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Title: The role of formyl peptide receptors in the regulation of platelet function
Author: Salamah, Maryam
ISNI:       0000 0004 7966 7552
Awarding Body: University of Reading
Current Institution: University of Reading
Date of Award: 2019
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Formyl peptide receptors (FPRs) belong to the family of G protein-coupled receptors (GPCRs) and play crucial roles in the regulation of innate immunity and host defence. FPRs include three family members; FPR1, FPR2/ALX and FPR3. They bind a wide variety of structurally and chemically diverse ligands that can exert various functions. Despite a plethora of research focusing on the role of FPRs in the regulation of immunity, there is a paucity of studies on their roles on the regulation of platelet haemostatic function. Here, we demonstrate the impact of both FPR1 and FPR2/ALX on the modulation of platelet reactivity, haemostasis and thrombosis. By using selective pharmacological inhibitors for FPR1 and FPR2/ALX, and Fpr1- and Fpr2/3-deficient mice, we were able to establish instrumental roles for these receptors in the regulation of the normal platelet haemostatic function. Additionally, we report a crucial role for fMLF in the regulation of platelet function through FPR1 signalling. fMLF exerted a priming effect on platelet activation through inducing distinct functions and enhances thrombus formation under arterial flow conditions. These effects were diminished in the presence of FPR1-selective pharmacological inhibitors and in platelets obtained from Fpr1- deficient mice. In addition, we investigated the role of LL37 in the regulation of platelet function and its modulation on platelet reactivity under pathological conditions, such as psoriasis, via acting through FPR2/ALX. We demonstrate that LL37 activates a range of platelet functions, enhances thrombus formation, and shortens the tail-bleeding time in mice. Moreover, we report the overexpression of mCRAMP (an LL37 murine orthologue) in affected skin and plasma of a murine [imiquimod (IMQ)-induced] model of human psoriasis and its ability to enhance platelet responses via Fpr2/3. We also report a role for Annexin A1 and its N-terminal peptide, Ac2-26, in the regulation of platelet function through FPR2/ALX. Ac2-26 induced the activation of various platelet functions. Moreover, AnxA1-deficient mice demonstrate enhanced functional responses towards Ac2-26, which may be attributable to the overexpression of Fpr2/3 in these mice. Since both FPR1 and FPR2/ALX and their ligands play critical roles in various pathological conditions, their influence on the modulation of platelet activation and thrombus formation will provide novel insights into the mechanisms that control platelet-mediated complications under various disease settings.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral