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Investigating microvascular dysfunction in sickle cell disease (SCD)

Cerebrovascular disease is a leading cause of mortality worldwide, with numbers on the rise. It is a serious complication of a number of disease states, including sickle cell disease (SCD), an inherited autosomal recessive disorder, resulting from a single amino acid substitution in the haemoglobin β chain. Upon deoxygenation, the haemoglobin β chain polymerizes, causing the characteristic crescent-shaped (sickled) red blood cells (RBCs), rendering RBCs prone to haemolysis, leading to the release of cell-free haemoglobin and heme in the circulation, where they catalyse the formation of reactive oxygen species (ROS), leading to oxidative stress and cell injury.1,2 The loss of deformability of sickled RBCs and their ability to interact with the vascular endothelium results in the major clinical hallmarks of SCD: haemolytic anaemia, vascular endothelial dysfunction and vaso-occlusion. These hallmarks all contribute to the increased risk for ischemic injury in SCD. However, the underlying pathways promoting the procoagulant and prothrombotic phenotype responsible for the recurring ischemic injuries in SCD (especially in the brain) are still unknown. We have shown that the causes for the prothrombotic SCD phenotype may relate to a well-established link between thrombosis and inflammation in that systemic inflammation can beget local thrombosis, and thrombosis can amplify inflammation.3,4

Although the molecular origin of SCD in the haemoglobin β chain of RBCs is clear, the mechanisms that contribute to the complex systemic manifestation and severe outcome of the disease have not been fully elucidated. Moreover, the underlying pathways promoting the procoagulant and prothrombotic phenotype responsible for the recurring ischemic injuries in SCD (especially in the brain) are still unknown. This PhD project will build on the solid foundation of our previous findings focussing on accelerated cerebral microvascular thrombosis associated with SCD,3,4 to further investigate and understand the fundamental role of neutrophils and platelets in the thrombo-inflammatory phenotype associated with SCD. In addition, data generated here will help to identify potential novel disease biomarkers for future clinical trials, providing both mechanism of action and proof of efficacy in accepted and validated in models relevant to the clinical condition.

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 using novel in vivo imaging techniques such as intravital microscopy and IVIS. The student will be trained in a number 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 to help answer the scientific questions and to translate in vivo findings to the clinic. 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 if 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. Ansari J, Gavins FNE. Ischemia-Reperfusion Injury in Sickle Cell Disease: From Basics to Therapeutics. Am J Pathol. 2019;189:706-718. 
  2. Ansari J, Moufarrej YE, Pawlinski R, Gavins FNE. Sickle cell disease: a malady beyond a hemoglobin defect in cerebrovascular disease. Expert Rev Hematol. 2017;11:45-55.
  3. 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.
  4. Gavins FNE. Russell J, Senchenkova EL, De Almeida Paula L, Damazo AS, Esmon CT, Kirchhofer D, Hebbel RP, Granger DN.’Mechanisms of enhanced thrombus formation in cerebral microvessels of mice expressing haemoglobin-S. Blood. 2011;117:4125-4133.

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.