The early events in signalling by platelet ITAM and ITAM-like receptors. (360G-Wellcome-088410_Z_09_Z)

£1,246,548

This application aims to establish (i) the very early events that underlie signalling by the three platelet ITAM receptors, GPVI, CLEC-2 and FcgammaRIIA, and (ii) the physiological and pathological roles of CLEC-2. ITAM receptors signal through sequential activation of Src and Syk tyrosine kinases, initiating a signalling cascade that leads to cell activation. The major goals of this proposal are (a) to identify the Src kinases in human and mouse platelets that mediate phosphorylation of pl atelet ITAM receptors; (b) to compare the regulation of Syk by platelet ITAM receptors; (c) to determine the molecular basis of activation of Syk by a single YxxL sequence; (d) to study the spatial and temporal nature of the protein-protein and protein-lipid interactions that underlie the very early signalling events by platelet ITAM receptors using FRET and TIRF microscopy, and (e) to determine the functional role of CLEC-2 using CLEC-2 knockout mice or mice which express a non-signalli ng mutant of CLEC-2 that retains the ability to bind to its endogenous ligand, podoplanin. These studies will focus on tissues that express CLEC-2 and podoplanin, and on a possible role of the interaction of podoplanin to CLEC-2 in cancer metastasis.

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Grant Details

Amount Awarded 1246548
Applicant Surname Watson
Approval Committee Physiological Sciences Funding Committee
Award Date 2009-05-07T00:00:00+00:00
Financial Year 2008/09
Grant Programme: Title Programme Grant
Internal ID 088410/Z/09/Z
Lead Applicant Prof Stephen Watson
Partnership Value 1246548
Planned Dates: End Date 2016-03-31T00:00:00+00:00
Planned Dates: Start Date 2009-08-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region West Midlands