Pharmacological strategies for resolution of inflammation

Inflammation plays a crucial role in the pathophysiological cascade of ischaemia reperfusion injury (I/RI), the incidence of which is extensive including myocardial infarction, stroke, peripheral artery disease, solid organ transplantation, sepsis, inflammatory bowel diseases, blood disorders (e.g. Sickle Cell Disease) and cancer. Although the exact mechanisms responsible for post-ischaemic damage (especially in the context of the brain) are not fully understood, there is increasing evidence suggesting that the inflammatory state following I/R is a crucial contributing factor to the pathophysiology and outcome. Endothelial cell activation, production of pro-inflammatory mediators and the recruitment and activation of leukocytes (especially neutrophils) and platelets have all shown to contribute to microvascular dysfunction and subsequent tissue injury post I/RI. Thus prevention of ischaemic events (especially in the context of the brain and stroke) has become a major part of modern health care.

The ideal outcome of inflammation following I/R is its resolution, which is a tightly orchestrated, active process involving specific pro-resolving mediators (e.g. Annexin A1 [AnxA1], resolvins, protectins, maresins) and pathways (e.g. formyl peptide receptor 2 [Fpr2/ALX] pathway). However, compelling evidence suggests pro-resolving mediators and pathways are disrupted in chronic inflammatory conditions leading to prolonged and exaggerated inflammatory responses with poor prognosis in humans. Inflammation post-CI/R contributes significantly to post-ischaemic damage (particularly in the cerebral microvasculature), although exact mechanisms remain undefined. We have made significant progress defining inflammatory events post I/R and have discovered an important protective role for Fpr2/ALX, supporting this key resolution pathway as a potential therapeutic target for I/RI.

The overarching objective of this project is to generate novel data in an area of scientific and clinical need, specifically, we aim to understand and characterise pathophysiological responses to I/RI in a number of clinical situations and disease states; we hope to discover potential prognostic biomarkers; we aim to identify anti-inflammatory mechanisms and pharmacological strategies that control the Fpr2/ALX-pathway to promote resolution post-I/RI, and we aim to develop ideal biased ligands and novel delivery methods (e.g. nanotechnology) for treatment of I/RI. Furthermore, these findings will also have an impact on helping to treat and reduce morbidity and mortality of patients with or susceptible to coronavirus disease of 2019 (COVID-19). Collectively, findings will help to guide innovative drug discovery programs focussed on Resolution biology to help treat and protect against I/RI.

Meet the Principal Investigator(s) for the project

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.

Related Research Group(s)

Inflammation Research and Translational Medicine - Driving scientific innovation and discovery for diagnosis, treatment, and management of cardiovascular disease, inflammatory and immune disorders, microbial resistance, and cancer.

Project last modified 27/09/2024