Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607140
Title: Investigation of the role of phosphoinositide lipid kinases and phosphatases in T lymphocyte biology
Author: Blunt , Matthew David
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2013
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Abstract:
P13K mediated signalling is crucial for various lymphocyte functions. Pharmacological targeting of PI3K is therefore an attractive target for therapeutic intervention in a range of inflammatory disorders as well as cancer. PI3K mediated signalling is regulated by the actions of lipid phosphatases, whilst pharmacological targeting of these lipid phosphatases offers an alternative means with which to modulate PI3K mediated signalling. This thesis aimed to utilise novel pharmacological compounds to probe the role of PI3K and the lipid phosphatases SHIP-1 and SHIP-2 in primary human T Iymphocytes. The acute inhibition of PI3Ko activity was shown to inhibit the secretion of IL-17A by human T Iymphocytes. In contrast, the prolonged inhibition of PI3Ko activity or the down-regulation of PI3Ko expression in primary human T Iymphocytes resulted in increased secretion of IL-1 7A. An allosteric activator of SHIP-1 was shown to inhibit chemokine mediated signalling and in vitro T cell motility. Activation of SHIP-1 also inhibited TCR mediated Akt phosphorylation, proliferation and cy10kine secretion. SHIP-1 activation reduced the affinity state of LFA-1 and abrogated the ability of primary human T lymphocy1es to adhere to fibronectin and ICAM1. Pharmacological inhibition of SHI P-1 activity also reduced chemokine mediated signalling and motility. In addition, SHIP-1 inhibition reduced TCR mediated signalling and adhesion. The reported SHIP-2 inhibitor BiPh(2,3',4,5',6)Ps was shown to inhibit the activity of SHIP-1 with equal potency as the inhibition of SHIP-2 activity. Pharmacological inhibition of SHIP-2 activity alone showed little effect on primary human T Iymphocyte function, indicating that SHIP-1 is the primary SHIP protein involved in T lymphOCy1e function. In addition, this thesis showed that the expression and activity of the lipid phosphatase INPP4b is not lost in leukemic cell lines. INPP4b was however found to be down-regulated in Th17 polarised cells, indicating a possible role for INPP4b in Th17 differentiation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.607140  DOI: Not available
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