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Title: Studies of the regulation of neutrophil signalling and function by soluble E-selectin
Author: McMeekin, Sarah Ruth
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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In this thesis I have investigated the functional consequences of soluble E-selectin upon neutrophil responses to proinflammatory mediators, the effects of soluble E-selectin on Ca2+ signalling, and the signalling events regulating this. Specifically, I have investigated the mechanism by which soluble E-selectin acted to prolong intracellular Ca2+ ([Ca2+]i). Soluble E-selectin alone are unable to initiate Ca2+ signalling but it allowed store operated calcium entry (SOCE) to occur following stimulation with PAF and I termed this effect permissive SOCE. This increase in [Ca2+]I in response to soluble E-selectin and PAF was shown to act through a G-protein coupled receptor (GPCR) coupled to PTX-insensitive Gq/11. This effect was mediated by canonical transient receptor potential channels (TRPC) due to its sensitivity to specific inhibition by a store operated channel (SOC) inhibitor, MRS1845 and a TRPC inhibitor, Gd3+. TRPC6 was the principal TRPC family member expressed by human neutrophils. In terms of mechanism, soluble E-selectin activated Src family tyrosine kinases, an effect that was upstream of PI 3-kinase in a signalling pathway that regulates permissive SOCE following exposure of neutrophils to PAF. I have also shown a regulatory role for PKC in control of the soluble E-selectin mediated prolongation of elevated Ca2+. Soluble E-selectin induced alterations in TRPC channel function acts to promote adhesion, reduce migratory capacity and augment neutrophil destructive potential and neutrophil survival. Soluble E-selectin was demonstrated to bind via and lectin domain, presumably through a putative E-selectin receptor present on neutrophils. Studies with activating and inhibitory antibodies indicated that the cell adhesion molecule CD66 may be involved in E-selectin mediated signalling. Ligation of CD66 with antibodies caused prolonged PAF-induced Ca2+ mobilization in a similar manner to that caused by soluble E-selectin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available