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Advancing Pharmacological Approaches for Resolving 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.

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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.

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