Ali, K.; (2007) Role of phosphoinositide 3-kinase p110delta in mast cell biology. Doctoral thesis , University of London.

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Abstract

Class IA phosphoinositide 3-kinases (PI(3)Ks) are critical control elements of signalling cascades with influence over cell survival, proliferation and migration. Mammals have 3 distinct class IA PI(3)K catalytic subunits. One of these, pi 106, is preferentially expressed in leukocytes. Previous murine genetic studies using strategies which target regulatory elements thereby disrupting class IA PI(3)K signalling indiscriminately of the catalytic subunits have established that PI(3)K are important for Kit signalling and mast cell homeostasis but not for mast cell activation and the allergic response. We have utilised a mouse model in which pi 108 is inactivated by introduction of a germline mutation in the ATP binding site, creating pi 105D910A , mimicking the effects of a pharmacological inhibitor for pi 105. Bone marrow mast cells (BMMCs) from pi 1 o D910A/D910A mice have severe defects in SCF/Kit responses including proliferation, migration and adhesion additionally BMMCs derived from these mice have a substantial defect in antigen receptor signalling and mast cell degranulation. pi 108D910A mice have tissue site-selective loss of mast cell populations and a substantial reduction in IgE/Ag-induced passive cutaneous anaphylaxis response. Using pi 108 isoform-selective inhibitors it is possible to replicate our genetic strategy and completely block the in vivo allergic immune response. Furthermore using such compounds and human mast cells we show that our findings have direct relevance to the human system.

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