected.

Good luck!

This is a self funded topic

Brunel offers a number of funding options to research students that help cover the cost of their tuition fees, contribute to living expenses or both. See more information here: https://www.brunel.ac.uk/research/Research-degrees/Research-degree-funding. The UK Government is also offering Doctoral Student Loans for eligible students, and there is some funding available through the Research Councils. Many of our international students benefit from funding provided by their governments or employers. Brunel alumni enjoy tuition fee discounts of 15%.