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Roles of the Class IA phosphoinositide 3-kinase isoforms in lymphocyte development and function

Reference	BB/C509890/1
Principal Investigator / Supervisor	Professor Klaus Okkenhaug
Co-Investigators / Co-Supervisors	Professor Bart Vanhaesebroeck
Institution	Babraham Institute
Department	Babraham Institute Department
Funding type	Research
Value (£)	304,709
Status	Completed
Type	Research Grant
Start date	25/10/2004
End date	24/10/2007
Duration	36 months

Abstract

Phosphoinositide 3-kinases (PI3Ks) are intracellular enzymes that generate second-messenger signalling molecules which regulate metabolism, growth, proliferation, survival and differentiation. We have previously cloned and characterised a PI3K isoform, p110delta, which plays an important role in B and T lymphocytes, but which is not required for normal development or survival of the organism. We will investigate the contributions of two related PI3K isoforms, p110alpha and p110beta, to lymphocyte development and function. In contrast to p110delta, these PI3Ks are essential for development of the embryo and mice lacking either of these PI3K isoforms die in utero. The PI3Ks p110alpha and p110beta will be functionally eliminated in lymphocytes using conditional gene-targeting in mice. In addition, compound mutant mice will be bred to investigate the extent of redundancy among the different isoforms. The effect of ablating specific p110 isoforms, alone or in combination, on the development of immature and mature lymphocyte subsets will be investigated by flow cytometry. Immunisation studies of gene-deficient mice will reveal the role to the different PI3K isoforms in T cell-dependent and T cell-independent immune responses. Proliferation and cytokine production stimulated by various agonists will also be investigated using cells from the gene-targeted mice. Direct visualisation of PI3K signalling at the single cell level will be done by crossing PI3K mutant mice with transgenic mice expressing GFP-PH fusion reporter proteins that translocate to the plasma membrane upon receptor activation. Together, these experiments seek to investigate the extent of redundant versus isoform-specific functions of each of the class IA PI3K catalytic subunits. Lymphocytes are ideal for this purpose since they naturally express high levels of each isoform and because viable adult mice can be obtained despite severe defects in lymphocyte development.

Summary

unavailable

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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