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Studying the immune systems first responders: neutrophils and platelets. Friends of foes?

Cardiovascular disease (CVD) remains the leading cause of death worldwide particularly in developed countries, with inflammation being central to its pathophysiology. Hence, inflammation is currently considered as a modifiable risk factor for CVD, with neutrophils playing a central role. Neutrophils make up 60-70% of human circulating leukocyte levels (10-25% in mice) and are generated in the bone marrow at a rate of 1011 cells per day. Mechanistically neutrophils have crucial functions in immunity and repair, providing the first line of defence, yet despite their involvement in immunity, neutrophils function as a double edged sword, because they also mediate tissue injury, perpetuate the inflammatory response and contribute to peripheral coagulation and platelet aggregation that accompanies a range of pathological conditions including ischaemia reperfusion injury (often unavoidable sequelae in solid organ transplantation [being linked to graft damage]), sepsis, inflammatory bowel diseases, blood disorders and cancer.1-8 Additionally, neutrophils display diversity in their phenotype in inflammation, although their association with CVD risk and outcome is still mainly unexplored.2,3

Extensive interactions occur between neutrophils and platelets which mediate their ability to regulate haemostasis, inflammation and innate immunity. These first responders of the immune system play crucial roles in maintaining vascular and tissue integrity and their crosstalk is thus a common feature of CVDs and inflammatory immune reactions. Platelet enrichment near the vessel increases neutrophil encounters, which increases the chances of heterotypic interactions, promoting intravascular thrombosis.1,2 We have previously shown that the N-terminal Annexin A1 mimetic peptide Ac2-26 promotes an endogenous biosynthetic circuit in which neutrophil-formyl peptide receptor 2 (Fpr2/ALX) (a key receptor involved in the resolution of inflammation) controls neutrophil platelet aggregate formation by rapid generation of the pro-resolving mediator aspirin triggered lipoxin A4, although the exact mechanism(s) remains unknown.3

This PhD project will build on previous studies to investigate and untangle the mechanism of neutrophil-platelet crosstalk and its consequence on neutrophil phenotype and function with the objective of developing novel drugs for the treatment and prevention of CVDs.

Training/techniques to be provided

The student will be trained in several in vivo skills including animal handling and maintenance, animal anaesthesia and surgical models. The candidate will be trained to use in vivo imaging techniques (e.g. intravital microscopy) and perform a variety of 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. The candidate may also be working with clinical samples. The student will have the opportunity to collaborate and work with a number of groups based both in the UK and globally.

This PhD project will be supervised by Professor Felicity Gavins. If you are interested in applying for this PhD project 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. 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. 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.
  4. Smith HK, Omura S, Vital SA, Becker F, Senchenkova EY, Kaur G, Tsunoda I, Peirce SM, Gavins FNE. Metallothionein I as a direct link between therapeutic hematopoietic stem/progenitor cells and cerebral protection in stroke. FASEB J. 2018;32:2381-2394.
  5. Omura S, Sato F, Park A, Fujita M, Nishio K, Gavins FNE, Tsunoda I. Bioinformatics Analysis of Gut Microbiota and CNS Transcriptome in Virus-Induced Acute Myelitis and Chronic Inflammatory Demyelination; Potential Association of Distinct Bacteria with CNS IgA upregulation. Frontiers in Immunology, section Mucosal Immunity. 2020;11:1138.
  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%.


Professor Felicity Gavins - Felicity read Pharmacology at the University of Sunderland, where she also embarked on an industrial placement year at Bayer Pharmaceuticals in Slough. After completing her BSc (Hons), she moved to London to study for a Ph.D. in Pharmacology at Queen Mary University London, supported by the British Heart Foundation (BHF). Felicity was then awarded a BHF Junior Research Fellowship to undertake further research both in the UK and the USA. In 2007 Felicity joined Imperial College London to take up a Lectureship position in the Centre for Integrative Mammalian Physiology and Pharmacology (CIMPP). This was shortly followed by a senior lectureship and the appointment to Deputy Head of The Centre of Neurodegeneration & Neuroinflammation. In 2013 she accepted an academic position in the USA at Louisiana State University Health Sciences Center-Shreveport (LSUHSC-S) and was appointed Director of The Small Animal Imaging Facility. Felicity is a Fellow of the British Pharmacological Society and of the Royal Society of Biology. She joined Brunel University London in August 2019 as Professor of Pharmacology and Royal Society Wolfson Fellow, and is the Director of The Centre for Inflammation Research and Translational Medicine (CIRTM). Throughout her academic career, Felicity has worked with and served on numerous national and international research councils, medical charities and learned societies. She has published widely in her field and received a number of awards and honours for her work. She has received funding for her research from a range of funders including: the Royal Society and the Wolfson Foundation (RSWF), the British Heart Foundation (BHF), the Medical Research Council (MRC), the Biotechnology and Biological Sciences Research Council (BBSRC), the American Heart Association (AHA), and the National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI). Felicity continues to be actively involved in public and patient organizations which has been immensely instructive for her research. She is also dedicated to promoting mentoring and collaborative research, along with facilitating mentoring of post-doctoral fellows/early-career investigators.