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Investigating thrombo-inflammation in disease

Cardiovascular disease (CVD), including heart disease and stroke are leading causes of mortality in the UK and worldwide. CVD is a multifactorial disease in which the number of risk factors correlates with disease progression and worse outcome.1 Common to the comorbidities and risk factors for CVDs is inflammation, which occurs through the crosstalk between inflammatory leukocytes, platelets and the vascular endothelium.1-7 Systemic inflammation is a potent prothrombotic stimulus, and inflammatory mechanisms upregulate procoagulant factors, downregulate natural anticoagulants and inhibit fibrinolytic activity.1-8 Thus, inflammation can beget local thrombosis, and thrombosis can amplify inflammation.

Ischemia reperfusion injury (I/RI) is a common complication of CVDs. The interdependent connection of both thrombosis and inflammation in eliciting a detrimental pro-thrombotic and pro-inflammatory state after I/RI has led to the concept of thrombo-inflammation.4 A thrombo-inflammatory state has been shown to be present in a number of common diseases including myocardial infarction, stroke, deep vein thrombosis, acute kidney disease, peripheral artery disease, infectious diseases, cancer and disseminated intravascular coagulation (DIC).1-8 During reperfusion, the rapid inflammatory response that ensues leads to microvascular dysfunction involving the adherence of platelets and neutrophils at ischaemic vascular lesions, which increase the risk of secondary thrombotic events and further tissue injury.4 Thus, thrombogenesis is being considered as a potential promising target for anti-thrombotic therapy.

Inflammation and hypercoagulability have been shown to link arterial and venous thrombosis and epidemiological studies have focussed on the presence of risk factors including hypertension, chronic kidney disease, obesity, diabetes, smoking and more recently coronavirus 2 (SARS-CoV-2) infection (which is associated with coagulopathy causing venous and arterial thrombosis). Interestingly, patients with venous thrombosis are at increased risk of arterial thrombosis and patients with arterial thrombosis are at increased risk of venous thrombosis. Furthermore, the global burden of thrombo-inflammation is likely to increase with the ageing population, because both thrombosis and inflammation increase with age.

A number of cellular constituents are involved in thrombo-inflammation, with neutrophils and platelets playing key roles. However, it remains poorly understood how neutrophil-platelet interactions are regulated under various thrombo-inflammatory disease conditions. We recently discovered a novel role for platelets in inflammation resolution,4 uncovering a major role for anti-inflammatory pro-resolving mediator Annexin A1 (AnxA1) which was able to suppress integrin (αIIbβ3) activation via small GTPase Ras-related protein 1, Rap1, altering platelet phenotype from pathogenic to regulatory in cerebral I/RI. This study was the first to link AnxA1 with integrin signalling, supporting AnxA1 as an anti-thrombotic agent.

PhD opportunities in the field of thrombo-inflammation will focus on this high unmet medical need area by further understanding and characterising thrombo-inflammation in different disease states, with a particular focus on the role of platelets beyond just haemostasis and thrombosis. A major clinical importance will be to define the drivers and molecular mechanisms regulating thrombo-inflammation in specific disease states, providing mechanistic insight into both inflammation and thrombosis as central pathological processes to CVDs. Additionally, we will focus on pharmacologically manipulating the thrombo-inflammatory profile to promote its resolution. Collectively, we aim to develop novel strategies to not only protect against I/RI, but to provide new therapeutic possibilities for patient populations with a thrombo-inflammatory phenotype.

Training/techniques to be provided

Several PhD opportunities are available. Depending upon the project, students will adopt a multidisciplinary approach, learning a number of different in vivo models of thrombosis (venous and arterial) and inflammation, coupled with imaging techniques (e.g. fluorescent intravital microscopy), laser doppler, IVIS. In vitro methodologies may include clot assays, immunohistochemistry, immune cell functional assays (e.g. chemotaxis, transmigration, granule release assays, NETosis), flow cytometry and flow chamber systems. Clinical samples (blood and tissue) will also be used to help test the relevant hypotheses. Students will collaborate and work with a number of groups based both in the UK and globally.

These PhD projects 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 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.
  2. Ansari J, Senchenkova EY, Vital SA, Al Yafeai Z, Kaur G, Sparkenbaugh EM, Orr AW, Pawlinski R RP, Hebbel, DN. Granger, P. Kubes, FNE. Gavins. Targeting AnxA1/Fpr2/ALX Regulates Neutrophil Function Promoting Thrombo-Inflammation Resolution in Sickle Cell Disease. Blood 2020.
  3. 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.
  4. 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.
  5. 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.
  6. Gavins FNE. Li G, Russell J, Perretti M, Granger DN. Microvascular thrombosis and CD40/CD40L signalling. J Thromb Haemost. 2010;9:574-581.
  7. Senchenkova EY, Russell J, Vital SA, Yildirim A, Orr AW, Granger DN, Gavins FNE. A Critical Role for Both CD40 and VLA5 in Angiotensin II-Mediated Thrombosis and Inflammation. FASEB J. 2018;32:3448-3456.
  8. 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.

 

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.