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dc.contributor.authorDufton, Neil Peter
dc.date.accessioned2011-02-07T15:37:44Z
dc.date.available2011-02-07T15:37:44Z
dc.date.issued2010
dc.identifier.urihttps://qmro.qmul.ac.uk/xmlui/handle/123456789/465
dc.descriptionPhDen_US
dc.description.abstractA novel Fpr2-/- mouse colony was used to explore the biology of Fpr2, a GPCR related to the human FPR2/ALX receptor that recognises lipoxin A4 (LXA4) annexin A1 (AnxA1) and serum amyloid A (SAA). Southern blotting, PCR and radio-ligand binding confirmed receptor deletion in the mouse Fpr2-/- colony. A GFP target/reporter strategy was employed in generating this novel transgenic to monitor promoter activity in living cells. This study revealed a propensity of Fpr2 for granulocytes, as well as a distinct role in macrophage (Mφ) maturation. Characterisation of Fpr2-/- Mφ revealed selective ERK phosphorylation triggered by the AnxA1-derived peptide Ac2-26, W peptide and Compound 43 (C43). Despite this Fpr-dependent signalling cascade via ERK, it was not a functional prognostic for cell migration in vitro or in vivo. Formyl peptide (fMLP) and serum amyloid A (SAA) chemotactic action was attenuated in Fpr2-/- Mφ, as well as the pro-phagocytic effects of Ac2-26 and LXA4. There was no observable naïve phenotype associated with Fpr2 depletion. To investigate the patho-physiology of Fpr2, acute and chronic inflammatory models were investigated in vivo to dissect different aspects of the receptor during disease progression. Notably Fpr2-/- mice exhibited stimulus specific discrepancies in inflammatory response. An acute IL-1β-induced air pouch model 6 revealed predominantly anti-migratory pharmacology of Fpr2 ligands, with a notable exception of SAA, discovered to be anti-migratory in the absence of Fpr2. Analysis of the full time-course of the zymosan peritonitis pointed to a subtle role for Fpr2 in neutrophil and monocyte migration as well as Mφ maturation. Of interest, exudate levels of SAA were augmented in Fpr2-/- mice revealing complex regulatory receptor/ligand circuits active during on-going inflammatory reactions. Finally, Fpr2-/- mice displayed pronounced arthritic responses upon treatment with the K/BxN arthrogenic serum, in comparison to their wild type controls. We conclude that Fpr2 can serve varied regulatory functions during the host response to inflammatory insult.en_US
dc.language.isoenen_US
dc.subjectMedicineen_US
dc.titleCharacterisation of the Fpr2 null mouseen_US
dc.typeThesisen_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author


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