Botindari, Fabrizio. Targeting SHIP1 and PI3Ky for a synergistic inhibition of mast cell activation. 2015, PhD Thesis, University of Basel, Faculty of Science.
Restricted to Repository staff only until 31 March 2018.
Official URL: http://edoc.unibas.ch/diss/DissB_11905
In the present work we demonstrate the possibility of inhibiting PI3Kγ signalling in mast cells in order to modulate hypersensitivity responses without affecting the phisiological functionality of class I PI3Ks in the other tissues.
In the first project described in the present manuscript, we show that during mast cells activation, the GPCR-mediated activation of PI3Kγinduces a signalling cascade that is not inhibited by the phosphatase activity of SHIP1 and therefore contribute to the reinforcement of the antigen-induced mast cells activation. Moreover we demonstrate that PI3Kγ and SHIP1 are two valid targets for a combined pharmacological inhibition of mast cells activation.
In the second project described in the manuscript, we demonstrate the possibility to selectively modulate PI3Kγ activation in mast cells by blocking the plasma membrane localization of the monomeric GTPase Ras using farnesyltransferase inhibitor. We demonstrate that Ras is required for the activation of PI3Kγ in cells that express p84 as adaptor subunit (p110γ/p84 heterodimer), such as mast cells but not in cells where the PI3Kγ active complex is p110γ/p101. In the final part of the manuscript we described the generation of three genetically modified mouse strains we developed: p101 knock-out, p84 knock-out and p84 knock-in. The two p84-mutant mice were designed as novel tools for the analysis of the physiological p110γ/p84 signalling in vivo and ex vivo, while the generation of the p101 mutant has been already characterised by other groups but will be further used in our research.
|Advisors:||Wymann, Matthias P. and Rolink, Antonius G.|
|Faculties and Departments:||03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Cancer- and Immunobiology (Wymann)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||1 Online-Ressource (178 Seiten)|
|Last Modified:||22 Feb 2017 14:22|
|Deposited On:||07 Dec 2016 11:23|
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