Dr Dawn Thompson - University of Aberdeen, Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition - firstname.lastname@example.org
Professor Adriano G Rossi - University of Edinburgh, Centre for Inflammation Research - email@example.com
This project will investigate the molecular processes engaged by activation of the Formyl peptide 2 receptor (FPR2) during the inflammatory response. Inflammation protects the body against infection by activating an initial, “pro-inflammatory stage” involving the recruitment of white blood cells to the site of injury followed by a second pro-resolution stage serving to switch off this process and a return to homeostasis. Failure to successfully regulate this leads to chronic inflammatory diseases namely sepsis, arthritis, cancer, irritable bowel disease and cardiovascular disease. Understanding the molecular mechanisms underlying inflammation regulation is therefore critical to well-being and for the development of more effective therapies . Recent research has shown FPR2 is essential in controlling the switch from pro-inflammation to pro-resolution signalling to enable tissue healing and, as such, has been proposed as a potential candidate for the development of novel therapeutics targeting chronic inflammation.
FPR2 belongs to the formyl peptide receptor (FPR) G protein-coupled receptor (GPCR) superfamily whose signalling is tightly regulated by a series of molecular events such as phosphorylation, desensitisation and endocytosis that titrate signalling at the cellular level . However, there is limited understanding between functional responses and their association with specific intracellular events, especially when considering receptor endocytosis and recycling. Excitingly, our recent work has uncovered new insight , indicating endocytic trafficking of FPR2 is critical for the resolution of inflammation. We have discovered disruption of FPR2 trafficking increased cellular apoptosis; reported as a key requirement for resolution . This finding provides a novel molecular target for understanding inflammation and the development of therapeutics. Finally, the consequences of FPR2 stimulation is ligand specific where activation by either Serum Amyloid A (SAA) or Annexin A1 results in pro-inflammation or pro-resolution signalling respectively . However, the molecular mechanisms defining these opposing physiological outcomes are poorly understood.
This studentship will combine expertise in GPCR pharmacology from the Thompson laboratory with the Rossi laboratory who investigate the mechanisms controlling the inflammatory response. In doing so, this project will be in three parts;
1. Investigate the molecular pharmacology and endocytic trafficking of FPR2 in response to pro-inflammatory and pro-resolution agonists.
2. Investigate functional outcomes of pro-inflammation and pro-resolution agonist activation of FPR2.
3. Analyse the functional consequences of altered FPR2 trafficking.
Training in diverse techniques such as cell culture, confocal microscopy and Western Blotting will be employed to elucidate the trafficking profiles and downstream signalling elicited by FPR2 activation and ELISAs and qPCR to investigate cytokine production and gene expression respectively. In addition, flow cytometry will be used to quantify functional responses (phagocytosis) and how FPR2 ligands influence molecular machinery important in these processes (i.e. MerTK, Tyro and Axl). Finally, FPR2 constructs lacking the ability to recycle will be introduced into mouse BMDMs using viral transduction and the impact on signalling and function investigated. This interdisciplinary project addresses the BBSRC strategy of world-class underpinning bioscience, promising to identify fundamental mechanisms regulating inflammation and potentially identify new molecular targets that could be exploited for the future development for the treatment of chronic inflammatory diseases.
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